1 00:00:09,142 --> 00:00:12,479 IT'S MY PLEASURE AND SINCERELY 2 00:00:12,545 --> 00:00:14,781 MY HONOR TO WELCOME YOU TO WHAT 3 00:00:14,848 --> 00:00:18,284 IS THE 20TH ANNUAL ROBERT 4 00:00:18,351 --> 00:00:20,653 WHITNEY NEWCOMB MEMORIAL LECTURE 5 00:00:20,720 --> 00:00:21,654 IN THE NEUROSCIENCES. 6 00:00:21,721 --> 00:00:23,857 THIS IS AN ANNUAL EVENT THAT I 7 00:00:23,923 --> 00:00:24,791 THINK EVERYONE IN THE COMMUNITY 8 00:00:24,858 --> 00:00:27,694 HAS COME TO LOOK FORWARD TO, 9 00:00:27,761 --> 00:00:30,363 IT'S SUPPORTED BY THE ROBERT 10 00:00:30,430 --> 00:00:33,466 WHITNEY NEWCOMB MEMORIAL FUND 11 00:00:33,533 --> 00:00:36,970 WHICH WAS ESTABLISHED BY 12 00:00:37,036 --> 00:00:37,871 DR. NEWCOMB'S FAMILY TO HONOR 13 00:00:37,937 --> 00:00:38,438 HIS MEMORY. 14 00:00:38,505 --> 00:00:40,907 WE ARE PLEASED TO BE JOINED 15 00:00:40,974 --> 00:00:44,144 TODAY BY DR. ROBERT NEWCOMB 16 00:00:44,210 --> 00:00:46,946 SENIOR AND HIS DAUGHTER GAIL 17 00:00:47,013 --> 00:00:49,215 NEWCOMB TODAY. 18 00:00:49,282 --> 00:00:51,217 WE ARE GRATEFUL FOR THE 19 00:00:51,284 --> 00:00:54,487 GENEROSITY O OF THE NEWCOMB FAMY 20 00:00:54,554 --> 00:00:55,121 AND THEIR FRIENDS FOR THE 21 00:00:55,188 --> 00:00:56,222 OPPORTUNITIES THAT THIS FUND 22 00:00:56,289 --> 00:00:57,557 PROVIDES TO THE NEUROSCIENCE 23 00:00:57,624 --> 00:00:59,726 COMMUNITY AT NIH. 24 00:00:59,793 --> 00:01:02,896 IT'S A TRIBUTE TO YOUR SON AND 25 00:01:02,962 --> 00:01:03,696 YOUR BROTHER. 26 00:01:03,763 --> 00:01:05,432 ROBERT BEGAN HIS SCIENTIFIC 27 00:01:05,498 --> 00:01:06,866 CAREER HERE AT THE NIH AS A HIGH 28 00:01:06,933 --> 00:01:08,034 SCHOOL STUDENT, WORKING DURING 29 00:01:08,101 --> 00:01:11,204 THE SUMMER IN A LAB AT NCI, AND 30 00:01:11,271 --> 00:01:12,539 THIS WAS CLEARLY AN EXPERIENCE 31 00:01:12,605 --> 00:01:14,507 THAT HAD AN ENORMOUS IMPACT ON 32 00:01:14,574 --> 00:01:17,243 HIS CAREER. 33 00:01:17,310 --> 00:01:19,312 AFTER THAT, HE WENT TO COLLEGE 34 00:01:19,379 --> 00:01:21,181 AT THE UNIVERSITY OF COLORADO 35 00:01:21,247 --> 00:01:23,216 AND THEN EARNED HIS PH.D. AT THE 36 00:01:23,283 --> 00:01:24,884 UNIVERSITY OF HAWAII, WHERE HE 37 00:01:24,951 --> 00:01:26,853 STUDIED THE STRUCTURE AND 38 00:01:26,920 --> 00:01:29,055 FUNCTION OF INVERTEBRATE 39 00:01:29,122 --> 00:01:30,390 NEUROPEPTIDES, AND THIS WAS AN 40 00:01:30,457 --> 00:01:32,659 INTEREST THAT HE CONTINUED AS A 41 00:01:32,725 --> 00:01:34,227 POSTDOCTORAL FELLOW AT STANFORD 42 00:01:34,294 --> 00:01:36,129 WITH RICHARD SHELLER. 43 00:01:36,196 --> 00:01:38,231 HE SPENT MUCH OF HIS CAREER 44 00:01:38,298 --> 00:01:43,503 WORKING AT NEUREX 45 00:01:43,570 --> 00:01:44,471 PHARMACEUTICALS, AND ALSO 46 00:01:44,537 --> 00:01:46,105 STUDIED MECHANISMS UNDERLYING 47 00:01:46,172 --> 00:01:49,609 TISSUE DAMAGE ARISING FROM 48 00:01:49,676 --> 00:01:50,477 ISCHEMIC STROKE. 49 00:01:50,543 --> 00:01:53,346 IT'S QUITE APPROPRIATE THEN THAT 50 00:01:53,413 --> 00:01:55,849 THIS FUND SUPPORTS AN ANNUAL 51 00:01:55,915 --> 00:01:57,383 LECTURE HERE BY AN EXPERT IN 52 00:01:57,450 --> 00:02:00,320 NEUROSCIENCE. 53 00:02:00,386 --> 00:02:02,288 THE FUND ALSO SUPPORTS STUDENT 54 00:02:02,355 --> 00:02:05,458 SCHOLARS EACH YEAR AS WELL AS 55 00:02:05,525 --> 00:02:07,060 EXCEPTIONAL POSTBACCALAUREATE 56 00:02:07,126 --> 00:02:08,628 STUDENTS, AND OVER THE YEARS, 57 00:02:08,695 --> 00:02:11,030 MORE THAN TWO DOZEN COLLEGE AND 58 00:02:11,097 --> 00:02:12,465 HIGH SCHOOL STUDENTS AND FIVE 59 00:02:12,532 --> 00:02:14,000 POSTBACKS HAVE BENEFITED FROM 60 00:02:14,067 --> 00:02:14,334 THIS SUPPORT. 61 00:02:14,400 --> 00:02:16,402 I SHOULD NOTE THAT THE FUND'S 62 00:02:16,469 --> 00:02:18,071 EMPHASIS ON SCIENCE EDUCATION IS 63 00:02:18,137 --> 00:02:20,573 NO ACCIDENT. 64 00:02:20,640 --> 00:02:22,542 AS BOTH OF ROBERT'S PARENTS, BOB 65 00:02:22,609 --> 00:02:25,478 AND SALLY, ARE THEMSELVES DEEPLY 66 00:02:25,545 --> 00:02:28,114 INVOLVED IN EDUCATION. 67 00:02:28,181 --> 00:02:29,649 WE'RE SORRY THAT SALLY COULDN'T 68 00:02:29,716 --> 00:02:33,520 JOIN US TODAY. 69 00:02:33,586 --> 00:02:35,655 SALLY HAS TWO MASTERS, ONE IN 70 00:02:35,722 --> 00:02:36,489 GEOCHEMISTRY AND EDUCATION AND 71 00:02:36,556 --> 00:02:37,891 THE OTHER IN HISTORY AND 72 00:02:37,957 --> 00:02:38,691 PHILOSOPHY OF SCIENCE. 73 00:02:38,758 --> 00:02:40,827 THAT SOUNDS LIKE FOUR MASTER'S 74 00:02:40,894 --> 00:02:43,696 DEGREES ACTUALLY. 75 00:02:43,763 --> 00:02:44,998 SHE'S TAUGHT IN CALIFORNIA, 76 00:02:45,064 --> 00:02:45,765 MARYLAND AND IN 77 00:02:45,832 --> 00:02:49,402 WASHINGTON, D.C., AND SHE'S BEEN 78 00:02:49,469 --> 00:02:51,371 AN ACTIVE GEOLOGIST AND MEMBER 79 00:02:51,437 --> 00:02:53,907 OF THE GEOLOGICAL SOCIETY OF 80 00:02:53,973 --> 00:02:56,509 AMERICA. 81 00:02:56,576 --> 00:02:58,111 I GUESS PERHAPS TO HOLD HIS OWN 82 00:02:58,177 --> 00:03:00,380 AT THE DINNER TABLE, BOB EARNED 83 00:03:00,446 --> 00:03:02,248 A MASTER'S DEGREE FROM STANFORD 84 00:03:02,315 --> 00:03:05,585 AND A PH.D. AT UC BERKELEY, AND 85 00:03:05,652 --> 00:03:08,555 IS PROFESSOR EMERITUS IN 86 00:03:08,621 --> 00:03:10,156 ELECTRICAL AND COMPUTER 87 00:03:10,223 --> 00:03:10,823 ENGINEERING AT THE UNIVERSITY OF 88 00:03:10,890 --> 00:03:13,159 MARYLAND. 89 00:03:13,226 --> 00:03:16,529 BOB HAS EARNED A NUMBER OF 90 00:03:16,596 --> 00:03:18,932 ACCOLADES FOR HIS LIFETIME OF 91 00:03:18,998 --> 00:03:19,365 WORK. 92 00:03:19,432 --> 00:03:20,466 THERE'S A VOICE RECOGNITION 93 00:03:20,533 --> 00:03:21,768 LABORATORY IN MADRID, SPAIN 94 00:03:21,834 --> 00:03:23,636 NAMED AFTER HIM, AND THERE'S 95 00:03:23,703 --> 00:03:26,039 ALSO AN UNDERGRADUATE FELLOWSHIP 96 00:03:26,105 --> 00:03:27,707 AT POHUNG UNIVERSITY IN SOUTH 97 00:03:27,774 --> 00:03:28,875 KOREA IN HIS HONOR. 98 00:03:28,942 --> 00:03:30,743 SO WE THANK THE NEWCOMB FAMILY 99 00:03:30,810 --> 00:03:33,046 AND THEIR FRIENDS FOR THEIR 100 00:03:33,112 --> 00:03:35,448 CONTRIBUTIONS TO THIS FUND, AND 101 00:03:35,515 --> 00:03:37,750 FOR RECOGNIZING THAT THE NIH 102 00:03:37,817 --> 00:03:39,352 PROVIDES A WONDERFUL ENVIRONMENT 103 00:03:39,419 --> 00:03:41,120 TO INSTILL IN YOUNG PEOPLE A 104 00:03:41,187 --> 00:03:43,222 PASSION FOR BRAIN RESEARCH AND 105 00:03:43,289 --> 00:03:44,557 FOR ELUCIDATING THE 106 00:03:44,624 --> 00:03:46,492 NEUROCHEMICAL BASES OF STROKE 107 00:03:46,559 --> 00:03:49,329 AND AGING, WHICH CLOSELY ALIGNS 108 00:03:49,395 --> 00:03:51,297 WITH DR. NEWCOMB'S CAREER 109 00:03:51,364 --> 00:03:52,732 INTERESTS. 110 00:03:52,799 --> 00:03:57,236 SO WITH THAT, I AM PLEASED TO 111 00:03:57,303 --> 00:03:58,738 ASK ARIEL LEVINE, SENIOR 112 00:03:58,805 --> 00:03:59,939 INVESTIGATOR AT NINDS, TO 113 00:04:00,006 --> 00:04:00,740 INTRODUCE TODAY'S SPEAKER. 114 00:04:00,807 --> 00:04:02,742 THANK YOU, ARIEL. 115 00:04:02,809 --> 00:04:09,816 [APPLAUSE] 116 00:04:09,882 --> 00:04:11,351 >> HELLO, THANK YOU ALL FOR 117 00:04:11,417 --> 00:04:12,652 COMING, AND I HAVE TO SAY, IT'S 118 00:04:12,719 --> 00:04:13,987 REALLY A DELIGHT TO LOOK OUT AND 119 00:04:14,053 --> 00:04:15,955 SEE THIS ROOM PACKED! 120 00:04:16,022 --> 00:04:16,923 AND I KNOW THAT IT BECAUSE WE 121 00:04:16,990 --> 00:04:20,526 HAVE A REALLY EXCITING DRAW. 122 00:04:20,593 --> 00:04:22,195 SO DR. DAN BEGAN HER SCIENTIFIC 123 00:04:22,262 --> 00:04:23,830 LIFE ACTUALLY AS A PHYSICIST. 124 00:04:23,896 --> 00:04:26,566 SHE STUDIED PHYSICS IN HER 125 00:04:26,633 --> 00:04:29,836 UNDERGRADUATE WORK AND IF I MAY, 126 00:04:29,902 --> 00:04:31,404 I THINK THAT ONE OF THE THINGS 127 00:04:31,471 --> 00:04:32,805 THAT YOU'LL SEE WILL 128 00:04:32,872 --> 00:04:36,009 CHARACTERIZE HER WORK IS SHE IS 129 00:04:36,075 --> 00:04:37,610 REALLY BRAVE ABOUT CROSSING 130 00:04:37,677 --> 00:04:39,145 SCALES AND DIFFERENT KINDS OF 131 00:04:39,212 --> 00:04:40,246 PERSPECTIVES ON NEUROSCIENCE, 132 00:04:40,313 --> 00:04:41,981 AND I WONDER IF IT PARTLY CAME 133 00:04:42,048 --> 00:04:43,616 FROM STARTING HER CAREER IN A 134 00:04:43,683 --> 00:04:45,151 DIFFERENT SPACE AND THEN MOVING 135 00:04:45,218 --> 00:04:47,220 INTO NEUROSCIENCE, WHICH SHE DID 136 00:04:47,286 --> 00:04:51,224 FOR HER PH.D., WHICH SHE PERF 137 00:04:51,290 --> 00:04:52,492 PERFORMED STUDYING SYNAPTIC 138 00:04:52,558 --> 00:04:56,195 TRANSMISSION AND PLASTICITY WITH 139 00:04:56,262 --> 00:05:01,134 MOO MING PAO. 140 00:05:01,200 --> 00:05:03,903 SHE OPENED HER OWN LAB IN 19 197 141 00:05:03,970 --> 00:05:05,238 AT THE UNIVERSITY OF CALIFORNIA, 142 00:05:05,304 --> 00:05:06,372 BERKELEY AND SINCE THEN, SHE'S 143 00:05:06,439 --> 00:05:08,141 MADE MAJOR CONTRIBUTIONS TO 144 00:05:08,207 --> 00:05:09,342 MULTIPLE DIFFERENT AREAS OF 145 00:05:09,409 --> 00:05:10,443 NEUROSCIENCE, SCALING FROM 146 00:05:10,510 --> 00:05:11,778 CELLULAR AND SYNAPTIC BIOLOGY 147 00:05:11,844 --> 00:05:14,580 ALL THE WAY UP TO COMPLEX 148 00:05:14,647 --> 00:05:15,782 BEHAVIORAL FUNCTIONS. 149 00:05:15,848 --> 00:05:17,850 IN THE LAST DECADE, HER LAB HAS 150 00:05:17,917 --> 00:05:20,486 HAD AN EXPLOSION OF BEAUTIFUL 151 00:05:20,553 --> 00:05:21,587 PAPERS, PARTICULARLY EXPLORING 152 00:05:21,654 --> 00:05:24,424 THE MOLECULAR, CELLULAR CIRCUIT 153 00:05:24,490 --> 00:05:26,726 AND ORGANISMAL PURPOSE, REALLY, 154 00:05:26,793 --> 00:05:27,593 OF SLEEP. 155 00:05:27,660 --> 00:05:30,029 SHE IS CURRENTLY THE 156 00:05:30,096 --> 00:05:31,431 CHANCELLOR'S CHAIR PROFESSOR IN 157 00:05:31,497 --> 00:05:32,765 THE DEPARTMENT OF MOLECULAR AND 158 00:05:32,832 --> 00:05:34,267 CELL BIOLOGY AT BERKELEY. 159 00:05:34,333 --> 00:05:36,903 SHE HAS BEEN A HOWARD HUGHES 160 00:05:36,969 --> 00:05:38,304 INVESTIGATOR SINCE 2008, A 161 00:05:38,371 --> 00:05:39,472 MEMBER OF THE NATIONAL ACADEMY 162 00:05:39,539 --> 00:05:42,575 OF SCIENCES SINCE 2018. 163 00:05:42,642 --> 00:05:44,010 SHE RECENTLY RECEIVED A REALLY 164 00:05:44,077 --> 00:05:49,482 MAJOR PRIZE, THE EDWARD SKULNIK 165 00:05:49,549 --> 00:05:50,583 PRIZE AND I THINK A FINAL 166 00:05:50,650 --> 00:05:52,752 FEATHER IN HER CAP, SHE'S 167 00:05:52,819 --> 00:05:55,254 MENTORED NEARLY 50 PH.D. AND 168 00:05:55,321 --> 00:05:56,689 POSTDOC TRAINEES AND OVER HALF 169 00:05:56,756 --> 00:05:57,890 OF THEM ALREADY HAVE THEIR OWN 170 00:05:57,957 --> 00:05:58,424 LABS. 171 00:05:58,491 --> 00:06:00,960 SO I THINK THAT REALLY SHOWS NOT 172 00:06:01,027 --> 00:06:01,994 JUST HER CONTRIBUTION AS A 173 00:06:02,061 --> 00:06:03,796 SCIENTIST BUT ALSO THEN AS A 174 00:06:03,863 --> 00:06:04,897 TEACHER, MAKING HER THE PER 175 00:06:04,964 --> 00:06:10,236 FEBRUARY PERSON TO --THE PERFES 176 00:06:10,303 --> 00:06:10,470 LECTURE. 177 00:06:10,536 --> 00:06:11,804 SO WITH THAT, I'D LIKE TO 178 00:06:11,871 --> 00:06:12,438 WELCOME YANG. 179 00:06:12,505 --> 00:06:21,080 [APPLAUSE] 180 00:06:21,147 --> 00:06:26,886 >> SO CAN YOU GUYS HEAR ME IN 181 00:06:26,953 --> 00:06:27,887 THE BACK? 182 00:06:27,954 --> 00:06:29,489 SO FIRST, THANK YOU SO MUCH, 183 00:06:29,555 --> 00:06:31,491 ARIEL, FOR THE VERY KIND 184 00:06:31,557 --> 00:06:31,958 INTRODUCTION. 185 00:06:32,024 --> 00:06:33,659 IT'S REALLY FLATTERING, AND ALSO 186 00:06:33,726 --> 00:06:38,397 IT'S MY GREAT HONOR TO BE GIVING 187 00:06:38,464 --> 00:06:39,565 THIS MEMORIAL LECTURE. 188 00:06:39,632 --> 00:06:42,101 SO I'M GOING TO TALK ABOUT 189 00:06:42,168 --> 00:06:44,036 SLEEP, FOCUSING ON TWO 190 00:06:44,103 --> 00:06:45,371 FUNDAMENTAL QUESTIONS, HOW WE 191 00:06:45,438 --> 00:06:47,006 SLEEP AND WHY WE SLEEP. 192 00:06:47,073 --> 00:06:50,843 SO I'M GOING TO SUMMARIZE OUR 193 00:06:50,910 --> 00:06:52,812 VIEWS ON BOTH TOPICS WITH A 194 00:06:52,879 --> 00:06:55,281 THEORY ON HOW AND HYPOTHESIS ON 195 00:06:55,348 --> 00:07:01,487 THE WHY. 196 00:07:01,554 --> 00:07:04,090 SO SLEEP IS AN ESSENTIAL INMATE 197 00:07:04,157 --> 00:07:05,057 BEHAVIOR. 198 00:07:05,124 --> 00:07:06,492 WE ACTUALLY KNOW HOW TO DO THIS 199 00:07:06,559 --> 00:07:07,126 EVEN BEFORE BIRTH. 200 00:07:07,193 --> 00:07:08,761 WE SPEND A LOT OF TIME SLEEPING 201 00:07:08,828 --> 00:07:10,730 IN OUR MOTHER'S WOMBS. 202 00:07:10,797 --> 00:07:14,033 AS FAR AS WE KNOW, ALL ANIMALS 203 00:07:14,100 --> 00:07:14,233 SLEEP. 204 00:07:14,300 --> 00:07:15,568 AS LONG AS YOU HAVE A NERVOUS 205 00:07:15,635 --> 00:07:16,202 SYSTEM, YOU SLEEP. 206 00:07:16,269 --> 00:07:18,404 SO THAT EVEN INCLUDES JELLYFISH, 207 00:07:18,471 --> 00:07:20,239 SO THESE GUYS DON'T EVEN HAVE A 208 00:07:20,306 --> 00:07:22,642 CENTRAL NERVOUS SYSTEM. 209 00:07:22,708 --> 00:07:24,844 ALL THEY HAVE IS A VERY 210 00:07:24,911 --> 00:07:27,180 PRIMITIVE KIND OF NEURAL NET OR 211 00:07:27,246 --> 00:07:29,982 SOMETHING, AND YET THEY SHOW 212 00:07:30,049 --> 00:07:30,983 SLEEP-LIKE BEHAVIOR. 213 00:07:31,050 --> 00:07:32,819 SO TOTAL SLEEP DEPRIVATION 214 00:07:32,885 --> 00:07:33,252 CAUSES DEATH. 215 00:07:33,319 --> 00:07:35,788 IN FACT, SLEEP DEPRIVATION CAN 216 00:07:35,855 --> 00:07:38,090 PROBABLY KILL AN ANIMAL FASTER 217 00:07:38,157 --> 00:07:39,192 THAN FOOD DEPRIVATION. 218 00:07:39,258 --> 00:07:43,996 SO IT'S REALLY ESSENTIAL. 219 00:07:44,063 --> 00:07:46,265 NOW, FOR NON-MAMMALIAN ANIMALS, 220 00:07:46,332 --> 00:07:47,967 SLEEP IS USUALLY DETECTED BY 221 00:07:48,034 --> 00:07:49,468 LACK OF MOVEMENT. 222 00:07:49,535 --> 00:07:52,872 SO FOR EXAMPLE, FOR DROSOPHILA, 223 00:07:52,939 --> 00:07:54,473 USED AS A VERY POWERFUL MODEL 224 00:07:54,540 --> 00:07:57,243 SYSTEM FOR STUDYING SLEEP, TO 225 00:07:57,310 --> 00:07:58,678 SCORE A SLEEP EPISODE, THE FLY 226 00:07:58,744 --> 00:08:02,148 HAS TO STAY STILL FOR AT LEAST 227 00:08:02,215 --> 00:08:03,349 FIVE MINUTES IN A ROW. 228 00:08:03,416 --> 00:08:06,385 THEN IF YOU APPLY GENTLE SENSORY 229 00:08:06,452 --> 00:08:08,254 STIMULATION, THEY SHOULD SHOW NO 230 00:08:08,321 --> 00:08:10,556 MOTOR RESPONSE, BUT THE READOUT 231 00:08:10,623 --> 00:08:11,357 IS ENTIRELY MOTOR. 232 00:08:11,424 --> 00:08:14,193 DO THEY MOVE OR NOT. 233 00:08:14,260 --> 00:08:16,963 FOR MAMMALIAN ANIMAL MODELS SUCH 234 00:08:17,029 --> 00:08:18,464 AS MICE, WHICH IS OUR ANIMAL 235 00:08:18,531 --> 00:08:20,299 MODEL, WE USUALLY MEASURE EEG 236 00:08:20,366 --> 00:08:23,369 AND EMG, SO THE EMG MEASURES 237 00:08:23,436 --> 00:08:25,771 SKELETAL MUSCLE TONE AND SOMATIC 238 00:08:25,838 --> 00:08:27,673 MOTOR ACTIVITY, AND IS CLEARLY 239 00:08:27,740 --> 00:08:28,741 REDUCED DURING SLEEP. 240 00:08:28,808 --> 00:08:32,545 AND THEN BASED ON EEG, WE CAN 241 00:08:32,612 --> 00:08:36,415 DISTINGUISH BETWEEN RAPID EYE 242 00:08:36,482 --> 00:08:37,350 MOVEMENT, REM SLEEP, DURING 243 00:08:37,416 --> 00:08:40,319 WHICH WE HAVE VIVID DREAMS, AND 244 00:08:40,386 --> 00:08:41,187 NON-REM SLEEP, WHICH IS 245 00:08:41,254 --> 00:08:43,489 BASICALLY A DEEP SLUMBER. 246 00:08:43,556 --> 00:08:45,725 NOW FOR HUMAN, IF YOU'RE BROUGHT 247 00:08:45,791 --> 00:08:46,893 TO A SLEEP CLINIC, IN ADDITION 248 00:08:46,959 --> 00:08:49,862 TO EEG AND EMG, WE ALSO MEASURE 249 00:08:49,929 --> 00:08:51,998 THINGS LIKE HEART BEAT AND 250 00:08:52,064 --> 00:08:52,331 BREATHING. 251 00:08:52,398 --> 00:08:54,000 SO THESE ALSO SLOW DOWN. 252 00:08:54,066 --> 00:08:56,068 THE POINT I WANT TO MAKE HERE IS 253 00:08:56,135 --> 00:08:58,371 THAT FALLING ASLEEP IS NOT JUST 254 00:08:58,437 --> 00:09:01,207 ABOUT CHANGES IN OUR STATE OF 255 00:09:01,274 --> 00:09:02,308 CONSCIOUSNESS OR BRAIN STATE 256 00:09:02,375 --> 00:09:03,943 THAT YOU CAN MEASURE WITH THE 257 00:09:04,010 --> 00:09:04,510 EEG. 258 00:09:04,577 --> 00:09:07,880 IT'S ALSO ABOUT REDUCTION OF 259 00:09:07,947 --> 00:09:10,049 SOMATIC AND AUTONOMIC MOTOR 260 00:09:10,116 --> 00:09:11,317 ACTIVITY. 261 00:09:11,384 --> 00:09:13,019 SO WHEN WE GOT INTO THE SLEEP 262 00:09:13,085 --> 00:09:16,222 FIELD MORE THAN A DECADE AGO, 263 00:09:16,289 --> 00:09:18,291 OUR MAIN OBSESSION AT THE TIME 264 00:09:18,357 --> 00:09:19,592 WAS THE QUESTION OF HOW DO WE 265 00:09:19,659 --> 00:09:19,926 SLEEP. 266 00:09:19,992 --> 00:09:21,327 AND WHAT WE DISCOVERED OVER THE 267 00:09:21,394 --> 00:09:23,963 YEARS IS THAT IN THE MAMMALIAN 268 00:09:24,030 --> 00:09:25,831 BRAIN, THE NEURONS THAT PUT US 269 00:09:25,898 --> 00:09:28,534 TO SLEEP ARE REALLY PART OF THE 270 00:09:28,601 --> 00:09:30,503 MOTOR CIRCUITS CONTROLLING 271 00:09:30,569 --> 00:09:32,271 SOMATIC OR AUTONOMIC MOTOR 272 00:09:32,338 --> 00:09:33,906 ACTIVITY. 273 00:09:33,973 --> 00:09:36,075 SO THIS IS A CIRCUIT DIAGRAM FOR 274 00:09:36,142 --> 00:09:37,410 SOMATIC MOTOR CONTROL. 275 00:09:37,476 --> 00:09:40,246 THE BLUE BOX HERE IS THE BASAL 276 00:09:40,313 --> 00:09:41,113 GANGLIA, SO THERE ARE ACTUALLY 277 00:09:41,180 --> 00:09:43,316 QUITE A FEW EXPERTS AT NIH 278 00:09:43,382 --> 00:09:45,217 STUDYING BASAL GANGLIA, AND YOU 279 00:09:45,284 --> 00:09:51,557 MIGHT RECOGNIZE THE T THE LOOP. 280 00:09:51,624 --> 00:09:54,894 YOU HAVE BRAIN AND BRAINSTEM 281 00:09:54,961 --> 00:09:57,330 CIRCUITS FOR MOTOR AK. 282 00:09:57,396 --> 00:09:59,598 SO NOW WE KNOW THERE ARE NEURONS 283 00:09:59,665 --> 00:10:00,666 THAT PROMOTE SLEEP IN ALL THE 284 00:10:00,733 --> 00:10:01,367 REGIONS CIRCLED IN RED. 285 00:10:01,434 --> 00:10:02,802 YOU CAN SEE THAT IT'S PRETTY 286 00:10:02,868 --> 00:10:06,505 MUCH EVERY LEVEL OF THE NETWORK. 287 00:10:06,572 --> 00:10:08,808 SO HERE'S THE CIRCUIT DIAGRAM 288 00:10:08,874 --> 00:10:10,576 FOR AUTONOMIC CONTROL OF THE 289 00:10:10,643 --> 00:10:11,877 CARDIOVASCULAR SYSTEM. 290 00:10:11,944 --> 00:10:13,512 AND WE HAVE FOUND SLEEP NEURONS 291 00:10:13,579 --> 00:10:16,015 IN ALL THE REGIONS CIRCLED IN 292 00:10:16,082 --> 00:10:16,248 RED. 293 00:10:16,315 --> 00:10:18,351 SO AGAIN, IT'S PRETTY MUCH EVERY 294 00:10:18,417 --> 00:10:21,187 LEVEL OF THE NETWORK. 295 00:10:21,253 --> 00:10:23,055 SO THIS LED US TO PROPOSE A 296 00:10:23,122 --> 00:10:24,991 MOTOR THEORY OF SLEEP CONTROL, 297 00:10:25,057 --> 00:10:27,093 WHICH IS THAT MAMMALIAN SLEEP IS 298 00:10:27,159 --> 00:10:30,129 REALLY CONTROLLED BY DISTRIBUTED 299 00:10:30,196 --> 00:10:31,764 NETWORKS OF NEURONS THAT ARE 300 00:10:31,831 --> 00:10:34,633 INTEGRAL TO SOMATIC AND 301 00:10:34,700 --> 00:10:35,835 AUTONOMIC MOTOR CONTROL. 302 00:10:35,901 --> 00:10:38,337 NOW, IN HINDSIGHT, THIS MIGHT 303 00:10:38,404 --> 00:10:39,772 SEEM EVEN OBVIOUS, RIGHT, 304 00:10:39,839 --> 00:10:42,041 BECAUSE AFTER ALL, MOST OF OUR 305 00:10:42,108 --> 00:10:43,075 MEASUREMENTS FOR DETECTING SLEEP 306 00:10:43,142 --> 00:10:45,344 ARE BASED ON MOTOR ACTIVITY. 307 00:10:45,411 --> 00:10:48,414 AND YET THIS IS NOT HOW THE 308 00:10:48,481 --> 00:10:49,415 FIELD HAS BEEN THINKING ABOUT 309 00:10:49,482 --> 00:10:51,117 IT, AND IT REALLY TOOK US QUITE 310 00:10:51,183 --> 00:10:52,218 A WHILE TO GET HERE. 311 00:10:52,284 --> 00:10:53,953 SO TODAY I WANT TO SHOW YOU SOME 312 00:10:54,020 --> 00:10:55,187 OF THE EXPERIMENTS THAT LED US 313 00:10:55,254 --> 00:10:58,324 TO THIS CONCLUSION. 314 00:10:58,391 --> 00:10:59,892 SO FIRST A LITTLE BIT OF 315 00:10:59,959 --> 00:11:03,796 HISTORICAL BACKGROUND. 316 00:11:03,863 --> 00:11:08,734 PIONEEWE ACTUALLY KNOW QUITE A T 317 00:11:08,801 --> 00:11:11,570 ABOUT THE NEURONS THAT KEEP US 318 00:11:11,637 --> 00:11:12,238 AWAKE. 319 00:11:12,304 --> 00:11:15,408 SO THESE INCLUDE A LOT OF THE 320 00:11:15,474 --> 00:11:17,043 WELL-KNOWN NEUROMODULATORY 321 00:11:17,109 --> 00:11:22,648 SYSTEMS, FOR EXAMPLE, THE 322 00:11:22,715 --> 00:11:24,283 DOPAMINERGIC NEURONS IN THE 323 00:11:24,350 --> 00:11:25,384 MIDBRAIN, CHOLINERGIC NEURONS IN 324 00:11:25,451 --> 00:11:29,755 BOTH THE BRAINSTEM AND BASAL 325 00:11:29,822 --> 00:11:31,857 FOREBRAIN, SEROTONIN NEURONS AND 326 00:11:31,924 --> 00:11:39,965 ALSO SOME PEPTIDE NEURONS, 327 00:11:40,032 --> 00:11:40,266 HYPOCRETIN. 328 00:11:40,332 --> 00:11:41,467 NOW THE SEARCH FOR THE SLEEP 329 00:11:41,534 --> 00:11:43,836 MECHANISM REALLY BEGAN WITH A 330 00:11:43,903 --> 00:11:48,541 LANDMARK DISCOVERY, SO WE JUST 331 00:11:48,607 --> 00:11:50,543 CAME OUT OF THIS BIG PANDEMIC, 332 00:11:50,609 --> 00:11:53,579 BUT RIGHT AFTER PROBABLY THE 333 00:11:53,646 --> 00:11:56,248 BIGGEST PANDEMIC IN HISTORY, 334 00:11:56,315 --> 00:11:57,283 ABOUT 100 YEARS AGO. 335 00:11:57,349 --> 00:11:58,517 SOME PEOPLE CALL IT THE SPANISH 336 00:11:58,584 --> 00:12:00,686 FLU THAT KILLED 50 MILLION 337 00:12:00,753 --> 00:12:01,887 PEOPLE WORLDWIDE. 338 00:12:01,954 --> 00:12:07,493 SO AFTER THAT BIG PANDEMIC, VON 339 00:12:07,560 --> 00:12:08,594 ECONOMO DISCOVERED THAT A SUBSET 340 00:12:08,661 --> 00:12:11,330 OF THE PATIENTS THAT RO RECOVERD 341 00:12:11,397 --> 00:12:13,265 FROM THAT FLU, THEY HAVE SEVERE 342 00:12:13,332 --> 00:12:14,266 INSOMNIA. 343 00:12:14,333 --> 00:12:15,901 AND THESE PATIENTS HAVE LESIONS 344 00:12:15,968 --> 00:12:17,970 IN THIS REGION CIRCLED IN RED. 345 00:12:18,037 --> 00:12:24,043 SO THIS WAS ACTUALLY VON 346 00:12:24,110 --> 00:12:25,177 ECONOMO'S ORIGINAL HAND DRAWING. 347 00:12:25,244 --> 00:12:27,713 THIS IS CALLED THE PRE-OP TICK 348 00:12:27,780 --> 00:12:30,649 AREA, THE POA IN THE 349 00:12:30,716 --> 00:12:31,550 HYPOTHALAMUS, SO THE IDEA IS 350 00:12:31,617 --> 00:12:32,418 THAT PERHAPS THIS REGION IS 351 00:12:32,485 --> 00:12:33,285 REALLY IMPORTANT FOR SLEEP 352 00:12:33,352 --> 00:12:34,720 BECAUSE IF YOU LOSE IT, YOU HAVE 353 00:12:34,787 --> 00:12:35,121 INSOMNIA. 354 00:12:35,187 --> 00:12:37,756 AND THIS WAS LATER CONFIRMED BY 355 00:12:37,823 --> 00:12:38,457 MANY ANIMAL EXPERIMENTS. 356 00:12:38,524 --> 00:12:42,928 YOU CAN DO LESIONS IN ANIMAL 357 00:12:42,995 --> 00:12:43,996 BRAIN AND THAT CONFIRMED THIS 358 00:12:44,063 --> 00:12:44,430 FINDING. 359 00:12:44,497 --> 00:12:46,365 SO THIS HAS LED TO THE TEXTBOOK 360 00:12:46,432 --> 00:12:49,135 MODEL WITH THE POA AS THE SLEEP 361 00:12:49,201 --> 00:12:49,668 CENTER. 362 00:12:49,735 --> 00:12:52,371 SO THE IDEA IS THAT THE POA 363 00:12:52,438 --> 00:12:54,406 PROMOTES SLEEP BY INHIBITING A 364 00:12:54,473 --> 00:12:59,011 LOT OF THESE WAKE-PROMOTING 365 00:12:59,078 --> 00:12:59,745 NEUROMODULATORY SYSTEMS. 366 00:12:59,812 --> 00:13:01,180 AND OF COURSE THE PROPERTIES OF 367 00:13:01,247 --> 00:13:03,516 THE POA SLEEP NEURONS HAVE BEEN 368 00:13:03,582 --> 00:13:06,418 CHARACTERIZED BY MANY LABS, 369 00:13:06,485 --> 00:13:09,054 INCLUDING CLIFFORD SAPER'S GROUP 370 00:13:09,121 --> 00:13:14,960 AND HIS MANY SCIENTIFIC DE16 371 00:13:15,027 --> 00:13:18,364 DESCENDANTS AND MANY OTHER LABS. 372 00:13:18,430 --> 00:13:20,099 EVEN BACK IN THE 1950s AND 373 00:13:20,166 --> 00:13:21,200 60s, SEVERAL STUDIES SHOW THAT 374 00:13:21,267 --> 00:13:23,169 THERE ARE NEURONS IN THE LOWER 375 00:13:23,235 --> 00:13:25,070 BRAINSTEM, REALLY POSTERIOR, SO 376 00:13:25,137 --> 00:13:27,873 THERE ARE SOME NEURONS THAT 377 00:13:27,940 --> 00:13:28,974 PROMOTE NON-REM SLEEP. 378 00:13:29,041 --> 00:13:31,544 THEN ABOUT A DECADE AGO, PATRICK 379 00:13:31,610 --> 00:13:32,678 FULLER'S LAB ALSO DISCOVERED 380 00:13:32,745 --> 00:13:36,315 THIS AREA CALLED THE PARAFACIAL 381 00:13:36,382 --> 00:13:39,485 ZONE IN THE MEDULLA THAT PROMOTE 382 00:13:39,552 --> 00:13:40,119 NON-REM SLEEP. 383 00:13:40,186 --> 00:13:42,655 SO WE ALSO ACCIDENTALLY STUMBLED 384 00:13:42,721 --> 00:13:45,824 UPON A MIDBRAIN REGION THAT 385 00:13:45,891 --> 00:13:48,994 REALLY PROMOTES NON-REM SLEEP 386 00:13:49,061 --> 00:13:49,495 QUITE POWERFULLY. 387 00:13:49,562 --> 00:13:50,963 SO IT SEEMS THAT THE 388 00:13:51,030 --> 00:13:51,931 SLEEP-PROMOTING MECHANISM IS 389 00:13:51,997 --> 00:13:53,899 ACTUALLY MORE DISTRIBUTED THAN 390 00:13:53,966 --> 00:13:56,869 THE STANDARD TEXTBOOK MODEL. 391 00:13:56,936 --> 00:13:59,471 SO TO TRY TO GET AN IDEA OF WHAT 392 00:13:59,538 --> 00:14:00,906 THE ENTIRE SLEEP PROMOTING 393 00:14:00,973 --> 00:14:02,975 MECHANISM MIGHT LOOK LIKE, WE 394 00:14:03,042 --> 00:14:04,410 DECIDED TO DO A WHOLE BRAIN 395 00:14:04,476 --> 00:14:06,612 SCREENING FOR SLEEP NEURONS. 396 00:14:06,679 --> 00:14:09,248 SO WE HAVE TWO BASIC CRITERIA 397 00:14:09,315 --> 00:14:10,749 FOR SLEEP NEURONS. 398 00:14:10,816 --> 00:14:12,985 FIRST THEY SHOULD BE 399 00:14:13,052 --> 00:14:14,453 SLEEP-PROMOTING, MEANING THAT 400 00:14:14,520 --> 00:14:15,854 THEIR ACTIVATION SHOULD INCREASE 401 00:14:15,921 --> 00:14:17,323 SLEEP AND THEIR INACTIVATION 402 00:14:17,389 --> 00:14:18,090 SHOULD DECREASE SLEEP. 403 00:14:18,157 --> 00:14:20,693 SO WE SHOULD ALWAYS DO 404 00:14:20,759 --> 00:14:21,460 BIDIRECTIONAL MANIPULATION. 405 00:14:21,527 --> 00:14:24,096 AND SECONDLY, THEY SHOULD BE 406 00:14:24,163 --> 00:14:25,130 SLEEP-ACTIVE, MEANING THAT WHEN 407 00:14:25,197 --> 00:14:27,032 YOU'RE NOT MANIPULATING THEM, IF 408 00:14:27,099 --> 00:14:28,467 YOU'RE JUST RECORDING THEIR 409 00:14:28,534 --> 00:14:30,603 ACTIVITY, THEY SHOULD BE ACTIVE 410 00:14:30,669 --> 00:14:32,171 EITHER RIGHT BEFORE OR DURING 411 00:14:32,238 --> 00:14:34,373 SLEEP, SO THEY SHOULD BE 412 00:14:34,440 --> 00:14:35,007 SPONTANEOUSLY ACTIVE AT THE 413 00:14:35,074 --> 00:14:38,444 RIGHT TIME TO DO THAT IR JOB. 414 00:14:38,510 --> 00:14:39,044 -- TO DO THEIR 415 00:14:39,111 --> 00:14:39,411 JOB. 416 00:14:39,478 --> 00:14:41,146 WHEN WE WERE DOING WHOLE BRAIN 417 00:14:41,213 --> 00:14:42,581 SCREENING WE ALSO HAVE TWO 418 00:14:42,648 --> 00:14:43,549 CORRESPONDING STRATEGIES. 419 00:14:43,616 --> 00:14:45,751 WE COULD EITHER SCREEN FOR 420 00:14:45,818 --> 00:14:47,319 SLEEP-PROMOTING NEURONS AND SEE 421 00:14:47,386 --> 00:14:49,555 IF THEY'RE ALSO SLEEP-ACTIVE, OR 422 00:14:49,622 --> 00:14:51,223 WE CAN DO SCREENING FOR 423 00:14:51,290 --> 00:14:52,358 SLEEP-ACTIVE NEURONS AND SEE IF 424 00:14:52,424 --> 00:14:53,959 THEY'RE ALSO SLEEP-PROMOTING. 425 00:14:54,026 --> 00:14:55,361 SO IT TURNS OUT THAT BOTH 426 00:14:55,427 --> 00:14:57,329 STRATEGIES WORKED QUITE WELL, 427 00:14:57,396 --> 00:14:58,464 BUT TODAY I'M JUST GOING TO 428 00:14:58,530 --> 00:14:59,965 FOCUS ON THE FIRST STRATEGY TO 429 00:15:00,032 --> 00:15:01,367 SEARCH FOR SLEEP-PROMOTING 430 00:15:01,433 --> 00:15:03,736 NEURONS. 431 00:15:03,802 --> 00:15:06,639 SO THIS EFFORT WAS BASED ON AN 432 00:15:06,705 --> 00:15:07,706 INCREDIBLY SIMPLE LOGIC, 433 00:15:07,773 --> 00:15:08,941 PROBABLY A JUNIOR HIGH SCHOOL 434 00:15:09,008 --> 00:15:10,009 STUDENT CAN COME UP WITH THIS 435 00:15:10,075 --> 00:15:10,676 IDEA. 436 00:15:10,743 --> 00:15:12,745 SO THE IDEA IS THAT WE'RE GOING 437 00:15:12,811 --> 00:15:15,814 TO START WITH THE WAKE-PROMOTING 438 00:15:15,881 --> 00:15:17,149 NEURONS, AS I MENTIONED BEFORE 439 00:15:17,216 --> 00:15:19,652 WE KNOW QUITE A FEW OF THEM. 440 00:15:19,718 --> 00:15:22,821 AND WE'RE GOING TO USE THIS 441 00:15:22,888 --> 00:15:24,456 RETROGRADE TRANS SYNAPTIC 442 00:15:24,523 --> 00:15:26,558 TRACING TO FIND THEIR INHIBITORY 443 00:15:26,625 --> 00:15:27,526 INPUT, BECAUSE WE KNOW THAT 444 00:15:27,593 --> 00:15:30,029 SLEEP AND WAKEFULNESS ARE 445 00:15:30,095 --> 00:15:31,063 MUTUALLY EXCLUSIVE, RIGHT? 446 00:15:31,130 --> 00:15:33,966 SO IF YOU'RE AWAKE, YOU CAN'T BE 447 00:15:34,033 --> 00:15:35,601 ASLEEP AND VICE VERSA. 448 00:15:35,668 --> 00:15:37,036 SO IF YOU CAN FIND NEURONS THAT 449 00:15:37,102 --> 00:15:38,704 INHIBIT THE NEURONS THAT KEEP US 450 00:15:38,771 --> 00:15:39,672 AWAKE, THEN PERHAPS THOSE 451 00:15:39,738 --> 00:15:41,640 NEURONS CAN PROMOTE SLEEP. 452 00:15:41,707 --> 00:15:42,941 IT'S A POSSIBILITY. 453 00:15:43,008 --> 00:15:45,344 AND THEN ONCE WE FIND THE 454 00:15:45,411 --> 00:15:46,345 INHIBITORY SLEEP NEURONS, WE'RE 455 00:15:46,412 --> 00:15:48,213 GOING TO TRACE ONE MORE STEP 456 00:15:48,280 --> 00:15:50,049 BACK, AND LOOK FOR THEIR 457 00:15:50,115 --> 00:15:51,150 EXCITATORY INPUT. 458 00:15:51,216 --> 00:15:54,153 BECAUSE IF YOU'RE A NEURON OONDD 459 00:15:54,219 --> 00:15:55,888 YOU CAN EXCITE A WHOLE BUNCH OF 460 00:15:55,954 --> 00:15:57,089 OTHER NEURONS THAT PROMOTE 461 00:15:57,156 --> 00:15:58,624 SLEEP, THEN PERHAPS YOU YOURSELF 462 00:15:58,691 --> 00:16:00,793 CAN PROMOTE SLEEP. 463 00:16:00,859 --> 00:16:04,963 SO THIS WAS DONE BY A REALLY, 464 00:16:05,030 --> 00:16:06,265 REALLY FANTASTIC FORMER POSTDOC 465 00:16:06,332 --> 00:16:08,067 IN MY LAB WHO'S RUNNING HER OWN 466 00:16:08,133 --> 00:16:11,837 LAB NOW. 467 00:16:11,904 --> 00:16:14,707 SO WE TARGETED A WHOLE BUNCH OF 468 00:16:14,773 --> 00:16:16,675 WAKE PROMOTING NEURONS AND USED 469 00:16:16,742 --> 00:16:19,311 TRACING BASED ON RABIES VIRUS TO 470 00:16:19,378 --> 00:16:21,480 IDENTIFY BRAIN REGIONS WITH 471 00:16:21,547 --> 00:16:23,982 RELATIVELY BROAD GABAERGIC INPUT 472 00:16:24,049 --> 00:16:26,518 TO THOSE WAKE-PROMOTING NEURONS. 473 00:16:26,585 --> 00:16:29,688 SO HERE IS THE LIST OF ALL THE 474 00:16:29,755 --> 00:16:33,525 WAKE-PROMOTING NEURONS THAT CH 475 00:16:33,592 --> 00:16:37,429 CHENYAN TARGETED. 476 00:16:37,496 --> 00:16:40,399 CHOLINERGIC, GABAERGIC NEURONS. 477 00:16:40,466 --> 00:16:41,700 THIS IS A LIST OF THE BRAIN 478 00:16:41,767 --> 00:16:44,336 REGIONS WITH RELATIVELY BROAD 479 00:16:44,403 --> 00:16:46,538 GABAERGIC, MEANING INHIBITORY 480 00:16:46,605 --> 00:16:48,273 PROJECTIONS TO THOSE 481 00:16:48,340 --> 00:16:48,741 WAKE-PROMOTING CELLS. 482 00:16:48,807 --> 00:16:50,876 SO YOU CAN SEE THAT THIS LIST 483 00:16:50,943 --> 00:16:53,078 INCLUDES THE POA, WHICH IS THE 484 00:16:53,145 --> 00:16:54,713 TEXTBOOK SLEEP CENTER. 485 00:16:54,780 --> 00:16:56,915 BUT TO OUR SURPRISE, THE TOP 486 00:16:56,982 --> 00:16:58,217 CANDIDATE THAT CAME OUT OF THIS 487 00:16:58,283 --> 00:17:01,653 SCREENING IS ACTUALLY THE 488 00:17:01,720 --> 00:17:03,856 CENTRAL NUCLEUS OF THE AMYGDALA, 489 00:17:03,922 --> 00:17:05,224 WHICH IS TRADITIONALLY THOUGHT 490 00:17:05,290 --> 00:17:08,394 TO BE A FEAR CENTER. 491 00:17:08,460 --> 00:17:10,362 AND SO CHENYAN WAS ABLE TO 492 00:17:10,429 --> 00:17:12,431 IDENTIFY A SUBSET OF THE 493 00:17:12,498 --> 00:17:15,834 GABAERGIC NEURONS IN THE CEA 494 00:17:15,901 --> 00:17:19,438 THAT EXPRESS -- SHE SHOWED THESE 495 00:17:19,505 --> 00:17:20,973 WERE BOTH SLEEP ACTIVE AND SLEEP 496 00:17:21,039 --> 00:17:23,375 PROMOTING AND ALSO THE 497 00:17:23,442 --> 00:17:26,445 NEUROPEPTIDE NEUROTENSIN ITSELF 498 00:17:26,512 --> 00:17:28,113 IS IMPORTANT FOR THE SLEEP 499 00:17:28,180 --> 00:17:28,547 PROMOTING EFFECT. 500 00:17:28,614 --> 00:17:31,717 FOR THE SAKE OF TIME, I'M GOING 501 00:17:31,784 --> 00:17:33,452 TO SKIP THAT AND FOCUS ON THE 502 00:17:33,519 --> 00:17:34,420 THIRD CANDIDATE REGION THAT CAME 503 00:17:34,486 --> 00:17:35,687 OUT OF THIS SCREENING. 504 00:17:35,754 --> 00:17:37,589 SO THIS WAS CHARACTERIZED BY 505 00:17:37,656 --> 00:17:40,893 ANOTHER BRILLIANT FORMER 506 00:17:40,959 --> 00:17:42,528 POSTDOC, WHO'S ALSO RUNNING HER 507 00:17:42,594 --> 00:17:44,163 OWN LAB NOW. 508 00:17:44,229 --> 00:17:45,464 SO MANY OF YOU PROBABLY KNOW 509 00:17:45,531 --> 00:17:50,102 THAT THE SNR, SUBSTANTIA NIGRA 510 00:17:50,169 --> 00:17:54,440 IS PART OF THE BASAL GANGLIA 511 00:17:54,506 --> 00:17:55,541 CONTROLLING MOTOR ACTIVITY AND 512 00:17:55,607 --> 00:17:58,110 YET WHEN WE WERE DOING THE 513 00:17:58,177 --> 00:17:59,344 SCREENING, WE WERE DOING WHOLE 514 00:17:59,411 --> 00:18:00,479 BRAIN SCREENING WITHOUT 515 00:18:00,546 --> 00:18:01,580 PRECONCEPTION OF WHAT THE BRAIN 516 00:18:01,647 --> 00:18:02,648 AREA MIGHT BE DOING. 517 00:18:02,714 --> 00:18:04,516 YET ONCE YOU KNOW IT'S THE SNR, 518 00:18:04,583 --> 00:18:07,152 YOU CAN'T IGNORE ALL THE 519 00:18:07,219 --> 00:18:07,853 PREVIOUS PUBLICATIONS. 520 00:18:07,920 --> 00:18:09,421 YOU HAVE TO TRY TO LINK TO WHAT 521 00:18:09,488 --> 00:18:10,956 WE KNOW ABOUT SNR. 522 00:18:11,023 --> 00:18:13,225 SO IN ADDITION TO EEG AND EMG, 523 00:18:13,292 --> 00:18:16,328 WHICH WE USUALLY MEASURE FOR 524 00:18:16,395 --> 00:18:18,497 SLEEP, WE ALSO ADDED THE VIDEO 525 00:18:18,564 --> 00:18:20,799 RECORDING TO LOOK AT THE MOTOR 526 00:18:20,866 --> 00:18:23,435 ACTIVITY OF THE MICE. 527 00:18:23,502 --> 00:18:25,537 AND WHEN WE WERE DOING THIS 528 00:18:25,604 --> 00:18:26,805 PROJECT, DEEP LEARNING IS ALL 529 00:18:26,872 --> 00:18:28,006 THE RAGE AND SO WE DIDN'T WANT 530 00:18:28,073 --> 00:18:30,209 TO BE LEFT BEHIND, SO WE LINED 531 00:18:30,275 --> 00:18:31,977 UP SOME COLLABORATORS WHO HELPED 532 00:18:32,044 --> 00:18:36,081 US TO USE DEEP LEARNING TO TRAIN 533 00:18:36,148 --> 00:18:37,216 THIS CONVOLUTION OF THE NEURAL 534 00:18:37,282 --> 00:18:38,951 NETWORK FOR AUTOMATIC IMAGE 535 00:18:39,017 --> 00:18:39,284 SEGMENTATION. 536 00:18:39,351 --> 00:18:40,786 SO THIS IS THE ORIGINAL IMAGE 537 00:18:40,853 --> 00:18:44,857 AND THIS IS THE -- MY CURSOR 538 00:18:44,923 --> 00:18:46,058 DOESN'T WORK VERY WELL. 539 00:18:46,125 --> 00:18:48,360 SO THIS IS THE SEGMENTED MOUSE. 540 00:18:48,427 --> 00:18:51,330 SO ONCE WE WERE ABLE TO AUTOMATE 541 00:18:51,396 --> 00:18:53,065 THIS STEP, IT'S PRETTY 542 00:18:53,131 --> 00:18:56,335 STRAIGHTFORWARD TO EXTRACT SOME 543 00:18:56,401 --> 00:18:57,035 MOVEMENT-RELATED PARAMETERS OF 544 00:18:57,102 --> 00:18:57,870 THE MICE. 545 00:18:57,936 --> 00:19:00,372 SO WE FOCUSED ON TWO PARAMETERS, 546 00:19:00,439 --> 00:19:02,040 ONE IS TRANSLATION AND THE OTHER 547 00:19:02,107 --> 00:19:04,009 IS TOTAL MOVEMENT. 548 00:19:04,076 --> 00:19:06,378 AND WHEN WE PLOTTED THESE TWO 549 00:19:06,445 --> 00:19:08,881 PARAMETERS IN THIS 550 00:19:08,947 --> 00:19:10,148 TWO-DIMENSIONAL SPACE, WE 551 00:19:10,215 --> 00:19:11,884 BASICALLY SAW THREE CLUSTERS. 552 00:19:11,950 --> 00:19:13,852 THE DARK GREEN CLUSTER 553 00:19:13,919 --> 00:19:14,786 CORRESPONDS TO LOCOMOTION. 554 00:19:14,853 --> 00:19:15,821 SO THESE MICE WERE NOT TRAINED 555 00:19:15,888 --> 00:19:16,822 TO DO ANYTHING, THEY WERE JUST 556 00:19:16,889 --> 00:19:18,757 IN THEIR HOME CAGE DOING 557 00:19:18,824 --> 00:19:19,424 WHATEVER THEY WANTED. 558 00:19:19,491 --> 00:19:20,959 SO THE BIGGEST MOST EXCITING 559 00:19:21,026 --> 00:19:22,160 MOVEMENT THAT THEY MAKE IS 560 00:19:22,227 --> 00:19:24,029 BASICALLY RUNNING AROUND IN THE 561 00:19:24,096 --> 00:19:26,098 HOME CAGE. 562 00:19:26,164 --> 00:19:27,733 AND THE LIGHTER GREEN CLUSTER IS 563 00:19:27,799 --> 00:19:30,369 ALL THE SMALLER MOVEMENT 564 00:19:30,435 --> 00:19:32,671 INCLUDING GROOMING, EATING, OR 565 00:19:32,738 --> 00:19:36,375 SOME POSTURAL ADJUSTMENT. 566 00:19:36,441 --> 00:19:38,777 AND THE GREY CLUSTER IS 567 00:19:38,844 --> 00:19:39,778 BASICALLY IMMOBILITY, RIGHT, 568 00:19:39,845 --> 00:19:41,647 THEY'RE NOT REALLY MOVING 569 00:19:41,713 --> 00:19:41,980 VISIBLY. 570 00:19:42,047 --> 00:19:44,049 BUT ONCE WE LOOK AT THE EEG AND 571 00:19:44,116 --> 00:19:45,651 EMG, IT TURNS OUT THERE ARE 572 00:19:45,717 --> 00:19:50,389 ACTUALLY TWO STATES, ONE IS -- 573 00:19:50,455 --> 00:19:51,590 AND THE OTHER IS ACTUAL SLEEP. 574 00:19:51,657 --> 00:19:54,660 SO BASICALLY WE CLASSIFIED FOUR 575 00:19:54,726 --> 00:19:55,928 BEHAVIORAL STATES: LOCOMOTION, 576 00:19:55,994 --> 00:19:58,697 THE LARGER MOVEMENT, SMALLER 577 00:19:58,764 --> 00:19:59,898 MOVEMENTS, QUIET WAKEFULNESS, 578 00:19:59,965 --> 00:20:04,703 AND SLEEP. 579 00:20:04,770 --> 00:20:06,471 SO HERE I'M PLOTTING THE EEG 580 00:20:06,538 --> 00:20:09,408 DELTA POWER ACROSS THE FOUR 581 00:20:09,474 --> 00:20:10,175 BEHAVIOR STATES, BASICALLY THE 582 00:20:10,242 --> 00:20:12,578 LOWER FREQUENCY ACTIVITY, BELOW 583 00:20:12,644 --> 00:20:13,579 4 HERTZ. 584 00:20:13,645 --> 00:20:15,080 THE HIGHER THE DELTA POWER, THE 585 00:20:15,147 --> 00:20:16,949 LESS AROUSED THE BRAIN IS. 586 00:20:17,015 --> 00:20:18,717 SO IF YOU SEE A HEIDEL TA POWER, 587 00:20:18,784 --> 00:20:20,552 IT MEANS THAT YOU'RE NOT 588 00:20:20,619 --> 00:20:23,822 THINKING MUCH OR YOU'RE NOT VERY 589 00:20:23,889 --> 00:20:24,056 EXCITED. 590 00:20:24,122 --> 00:20:27,025 SO -- AND THIS IS THE TOTAL EMG 591 00:20:27,092 --> 00:20:29,094 POWER. 592 00:20:29,161 --> 00:20:30,362 THE POINT I WANT TO MAKE IS IF 593 00:20:30,429 --> 00:20:31,496 YOU LOOK AT THE THREE GREENISH 594 00:20:31,563 --> 00:20:32,931 STATES, SO THESE ARE ALL WAKE 595 00:20:32,998 --> 00:20:35,901 STATES, SO WE TEND TO THINK OF 596 00:20:35,968 --> 00:20:36,768 THAT DIFFERENCE IN TERMS OF 597 00:20:36,835 --> 00:20:38,303 MOTOR ACTIVITY, AND OF COURSE 598 00:20:38,370 --> 00:20:40,372 THERE'S EMG CHANGE. 599 00:20:40,439 --> 00:20:42,908 BUT IN FACT, YOU ALSO SEE A VERY 600 00:20:42,975 --> 00:20:46,044 CLEAR DIFFERENCE IN THE EEG. 601 00:20:46,111 --> 00:20:48,714 AND IF YOU COMPARE QUIET 602 00:20:48,780 --> 00:20:50,549 WAKEFULNESS AND SLEEP, SO BOTH 603 00:20:50,616 --> 00:20:52,184 ARE IMMOBILITY STATES, YOU CAN'T 604 00:20:52,250 --> 00:20:54,920 SEE VISIBLE MOVEMENT, SO WE TEND 605 00:20:54,987 --> 00:20:55,887 TO THINK OF THE DIFFERENCE IN 606 00:20:55,954 --> 00:20:57,389 TERMS OF BRAIN SPACE, BUT IN 607 00:20:57,456 --> 00:21:00,058 FACT, THERE'S ALSO CLEAR EMG 608 00:21:00,125 --> 00:21:00,392 DIFFERENCE. 609 00:21:00,459 --> 00:21:02,694 SO IN FACT, THIS IS WHY IF YOU 610 00:21:02,761 --> 00:21:04,763 FOLLOW SLEEP DURING MY TALK -- 611 00:21:04,830 --> 00:21:06,298 FALL ASLEEP DURING MY TALK, THE 612 00:21:06,365 --> 00:21:07,499 FIRST THING I WOULD KNOTS IS YOU 613 00:21:07,566 --> 00:21:09,468 NOD OFF BECAUSE YOU LOSE YOUR 614 00:21:09,534 --> 00:21:11,436 NECK MUSCLE EMG, SO THERE'S A 615 00:21:11,503 --> 00:21:12,504 CLEAR EMG DIFFERENCE. 616 00:21:12,571 --> 00:21:15,507 NOW THE POINT HERE IS THAT BRAIN 617 00:21:15,574 --> 00:21:17,809 SPACE MEASURED BY EEG AND MOTOR 618 00:21:17,876 --> 00:21:21,446 STATE MEASURED BY EMG ARE 619 00:21:21,513 --> 00:21:22,547 CORRELATED ACROSS MULTIPLE 620 00:21:22,614 --> 00:21:23,281 BEHAVIOR STATES. 621 00:21:23,348 --> 00:21:24,716 EVEN DURING WAKEFULNESS, THE 622 00:21:24,783 --> 00:21:26,018 MORE ACTIVE YOUR BODY IS, THE 623 00:21:26,084 --> 00:21:27,219 MORE AROUSED YOUR BRAIN IS. 624 00:21:27,285 --> 00:21:34,026 SO THIS IS IMPORTANT. 625 00:21:34,092 --> 00:21:36,194 SO WHEN WE LOOK AT TRANSITIONS 626 00:21:36,261 --> 00:21:37,596 BETWEEN THESE STATES THEY'RE NOT 627 00:21:37,663 --> 00:21:38,063 RANDOM AT ALL. 628 00:21:38,130 --> 00:21:40,032 IF THE MOUSE STARTED OUT 629 00:21:40,098 --> 00:21:41,233 RUNNING, IF WE LOOK AT THE NEXT 630 00:21:41,299 --> 00:21:42,534 MOMENT, LET'S SAY THE NEXT 631 00:21:42,601 --> 00:21:44,302 SECOND, THEY ALWAYS -- IF THEY 632 00:21:44,369 --> 00:21:45,604 TRANSITION AT ALL, THEY ALWAYS 633 00:21:45,671 --> 00:21:46,571 TRANSITION INTO SMALLER 634 00:21:46,638 --> 00:21:46,972 MOVEMENTS. 635 00:21:47,039 --> 00:21:48,206 WE HAVE NEVER SEEN A CASE WHERE 636 00:21:48,273 --> 00:21:49,908 THE MOUSE WAS LIKE RUNNING ONE 637 00:21:49,975 --> 00:21:51,176 MOMENT AND BANG, JUST FALL 638 00:21:51,243 --> 00:21:52,177 ASLEEP THE NEXT MOMENT. 639 00:21:52,244 --> 00:21:53,612 JUST LIKE WE HUMANS DON'T DO 640 00:21:53,679 --> 00:21:54,146 THAT, RIGHT? 641 00:21:54,212 --> 00:21:56,114 IT'S NOT LIKE WE RUN AND THEN WE 642 00:21:56,181 --> 00:21:58,283 JUST, YOU KNOW, CRASH AND FALL 643 00:21:58,350 --> 00:21:59,951 ASLEEP. 644 00:22:00,018 --> 00:22:01,253 AND SO IF THEY STARTED OUT IN 645 00:22:01,319 --> 00:22:02,454 OTHER MOVEMENTS, THEY EITHER GO 646 00:22:02,521 --> 00:22:04,423 BACK TO RUNNING OR INTO QUIET 647 00:22:04,489 --> 00:22:05,057 WAKEFULNESS. 648 00:22:05,123 --> 00:22:05,957 THEY DON'T GO TO SLEEP RIGHT 649 00:22:06,024 --> 00:22:07,025 AWAY. 650 00:22:07,092 --> 00:22:09,127 SO IF WE PUT THESE FOUR STATES 651 00:22:09,194 --> 00:22:10,929 IN A SINGLE CHAIN, ONE 652 00:22:10,996 --> 00:22:12,197 DIMENSIONAL CHAIN, THEN MOST OF 653 00:22:12,264 --> 00:22:15,233 THE TRANSITIONS ARE BETWEEN 654 00:22:15,300 --> 00:22:16,768 NEIGHBORING SPACE, THERE ARE 655 00:22:16,835 --> 00:22:17,669 VERY FEW EXCEPTIONS. 656 00:22:17,736 --> 00:22:21,039 THIS SUGGESTS TO US THAT BOTH 657 00:22:21,106 --> 00:22:23,208 MENTAL AROUSAL AND BEHAVIORAL 658 00:22:23,275 --> 00:22:24,976 MOTOR STATES TEND TO CHANGE 659 00:22:25,043 --> 00:22:28,380 GRADUALLY RATHER THAN ABRUPTLY. 660 00:22:28,447 --> 00:22:30,115 SO ALL OF THIS IS JUST BEHAVIOR, 661 00:22:30,182 --> 00:22:31,450 AND WHAT ABOUT SNR? 662 00:22:31,516 --> 00:22:33,518 SO IT TURNS OUT THAT THERE ARE 663 00:22:33,585 --> 00:22:35,153 ACTUALLY TWO SUBTYPES OF 664 00:22:35,220 --> 00:22:38,223 GABAERGIC NEURONS IN THE SNR. 665 00:22:38,290 --> 00:22:40,625 THE PV POSITIVE CELLS TEND TO BE 666 00:22:40,692 --> 00:22:43,228 LOCATED IN THE LATERAL SNR, AND 667 00:22:43,295 --> 00:22:46,965 THE GATU POSITIVE BUT PV 668 00:22:47,032 --> 00:22:47,966 NEGATIVE TEND TO BE IN THE 669 00:22:48,033 --> 00:22:48,934 MEDIAL SNR. 670 00:22:49,000 --> 00:22:52,637 SO NEXT WE TRACKED EACH CELL 671 00:22:52,704 --> 00:22:55,073 TYPE OPTOGENETICALLY 672 00:22:55,140 --> 00:22:55,741 EXPRESSING -- AND THEN WE 673 00:22:55,807 --> 00:22:56,808 RECORDED THEIR ACTIVITY USING 674 00:22:56,875 --> 00:22:58,877 THIS THING CALLED THE -- IT'S 675 00:22:58,944 --> 00:23:00,312 BASICALLY AN OPTIC FIBER 676 00:23:00,378 --> 00:23:06,985 SURROUNDED BY A BUNCH OF AT T -O 677 00:23:07,052 --> 00:23:09,721 WE BELIEVE THIS IS A GAD2 CELL 678 00:23:09,788 --> 00:23:11,690 BECAUSE WE RECORDED IN THE 679 00:23:11,757 --> 00:23:12,190 GAD2 CRE MOUSE. 680 00:23:12,257 --> 00:23:14,526 WE TURN ON THE LIGHT BRIEFLY, 681 00:23:14,593 --> 00:23:15,627 FOR 10 MILLISECONDS. 682 00:23:15,694 --> 00:23:16,828 EVERYBODY TIME WE TURN ON THE 683 00:23:16,895 --> 00:23:19,231 LASER, THE LITTLE BLUE DOT, IT 684 00:23:19,297 --> 00:23:20,766 EVOKED A SPIKING, SO WE THINK 685 00:23:20,832 --> 00:23:24,703 THIS CELL EXPRESSES CHAN EL DOB 686 00:23:24,770 --> 00:23:26,037 SIN, ONCE WE IDENTIFY THE CELL 687 00:23:26,104 --> 00:23:28,206 TYPE, WE TURN OFF THE LASER AND 688 00:23:28,273 --> 00:23:29,841 JUST RECORD THE SPONTANEOUS 689 00:23:29,908 --> 00:23:30,175 ACTIVITY. 690 00:23:30,242 --> 00:23:33,111 SO HERE YOU CAN SEE THAT THIS 691 00:23:33,178 --> 00:23:36,181 SELL HAS A HIGHER FIRING RATE 692 00:23:36,248 --> 00:23:37,482 DURING NON-REM SLEEP WHICH IS 693 00:23:37,549 --> 00:23:38,483 THE ORANGE PERIOD, AND THEY TEND 694 00:23:38,550 --> 00:23:39,885 TO HAVE LOWER ACTIVITY WHEN THE 695 00:23:39,951 --> 00:23:42,420 MOUSE IS MOVING, EITHER RUNNING 696 00:23:42,487 --> 00:23:44,589 OR OTHER MOVEMENTS. 697 00:23:44,656 --> 00:23:45,590 AND HERE'S THE POPULATION 698 00:23:45,657 --> 00:23:46,258 SUMMARY. 699 00:23:46,324 --> 00:23:47,459 THIS MAGENTA LINE IS THE 700 00:23:47,526 --> 00:23:49,094 POPULATION AVERAGE OF THE 701 00:23:49,161 --> 00:23:50,195 GAD2 CELLS AND YOU CAN SEE THAT 702 00:23:50,262 --> 00:23:51,730 THESE CELLS TEND TO BE MOST 703 00:23:51,797 --> 00:23:54,733 ACTIVE DURING SLEEP AND LESS 704 00:23:54,800 --> 00:23:56,134 ACTIVE DURING HIGH MOTOR 705 00:23:56,201 --> 00:23:56,668 ACTIVITY. 706 00:23:56,735 --> 00:23:59,004 BUT THE PV CELLS TEND TO SHOW 707 00:23:59,070 --> 00:23:59,771 THE OPPOSITE SIGN. 708 00:23:59,838 --> 00:24:03,141 SO IT'S THE GAD2 CELLS THAT ARE 709 00:24:03,208 --> 00:24:04,910 SLEEP-ACTIVE BUT NOT THE PV 710 00:24:04,976 --> 00:24:05,110 CELLS. 711 00:24:05,177 --> 00:24:06,978 SO THIS IS OUR FIRST CRITERION 712 00:24:07,045 --> 00:24:10,715 FOR BEING A SLEEP NEURON. 713 00:24:10,782 --> 00:24:11,917 SO NEXT WE LOOKED AT WHAT 714 00:24:11,983 --> 00:24:12,918 HAPPENS IF WE ACTIVATE THESE 715 00:24:12,984 --> 00:24:13,351 CELLS. 716 00:24:13,418 --> 00:24:16,388 SO IN OUR LAB, OUR STANDARD 717 00:24:16,454 --> 00:24:19,157 PROTOCOL IS TO TURN ON THE LASER 718 00:24:19,224 --> 00:24:20,425 AT 10 HERTZ STIMULATION FOR TWO 719 00:24:20,492 --> 00:24:22,994 MINUTES PER TRIAL AND SO THAT 720 00:24:23,061 --> 00:24:24,229 SHOWS IN THIS BLUE SHADING. 721 00:24:24,296 --> 00:24:28,033 AND YOU CAN SEE THAT EVERY TIME 722 00:24:28,099 --> 00:24:30,001 WE TURN ON LASER AT TIME ZERO, 723 00:24:30,068 --> 00:24:31,269 THERE'S AN IMMEDIATE REDUCTION 724 00:24:31,336 --> 00:24:33,405 OF RUNNING AND ALSO OTHER MOTOR 725 00:24:33,471 --> 00:24:34,039 ACTIVITY. 726 00:24:34,105 --> 00:24:35,140 AND THERE'S AN INCREASE IN 727 00:24:35,207 --> 00:24:36,775 SLEEP. 728 00:24:36,842 --> 00:24:38,643 BUT PV NEURON ACTIVATION HAS 729 00:24:38,710 --> 00:24:41,379 MUCH WEAKER EFFECT. 730 00:24:41,446 --> 00:24:43,982 AND WHEN WE INACTIVATED THESE 731 00:24:44,049 --> 00:24:46,751 CELLS THROUGH THIS INHIBITORY -- 732 00:24:46,818 --> 00:24:47,819 WE SEE THE OPPOSITE. 733 00:24:47,886 --> 00:24:49,688 SO GAD2 INACTIVATION CAUSED AN 734 00:24:49,754 --> 00:24:50,889 INCREASE IN MOVEMENT AND 735 00:24:50,956 --> 00:24:55,694 DECREASE IN SLEEP, AND THE PV 736 00:24:55,760 --> 00:24:57,362 ACTIVATION HAS MUCH WEAKER 737 00:24:57,429 --> 00:24:57,596 EFFECT. 738 00:24:57,662 --> 00:25:00,165 SO IT'S THE GAD2 BUT NOT THE PV 739 00:25:00,232 --> 00:25:02,133 CELLS THAT ARE SLEEP ACTIVE AND 740 00:25:02,200 --> 00:25:03,802 ALSO THEIR ACTIVATION PROMOTES 741 00:25:03,869 --> 00:25:05,337 SLEEP, SO THIS IS OUR SECOND 742 00:25:05,403 --> 00:25:06,204 CRITERION FOR BEING A SLEEP 743 00:25:06,271 --> 00:25:07,739 NEURON. 744 00:25:07,806 --> 00:25:08,073 OKAY. 745 00:25:08,139 --> 00:25:11,276 SO EVEN THE GAD2 CELLS SUPPRESS 746 00:25:11,343 --> 00:25:12,978 MOTOR ACTIVITY AND INCREASE 747 00:25:13,044 --> 00:25:15,280 SLEEP, THEY DON'T CAUSE DIRECT 748 00:25:15,347 --> 00:25:16,481 TRANSITION FROM MOVEMENT TO 749 00:25:16,548 --> 00:25:18,450 SLEEP, WHICH IS NOT OBSERVED 750 00:25:18,516 --> 00:25:19,751 NORMALLY. 751 00:25:19,818 --> 00:25:21,953 INSTEAD, THEY ONLY BIAS THE 752 00:25:22,020 --> 00:25:24,122 DIRECTION OF THE NATURAL 753 00:25:24,189 --> 00:25:25,223 TRANSITIONS, SO THESE ARE ALL 754 00:25:25,290 --> 00:25:26,958 THE TRANSITIONS WE SEE DURING 755 00:25:27,025 --> 00:25:29,060 LASER STIMULATION, SO NONE OF 756 00:25:29,127 --> 00:25:30,795 THEM IS ARTIFICIAL, SO WE SEE 757 00:25:30,862 --> 00:25:33,798 ALL THESE TRANSITIONS WITH THE 758 00:25:33,865 --> 00:25:34,266 SPONTANEOUS BEHAVIOR. 759 00:25:34,332 --> 00:25:36,268 BUT YOU CAN SEE THAT ALL THE RED 760 00:25:36,334 --> 00:25:38,670 ARROWS ARE THE ONES PROMOTED BY 761 00:25:38,737 --> 00:25:39,905 LASER STIMULATION AND THE BLUE 762 00:25:39,971 --> 00:25:42,307 ONES ARE SUPPRESSED. 763 00:25:42,374 --> 00:25:45,343 SO ALL THE PR PROMOTED ONES GO 764 00:25:45,410 --> 00:25:45,810 DOWNWARDS, RIGHT? 765 00:25:45,877 --> 00:25:46,444 OKAY. 766 00:25:46,511 --> 00:25:48,313 SO HERE AGAIN, I WANT TO MAKE A 767 00:25:48,380 --> 00:25:49,514 SLIGHT DIGRESSION. 768 00:25:49,581 --> 00:25:52,150 NOW, IF YOU'RE A SYSTEMS 769 00:25:52,217 --> 00:25:54,653 NEUROSCIENTIST LIKE ME AND YOU 770 00:25:54,719 --> 00:25:57,289 OPT GENETICALLY ACTIVATE SOME 771 00:25:57,355 --> 00:25:58,256 NEURONS IN THE BRAIN AND YOU SEE 772 00:25:58,323 --> 00:25:59,557 EVERY TIME YOU TURN ON THE LASER 773 00:25:59,624 --> 00:26:00,659 THE MOUSE STOPS RUNNING AND THEY 774 00:26:00,725 --> 00:26:02,761 START DOING OTHER THINGS, RIGHT, 775 00:26:02,827 --> 00:26:04,262 WHAT WOULD YOU CONCLUDE? 776 00:26:04,329 --> 00:26:06,031 YOU WOULD SAY I FOUND SOME 777 00:26:06,097 --> 00:26:06,798 NEURONS INVOLVED IN MOTOR 778 00:26:06,865 --> 00:26:07,365 CONTROL, RIGHT? 779 00:26:07,432 --> 00:26:09,634 BECAUSE YOU SEE A DIFFERENCE IN 780 00:26:09,701 --> 00:26:11,770 BEHAVIOR. 781 00:26:11,836 --> 00:26:13,505 IF YOU GO FROM MOVEMENTS TO 782 00:26:13,571 --> 00:26:15,273 QUIET WAKEFULNESS, YOU WOULD SAY 783 00:26:15,340 --> 00:26:17,876 THAT'S ALSO MOTOR CONTROL. 784 00:26:17,943 --> 00:26:19,311 BUT IF YOU FIND NEURONS THAT 785 00:26:19,377 --> 00:26:20,712 TRIGGER CHANGES FROM QUIET 786 00:26:20,779 --> 00:26:23,014 WAKEFULNESS TO SLEEP, YOU WOULD 787 00:26:23,081 --> 00:26:24,182 SAY THAT'S BRAIN STATE CONTROL, 788 00:26:24,249 --> 00:26:25,317 BECAUSE THERE'S NO CHANGE IN 789 00:26:25,383 --> 00:26:27,852 MOTOR ACTIVITY, RIGHT? 790 00:26:27,919 --> 00:26:29,821 BUT IN FACT, AS I MENTIONED 791 00:26:29,888 --> 00:26:31,222 BEFORE, FOR EACH OF THESE 792 00:26:31,289 --> 00:26:32,524 TRANSITIONS, THERE ARE CHANGES 793 00:26:32,590 --> 00:26:35,493 IN BOTH EEG, BRAIN STATE, AND 794 00:26:35,560 --> 00:26:37,696 EMG, WHICH IS MOTOR ACTIVITY. 795 00:26:37,762 --> 00:26:40,198 AND IN FACT, THESE SNR NEURONS, 796 00:26:40,265 --> 00:26:42,067 THEY REALLY DON'T CARE WHAT WE 797 00:26:42,133 --> 00:26:43,802 CALL THESE TRANSITIONS, RIGHT? 798 00:26:43,868 --> 00:26:45,437 ALL THEY DO IS TO PUSH THE 799 00:26:45,503 --> 00:26:48,340 ANIMAL DOWN THE CHAIN ONE STEP 800 00:26:48,406 --> 00:26:49,741 AT A TIME. 801 00:26:49,808 --> 00:26:51,142 IN OTHER WORDS, THE BEHAVIORAL 802 00:26:51,209 --> 00:26:52,577 EFFECT DEPENDS ON WHERE THE 803 00:26:52,644 --> 00:26:53,445 MOUSE WAS. 804 00:26:53,511 --> 00:26:54,646 IF THEY'RE RUNNING, YOUR LASER 805 00:26:54,713 --> 00:26:56,047 IS GOING TO PUSH THEM INTO OTHER 806 00:26:56,114 --> 00:26:56,381 MOVEMENTS. 807 00:26:56,448 --> 00:26:57,749 IF THEY'RE DOING GROOMING, 808 00:26:57,816 --> 00:26:59,117 THEY'RE GOING TO STOP DOING THE 809 00:26:59,184 --> 00:27:00,885 GROOMING AND IF THEY'RE IN QUIET 810 00:27:00,952 --> 00:27:01,686 WAKEFULNESS, YOU CAN PUSH THEM 811 00:27:01,753 --> 00:27:02,187 TO SLEEP. 812 00:27:02,253 --> 00:27:05,890 SO IT'S VERY CONTACT-DEPENDENT. 813 00:27:05,957 --> 00:27:06,891 IN OTHER WORDS, SLEEP IN MY MIND 814 00:27:06,958 --> 00:27:08,526 IS REALLY JUST THE LAST STEP IN 815 00:27:08,593 --> 00:27:11,696 A SERIES OF TRANSITIONS THAT 816 00:27:11,763 --> 00:27:13,465 REDUCE BOTH MENTAL AROUSAL AND 817 00:27:13,531 --> 00:27:15,333 MOTOR ACTIVITY. 818 00:27:15,400 --> 00:27:17,002 AND WHEN WE DID THE 819 00:27:17,068 --> 00:27:18,136 INACTIVATION, WE AGAIN DON'T 820 00:27:18,203 --> 00:27:19,571 CREATE ANY ARTIFICIAL 821 00:27:19,637 --> 00:27:21,906 TRANSITIONS, ALL WE DO IS THE 822 00:27:21,973 --> 00:27:23,541 BIAS THE TRANSITIONS IN THE 823 00:27:23,608 --> 00:27:25,477 UPWARD DIRECTION. 824 00:27:25,543 --> 00:27:25,810 OKAY. 825 00:27:25,877 --> 00:27:28,747 SO NEXT WE LOOKED AT THE 826 00:27:28,813 --> 00:27:29,881 DOWNSTREAM TARGETS OF THE SNR 827 00:27:29,948 --> 00:27:30,181 NEURONS. 828 00:27:30,248 --> 00:27:31,816 IF YOU LOOK AT THE PV CELLS, 829 00:27:31,883 --> 00:27:33,451 THEY PROJECT TO THE MOTOR 830 00:27:33,518 --> 00:27:35,653 THALAMUS, THE KNOW LAYERS OF THE 831 00:27:35,720 --> 00:27:37,956 SUPERIOR COLLICULUS AND THIS 832 00:27:38,023 --> 00:27:43,828 REGION THAT PEOPLE CALL THE -- 833 00:27:43,895 --> 00:27:44,896 PEOPLE KNOW FOR A LONG TIME IF 834 00:27:44,963 --> 00:27:46,064 YOU DO ELECTRICAL STIMULATION IN 835 00:27:46,131 --> 00:27:47,565 THAT AREA, YOU BASICALLY CAUSE 836 00:27:47,632 --> 00:27:48,566 RUNNING OR INCREASE SPEED. 837 00:27:48,633 --> 00:27:51,202 SO ALL OF THESE ARE VERY 838 00:27:51,269 --> 00:27:53,138 WELL-KNOWN MOTOR REGIONS. 839 00:27:53,204 --> 00:27:55,040 CONTROLLED BY THE BASAL GANGLIA. 840 00:27:55,106 --> 00:27:58,209 BUT IF YOU LOOK AT THE GAD2 841 00:27:58,276 --> 00:27:59,044 NEURONS, IN ADDITION TO THESE 842 00:27:59,110 --> 00:28:01,112 MOTOR AREAS THAT ARE COVERED BY 843 00:28:01,179 --> 00:28:04,315 THE PV CELLS, THEY ALSO PROTECT 844 00:28:04,382 --> 00:28:06,718 THE DORSAL RAFFAE, WHICH 845 00:28:06,785 --> 00:28:09,254 CONTAINS BOTH SEROTONIN AND 846 00:28:09,320 --> 00:28:10,221 DOPAMINERGIC NEURONS THAT 847 00:28:10,288 --> 00:28:12,957 REGULATE BRAIN AROUSAL. 848 00:28:13,024 --> 00:28:15,927 THEY ALSO PROTECT THE LOCUS 849 00:28:15,994 --> 00:28:17,562 JUIUS, AGAIN INVOLVED IN BRAIN 850 00:28:17,629 --> 00:28:19,531 AROUSAL REGULATION. 851 00:28:19,597 --> 00:28:21,733 AND WHEN WE USE THE VIRUS TRICK 852 00:28:21,800 --> 00:28:24,569 TO LABEL THE SUBSET OF THE SNR 853 00:28:24,636 --> 00:28:26,504 NEURONS THAT PROJECT TO THE 854 00:28:26,571 --> 00:28:29,040 MOTOR THALAMUS, WES ARE SAW 855 00:28:29,107 --> 00:28:31,109 THE -- COLLATERALS IN THE DORSAL 856 00:28:31,176 --> 00:28:33,178 RAFFAE AND LOCUS JULIUS AND 857 00:28:33,244 --> 00:28:34,312 CONVERSELY WHEN WE LABELED THE 858 00:28:34,379 --> 00:28:37,582 CELLS THAT PROTECT THE DORSAL 859 00:28:37,649 --> 00:28:40,652 RAFFAE WE ALSO SAW THEIR AXON 860 00:28:40,718 --> 00:28:41,419 COLLATERALS IN THESE MOTOR 861 00:28:41,486 --> 00:28:42,720 REASONS SO WE THINK IT COULD BE 862 00:28:42,787 --> 00:28:44,255 THE SAME NEURONS THAT INNERVATE 863 00:28:44,322 --> 00:28:46,658 BOTH THE REGIONS FOR BRAIN 864 00:28:46,724 --> 00:28:47,759 AROUSAL CONTROL AND ALSO MOTOR 865 00:28:47,826 --> 00:28:48,526 CONTROL. 866 00:28:48,593 --> 00:28:51,463 AND WE THINK THAT THIS KIND OF 867 00:28:51,529 --> 00:28:52,897 COLLATERAL ARRANGEMENT ALLOWS 868 00:28:52,964 --> 00:28:55,733 THESE NEURONS TO COORDINATE THE 869 00:28:55,800 --> 00:28:56,935 CHANGES IN BRAIN STATES AND 870 00:28:57,001 --> 00:28:59,237 MOTOR STATES. 871 00:28:59,304 --> 00:29:02,107 OKAY, SO NOW WE HAVE FOUND THE 872 00:29:02,173 --> 00:29:03,408 POPULATION OF THE GABERGIC 873 00:29:03,475 --> 00:29:04,876 NEURONS THAT PROMOTE SLEEP AND 874 00:29:04,943 --> 00:29:06,244 AS PROMISED, WE'RE GOING TO 875 00:29:06,311 --> 00:29:07,245 TRACE ONE MORE STEP BACK AND 876 00:29:07,312 --> 00:29:09,414 LOOK FOR THEIR EXCITATORY INPUT. 877 00:29:09,481 --> 00:29:11,082 NOW, IF YOU STUDY THE BASAL 878 00:29:11,149 --> 00:29:13,251 GANGLIA, THIS IS ALL OLD NEWS, 879 00:29:13,318 --> 00:29:15,120 YOU KNOW VERY WELL THAT THE 880 00:29:15,186 --> 00:29:17,388 MAJOR INPUT TO THE SNR COMES 881 00:29:17,455 --> 00:29:21,759 FROM THE SUBTHALAMIC NUCLEUS, 882 00:29:21,826 --> 00:29:22,760 THE EXCITATORY INPUT SO THAT'S 883 00:29:22,827 --> 00:29:24,195 CALLED THE STN. 884 00:29:24,262 --> 00:29:26,464 SO THEY ALSO EXPRESS A 885 00:29:26,531 --> 00:29:27,398 NEUROPEPTIDE NEURO10 SIN AND 886 00:29:27,465 --> 00:29:30,768 WHEN WE TARGET THE STN NEURONS 887 00:29:30,835 --> 00:29:34,906 IN NEURO10SIN CRE MICE, WE ALSO 888 00:29:34,973 --> 00:29:37,408 SAW AN INCREASE IN NON-REM SLEEP 889 00:29:37,475 --> 00:29:39,711 AND DECREASE IN WAKEFULNESS SO 890 00:29:39,777 --> 00:29:42,113 THE UPSTREAM EXCITATORY NEURONS 891 00:29:42,180 --> 00:29:43,748 ALSO PROMOTE SLEEP. 892 00:29:43,815 --> 00:29:44,315 OKAY. 893 00:29:44,382 --> 00:29:46,384 SO AS I MENTIONED AT THE 894 00:29:46,451 --> 00:29:47,585 BEGINNING, FALLING ASLEEP IS 895 00:29:47,652 --> 00:29:49,220 ASSOCIATED WITH REDUCTIONS OF 896 00:29:49,287 --> 00:29:52,524 BOTH SOMATIC MOTOR ACTIVITY AND 897 00:29:52,590 --> 00:29:54,159 AUTONOMIC MOTOR ACTIVITY, SO THE 898 00:29:54,225 --> 00:29:55,360 HEARTBEAT ALSO SLOWS DOWN. 899 00:29:55,426 --> 00:29:59,531 SO I JUST TOLD YOU ABOUT THE 900 00:29:59,597 --> 00:30:00,932 STN-SNR PATHWAY FOR SOMATIC 901 00:30:00,999 --> 00:30:02,400 MOTOR CONTROL AND NOW I WANT TO 902 00:30:02,467 --> 00:30:03,468 SPEND JUST THE NEXT FEW MINUTES 903 00:30:03,535 --> 00:30:05,670 TO TALK ABOUT A CIRCUIT FOR 904 00:30:05,737 --> 00:30:07,539 CARDIOVASCULAR CONTROL. 905 00:30:07,605 --> 00:30:10,808 SO THIS CIRCUIT IS INVOLVED IN 906 00:30:10,875 --> 00:30:13,545 CARDIOVASCULAR -- REFLEX AND IS 907 00:30:13,611 --> 00:30:15,713 CHARACTERIZED BY YAO, ANOTHER 908 00:30:15,780 --> 00:30:17,615 FORMER POSTDOC NOW RUNNING HER 909 00:30:17,682 --> 00:30:18,650 OWN LAB. 910 00:30:18,716 --> 00:30:20,752 SO THE BARREL REFLEX IS A RAPID 911 00:30:20,818 --> 00:30:23,288 NEGATIVE FEEDBACK MECHANISM FOR 912 00:30:23,354 --> 00:30:24,589 STABILIZING THE BLOOD PRESSURE. 913 00:30:24,656 --> 00:30:26,124 SO THE BLOOD PRESSURE IS NOT 914 00:30:26,191 --> 00:30:28,326 SOMETHING THAT YOU WANT TO 915 00:30:28,393 --> 00:30:30,161 CHANGE OVER HUGE RANGE, BECAUSE 916 00:30:30,228 --> 00:30:32,764 EITHER YOU FAINT OR YOU MIGHT 917 00:30:32,830 --> 00:30:33,731 HAVE A STROKE. 918 00:30:33,798 --> 00:30:37,335 SO THE MECHANISM IS QUITE WELL 919 00:30:37,402 --> 00:30:40,738 UNDERSTOOD THE RECEPTORS SIT IN 920 00:30:40,805 --> 00:30:42,140 A CERTAIN PART OF THE ARTERY AND 921 00:30:42,207 --> 00:30:44,242 THEY'RE ACTIVATED BY AN INCREASE 922 00:30:44,309 --> 00:30:47,278 IN BLOOD PRESSURE, BP, AND THAT 923 00:30:47,345 --> 00:30:48,713 SIGNAL IS TRANSMITTED TO THE 924 00:30:48,780 --> 00:30:50,014 BRAINSTEM, IT'S CALLED THE 925 00:30:50,081 --> 00:30:51,249 NUCLEUS OF THE SOLITARY TRACT, 926 00:30:51,316 --> 00:30:53,318 SO THESE NEURONS ARE PART OF THE 927 00:30:53,384 --> 00:30:55,620 VAGUS NERVE. 928 00:30:55,687 --> 00:30:58,022 AND THEN THAT SIGNAL TRIGGERS A 929 00:30:58,089 --> 00:30:59,657 SERIES OF CHANGES IN THE HEART 930 00:30:59,724 --> 00:31:01,392 AND THE BLOOD VESSELS TO 931 00:31:01,459 --> 00:31:03,161 STABILIZE THE BLOOD PRESSURE. 932 00:31:03,228 --> 00:31:05,463 SO THE NEUROCIRCUIT IS ALSO 933 00:31:05,530 --> 00:31:06,431 QUITE WELL UNDERSTOOD. 934 00:31:06,497 --> 00:31:10,168 THERE ARE TWO PAIN PATHWAYS, IN 935 00:31:10,235 --> 00:31:12,437 ONE PATHWAY THE NUCLEUS OF THE 936 00:31:12,503 --> 00:31:14,739 SOLITARY TRACT, NST, PROVIDES 937 00:31:14,806 --> 00:31:18,243 EXCITATORY PROTECTION TO THE -- 938 00:31:18,309 --> 00:31:22,180 NUCLEUS, WHICH CONTAINS 939 00:31:22,247 --> 00:31:26,117 PREGANGLIONIC CHOLINERGIC 940 00:31:26,184 --> 00:31:27,752 NEURONS, PART OF THE 941 00:31:27,819 --> 00:31:28,586 PARASYMPATHETIC PATHWAY. 942 00:31:28,653 --> 00:31:29,988 THE OTHER BRANCH, THE SOLITARY 943 00:31:30,054 --> 00:31:35,026 TRACT, PROVIDES A GLUTE -- TO 944 00:31:35,093 --> 00:31:38,196 THIS REGION CALLED THE CVLN, 945 00:31:38,263 --> 00:31:40,031 CAUDAL VENTRAL LATERAL MEDULLA, 946 00:31:40,098 --> 00:31:43,534 AND THE VVLN CONTAINS GABERGIC 947 00:31:43,601 --> 00:31:47,905 NEURONS THAT INHIBIT THE RVLM, 948 00:31:47,972 --> 00:31:49,841 ROSTRAL VENTRAL LATERAL ME DID 949 00:31:49,907 --> 00:31:52,410 YOU TA, WHICH CONTAINS 950 00:31:52,477 --> 00:31:56,447 ADRENERGIC NEURONS PART OF THE 951 00:31:56,514 --> 00:31:57,315 PATHWAY. 952 00:31:57,382 --> 00:31:58,750 BASICALLY IN ONE BRANCH YOU 953 00:31:58,816 --> 00:32:00,318 EXCITE THE PARASYMPATHETIC 954 00:32:00,385 --> 00:32:01,719 PATHWAY AND IN THIS OTHER 955 00:32:01,786 --> 00:32:03,688 BRANCH, YOU INHIBIT THE 956 00:32:03,755 --> 00:32:04,455 SYMPATHETIC PATHWAY. 957 00:32:04,522 --> 00:32:08,159 SO THE FIRST THING THAT YUANYUAN 958 00:32:08,226 --> 00:32:12,230 DID IS TO IDENTIFY THE SUBSET 959 00:32:12,297 --> 00:32:13,564 INVOLVED IN CARDIOVASCULAR 960 00:32:13,631 --> 00:32:14,899 CONTROL, BECAUSE THE SOLITARY 961 00:32:14,966 --> 00:32:16,267 TRACT IS THE FIRST STOP OF THE 962 00:32:16,334 --> 00:32:18,569 VAGUS NERVE AND IT'S INVOLVED IN 963 00:32:18,636 --> 00:32:19,904 ALL THE INTERNAL SENSING. 964 00:32:19,971 --> 00:32:21,539 THE GODS, THE STOMACH, WHATEVER, 965 00:32:21,606 --> 00:32:22,573 SO THE LUNGS AND EVERYTHING. 966 00:32:22,640 --> 00:32:24,976 SO ONLY A SUBSET OF THE NEURONS 967 00:32:25,043 --> 00:32:25,743 ARE CARDIOVASCULAR. 968 00:32:25,810 --> 00:32:28,046 SO THE WAY THAT WE DID THAT WAS 969 00:32:28,112 --> 00:32:31,849 TO USE A FALSE TRACK DEVELOPED 970 00:32:31,916 --> 00:32:33,484 AT STANFORD SO I WON'T GO INTO 971 00:32:33,551 --> 00:32:35,787 THE DETAILS BUT BASICALLY WHAT 972 00:32:35,853 --> 00:32:39,957 UANUAN DID WAS TO INJECT THIS 973 00:32:40,024 --> 00:32:43,728 DRUG, YOU CAN SEE AS SOON AS WE 974 00:32:43,795 --> 00:32:45,496 DID INJECTION, YOU SEE IMMEDIATE 975 00:32:45,563 --> 00:32:46,564 INCREASE IN BLOOD PRESSURE AND 976 00:32:46,631 --> 00:32:50,501 ALSO DECREASE IN HEART RATE 977 00:32:50,568 --> 00:32:53,204 SO THIS INDICATES THE BAROREFLEX 978 00:32:53,271 --> 00:32:53,805 HAS KICKED IN. 979 00:32:53,871 --> 00:32:58,743 YOU CAN SEE AFTER PE INJECTION, 980 00:32:58,810 --> 00:33:01,913 YUANYUAN LABELED A LOT MORE -- 981 00:33:01,979 --> 00:33:03,781 THIS IS JUST SAYING THAT THE 982 00:33:03,848 --> 00:33:04,982 TRACK METHOD WORKS. 983 00:33:05,049 --> 00:33:07,719 AND THEN NEXT YUANYUAN WANTED TO 984 00:33:07,785 --> 00:33:09,687 MAKE SURE THE TRACK NEURONS ARE 985 00:33:09,754 --> 00:33:11,856 INDEED CARDIOVASCULAR, BECAUSE 986 00:33:11,923 --> 00:33:13,958 THE TRACK TECHNIQUE, THE 987 00:33:14,025 --> 00:33:15,593 SPECIFICITY DEPENDS ON THE CELL 988 00:33:15,660 --> 00:33:17,228 TYPE, THE REGION, SO YOU DO HAVE 989 00:33:17,295 --> 00:33:18,563 TO VALIDATE THAT FUNCTIONALLY. 990 00:33:18,629 --> 00:33:22,200 AGAIN THE WAY SHE DID THAT WAS 991 00:33:22,266 --> 00:33:25,370 TO -- WITH CHAN ELDOXIN AND 992 00:33:25,436 --> 00:33:27,572 IDENTIFIED THEM WITH 993 00:33:27,638 --> 00:33:28,005 OPTORECORDING. 994 00:33:28,072 --> 00:33:29,107 HERE'S AN EXAMPLE, THE MOUSE WAS 995 00:33:29,173 --> 00:33:31,609 AGAIN RUNNING AROUND IN HIS HOME 996 00:33:31,676 --> 00:33:33,478 CAGE DOING WHATEVER HE WANTED. 997 00:33:33,544 --> 00:33:35,079 YOU CAN SEE THE HEART RATE AND 998 00:33:35,146 --> 00:33:36,447 BLOOD PRESSURE SORT OF FLUCTUATE 999 00:33:36,514 --> 00:33:37,448 DEPENDING ON WHAT THE MICE WERE 1000 00:33:37,515 --> 00:33:39,083 DOING. 1001 00:33:39,150 --> 00:33:40,151 AND HERE'S ONE IDENTIFIED CELL, 1002 00:33:40,218 --> 00:33:42,920 YOU CAN SEE THE FIRING RATE 1003 00:33:42,987 --> 00:33:45,556 ACTUALLY TRACKS THE UPS AND 1004 00:33:45,623 --> 00:33:46,457 DOWNS OF THE BLOOD PRESSURE 1005 00:33:46,524 --> 00:33:47,859 QUITE WELL. 1006 00:33:47,925 --> 00:33:52,663 AND WHEN WE ZOOM TEMPORALLY, WE 1007 00:33:52,730 --> 00:33:54,966 ACTUALLY FOUND A SUBSET OF THE 1008 00:33:55,032 --> 00:33:57,034 NEURONS, THEIR SPIKING IS TIME 1009 00:33:57,101 --> 00:33:58,035 LOCKED TO INDIVIDUAL HEART 1010 00:33:58,102 --> 00:33:59,237 BEATS. 1011 00:33:59,303 --> 00:34:00,571 SO THAT SUGGESTS TO US THAT 1012 00:34:00,638 --> 00:34:01,806 THESE NEURONS ARE ACTUALLY 1013 00:34:01,873 --> 00:34:04,709 SENSITIVE TO THE BLOOD PRESSURE 1014 00:34:04,776 --> 00:34:05,877 FLUCTUATIONS IN INDIVIDUAL 1015 00:34:05,943 --> 00:34:08,780 CARDIAC CYCLES. 1016 00:34:08,846 --> 00:34:10,648 SO ALL OF THESE ARE JUST SAYING 1017 00:34:10,715 --> 00:34:12,183 THAT THE TRAP TECHNIQUE KIND OF 1018 00:34:12,250 --> 00:34:13,584 WORKED QUITE WELL IN THIS METHOD 1019 00:34:13,651 --> 00:34:14,585 AND NEURONS THAT WE HAVE LABELED 1020 00:34:14,652 --> 00:34:17,088 ARE INDEED CARDIOVASCULAR. 1021 00:34:17,155 --> 00:34:18,156 SO NEXT THE QUESTION IS WHAT 1022 00:34:18,222 --> 00:34:19,624 HAPPENS IF WE ACTIVATE THESE 1023 00:34:19,690 --> 00:34:20,258 CELLS? 1024 00:34:20,324 --> 00:34:23,928 SO THIS IS OUR STANDARD PROTOCOL 1025 00:34:23,995 --> 00:34:26,731 IN MY LAB AS I MENTIONED, WE 1026 00:34:26,798 --> 00:34:29,133 TURN ON LASER FOR 2 MINUTES PER 1027 00:34:29,200 --> 00:34:30,735 TRIAL, AND INTERVAL WAS ABOUT 10 1028 00:34:30,802 --> 00:34:32,770 MINUTES OR SO, SO THE BLUE 1029 00:34:32,837 --> 00:34:35,706 SHADING INDICATES OPTOGENETIC 1030 00:34:35,773 --> 00:34:36,007 STIMULATION. 1031 00:34:36,073 --> 00:34:37,241 HERE'S THE POPULATION AVERAGE. 1032 00:34:37,308 --> 00:34:38,676 SO AS SOON AS WE TURN ON THE 1033 00:34:38,743 --> 00:34:40,011 LASER, WITHIN A COUPLE SECONDS, 1034 00:34:40,077 --> 00:34:42,413 YOU SEE A DRAMATIC DEGREECE IN 1035 00:34:42,480 --> 00:34:46,651 BLOOD PDE --DECREASE IN BLOOD PD 1036 00:34:46,717 --> 00:34:48,453 ALSO HEART RATE, CONSISTENT WITH 1037 00:34:48,519 --> 00:34:52,190 THE FACT THAT THESE ARE 1038 00:34:52,256 --> 00:34:52,757 CARDIOVASCULAR, BY DESIGN. 1039 00:34:52,824 --> 00:34:56,461 IN ADDITION WE SAW A SLOW BUT 1040 00:34:56,527 --> 00:34:57,795 CONSISTENT INCREASE IN NON-REM 1041 00:34:57,862 --> 00:34:58,196 SLEEP. 1042 00:34:58,262 --> 00:34:59,630 SO NEXT WE LOOKED AT THE 1043 00:34:59,697 --> 00:35:00,631 DOWNSTREAM TARGETS OF THESE 1044 00:35:00,698 --> 00:35:01,165 CELLS. 1045 00:35:01,232 --> 00:35:05,336 WHEN WE ACTIVATED THE CVLM 1046 00:35:05,403 --> 00:35:07,305 GABERGIC NEURONS, IT ALSO 1047 00:35:07,371 --> 00:35:08,306 INCREASED NON-RECOMMEND SLEEP 1048 00:35:08,372 --> 00:35:10,475 AND WE THINK THIS EFFECT IS 1049 00:35:10,541 --> 00:35:12,477 PARTLY MEDIATED BY THEIR 1050 00:35:12,543 --> 00:35:14,979 INHIBITION OF THE RVLM NEURONS 1051 00:35:15,046 --> 00:35:17,081 BECAUSE DIRECT OPT GENOMIC 1052 00:35:17,148 --> 00:35:20,785 INACTIVATION OF THE RVLM 1053 00:35:20,852 --> 00:35:22,553 ADRENERGIC NEURONS ALSO CAUSE AN 1054 00:35:22,620 --> 00:35:23,754 INCREASE IN SLEEP. 1055 00:35:23,821 --> 00:35:25,356 CONVERSELY WHEN WE INACTIVATED 1056 00:35:25,423 --> 00:35:30,428 THE CVLM, WE SAW INCREASE IN 1057 00:35:30,495 --> 00:35:31,963 WAKEFULNESS AND THE SAME IS TRUE 1058 00:35:32,029 --> 00:35:34,065 IF WE ACTIVATE RVLM. 1059 00:35:34,131 --> 00:35:35,500 THIS LAST EXPERIMENT WAS REALLY 1060 00:35:35,566 --> 00:35:36,701 JUST A REPETITION OF AN 1061 00:35:36,767 --> 00:35:37,802 EXPERIMENT PUBLISHED WAY BEFORE 1062 00:35:37,869 --> 00:35:39,237 WE GOT INTO THIS FIELD. 1063 00:35:39,303 --> 00:35:46,344 SO THIS WAS PUBLISHED BY PATRICE 1064 00:35:46,410 --> 00:35:48,446 GYNES LAB SPECIALIZING IN THE 1065 00:35:48,513 --> 00:35:49,780 SYMPATHETIC NERVOUS SYSTEM. 1066 00:35:49,847 --> 00:35:52,083 THEY SHOWED THIS ALSO WAKES UP 1067 00:35:52,149 --> 00:35:53,484 THE ANIMAL AND THAT EFFECT IS 1068 00:35:53,551 --> 00:35:55,453 PARTLY MEDIATED BY THE 1069 00:35:55,520 --> 00:35:56,654 EXCITATORY PROTECTION FROM THESE 1070 00:35:56,721 --> 00:35:58,556 CELLS TO THE LOCUST JULIUS, 1071 00:35:58,623 --> 00:36:00,525 WHICH IS INVOLVED IN WAKING UP 1072 00:36:00,591 --> 00:36:05,463 THE BRAIN. 1073 00:36:05,530 --> 00:36:05,997 THAT'S ONE PATHWAY. 1074 00:36:06,063 --> 00:36:07,198 WE ALSO LOOKED AT THIS OTHER 1075 00:36:07,265 --> 00:36:11,035 PATHWAY BY DIRECTLY ACTIVATING 1076 00:36:11,102 --> 00:36:12,537 THE CHOLINERGIC NEURONS, KNOWN 1077 00:36:12,603 --> 00:36:14,105 TO BE PARASYMPATHETIC. 1078 00:36:14,171 --> 00:36:16,607 WHEN WE ACTIVATED THESE CELLS 1079 00:36:16,674 --> 00:36:20,678 CHEMO GENETICALLY IN ADDITION TO 1080 00:36:20,745 --> 00:36:23,281 DECREASE IN HEART RATE WE ALSO 1081 00:36:23,347 --> 00:36:28,786 SAALSO -- THESE NEURONS ALSO 1082 00:36:28,853 --> 00:36:29,754 MOONLIGHT IN SLEEP CONTROL. 1083 00:36:29,820 --> 00:36:32,723 SO THEY HAVE A SECONDARY JOB IN 1084 00:36:32,790 --> 00:36:34,292 CONTROLLING BEHAVIOR AND BRAIN 1085 00:36:34,358 --> 00:36:36,594 STATES. 1086 00:36:36,661 --> 00:36:37,094 OKAY. 1087 00:36:37,161 --> 00:36:39,530 JUST TO SUM UP THIS PART, AS I 1088 00:36:39,597 --> 00:36:41,065 MENTIONED AT THE BEGINNING, 1089 00:36:41,132 --> 00:36:42,500 FALLING ASLEEP IS ASSOCIATED 1090 00:36:42,567 --> 00:36:46,304 WITH REDUCTIONS IN BRAIN AROUSAL 1091 00:36:46,370 --> 00:36:48,706 AND ALSO SOMATIC AND AUTONOMIC 1092 00:36:48,773 --> 00:36:51,042 MOTOR ACTIVITY. 1093 00:36:51,108 --> 00:36:52,577 SO JUST LOGICALLY IT KIND OF 1094 00:36:52,643 --> 00:36:53,644 MAKES SENSE FOR THE SLEEP 1095 00:36:53,711 --> 00:36:55,813 CONTROL MECHANISM TO INHIBIT ALL 1096 00:36:55,880 --> 00:36:58,149 THREE SYSTEMS, RIGHT? 1097 00:36:58,215 --> 00:37:00,885 BRAIN AROUSAL, AUTONOMIC AND 1098 00:37:00,952 --> 00:37:02,186 SOMATIC MOTOR SYSTEMS. 1099 00:37:02,253 --> 00:37:03,754 NOW FOR THE SOMATIC MOTOR 1100 00:37:03,821 --> 00:37:07,892 SYSTEM, I SHOWED YOU THE DATA ON 1101 00:37:07,959 --> 00:37:09,427 THE SDN -- EVEN THOUGH MY LAB 1102 00:37:09,493 --> 00:37:13,064 DID NOT LOOK AT THE STRIATUM, 1103 00:37:13,130 --> 00:37:14,699 OTHERS HAVE SHOWN THAT IN BOTH 1104 00:37:14,765 --> 00:37:18,536 THE DORSAL STRIATUM AND VENTRAL 1105 00:37:18,603 --> 00:37:20,538 STRIATUM ALSO CALLED THE NUCLEUS 1106 00:37:20,605 --> 00:37:22,707 ACCUMBENS, THE NEURONS, MEDIUM 1107 00:37:22,773 --> 00:37:25,876 SPIKING NEURONS THAT EXPRESS THE 1108 00:37:25,943 --> 00:37:28,946 DOPAMINE RECEPTORS, THOUGH 1109 00:37:29,013 --> 00:37:29,947 INDUCES NON-REM SLEEP. 1110 00:37:30,014 --> 00:37:31,148 AND OF COURSE BASED ON DECADES 1111 00:37:31,215 --> 00:37:33,718 OF STUDIES IN THE BASAL GANGLIA, 1112 00:37:33,784 --> 00:37:36,187 WE KNOW ACTIVATION OF THE 1113 00:37:36,253 --> 00:37:37,588 DRD2 NEURONS IN THE STRIATUM CAN 1114 00:37:37,655 --> 00:37:39,924 LEAD TO THE ACTIVATION OF THE 1115 00:37:39,991 --> 00:37:42,460 STN AND SNR NEURONS THAT WE HAVE 1116 00:37:42,526 --> 00:37:43,995 STUDIED THROUGH THE SO-CALLED 1117 00:37:44,061 --> 00:37:44,795 INDIRECT PATHWAY. 1118 00:37:44,862 --> 00:37:47,164 SO THE DIRECT PATHWAY/INDIRECT 1119 00:37:47,231 --> 00:37:50,701 PATHWAY, THAT'S LIKE THE CLASSIC 1120 00:37:50,768 --> 00:37:51,569 BASAL GANGLIA STUFF. 1121 00:37:51,636 --> 00:37:52,436 SO EVERYTHING MAKES SENSE. 1122 00:37:52,503 --> 00:37:53,971 AND IT ALSO SHOWS THAT EVEN 1123 00:37:54,038 --> 00:37:55,406 THOUGH THERE ARE A LOT OF 1124 00:37:55,473 --> 00:37:57,274 POPULATIONS OF SLEEP NEURONS, 1125 00:37:57,341 --> 00:37:58,042 THEY'RE NOT INDEPENDENT. 1126 00:37:58,109 --> 00:38:04,048 THEY'RE REALLY INTERCOULD NCTEDD 1127 00:38:04,115 --> 00:38:05,216 WITH EACH OTHER. 1128 00:38:05,282 --> 00:38:07,718 IN THE VENTRAL MEDULLA, THERE'S 1129 00:38:07,785 --> 00:38:09,620 A POPULATION OF INHIBITORY 1130 00:38:09,687 --> 00:38:10,488 NEURONS, IF YOU ACTIVATE THOSE, 1131 00:38:10,554 --> 00:38:12,990 THE MICE, IF THEY'RE MOVING, YOU 1132 00:38:13,057 --> 00:38:14,025 ACTIVATE THEM, THEY STOP MOVING. 1133 00:38:14,091 --> 00:38:16,227 IN FACT, THEIR BODY COLLAPSES 1134 00:38:16,293 --> 00:38:17,395 BECAUSE THEY LOSE THEIR MUSCLE 1135 00:38:17,461 --> 00:38:17,928 TONE. 1136 00:38:17,995 --> 00:38:19,597 SO HER LAB IS A MOTOR LAB, AND 1137 00:38:19,664 --> 00:38:20,798 THAT'S WHAT THEY FIND. 1138 00:38:20,865 --> 00:38:23,968 IN MY LAB, WE ALSO FOUND THAT 1139 00:38:24,035 --> 00:38:26,303 THAT POPULATION INDUCES SLEEP 1140 00:38:26,370 --> 00:38:27,605 BECAUSE WE MEASURE THE EEG. 1141 00:38:27,672 --> 00:38:29,573 SO ANOTHER EXAMPLE THAT YOU'RE 1142 00:38:29,640 --> 00:38:30,441 IN DIFFERENT FIELD AND YOU SORT 1143 00:38:30,508 --> 00:38:32,777 OF MAKE THESE DIFFERENT CLAIMS 1144 00:38:32,843 --> 00:38:34,412 BUT VERY OFTEN THEY'RE ACTUALLY 1145 00:38:34,478 --> 00:38:35,179 REALLY CONNECTED TO EACH OTHER. 1146 00:38:35,246 --> 00:38:37,381 SO AGAIN, ANOTHER EXAMPLE OF THE 1147 00:38:37,448 --> 00:38:40,117 CLOSE RELATIONSHIP BETWEEN MOTOR 1148 00:38:40,184 --> 00:38:42,620 CONTROL AND SLEEP CONTROL. 1149 00:38:42,687 --> 00:38:44,822 NOW, FOR THE AUTONOMIC NERVOUS 1150 00:38:44,889 --> 00:38:47,358 SYSTEM, I SHOWED YOU THE DATA 1151 00:38:47,425 --> 00:38:49,860 SHOWING THERE ARE SLEEP NEURONS 1152 00:38:49,927 --> 00:38:53,364 IN THE SOLITARY TRACT, BUT WE 1153 00:38:53,431 --> 00:38:57,334 ALSO FOUND SLEEP NEURONS IN THE 1154 00:38:57,401 --> 00:38:59,170 PERIAQUEDUCTAL GREY, THE AMIGD 1155 00:38:59,236 --> 00:39:03,140 AMYGDALA AND OF COURSE THE 1156 00:39:03,207 --> 00:39:03,741 HYPOTHALAMUS. 1157 00:39:03,808 --> 00:39:07,078 THERE ARE SUBSETS THAT ALSO 1158 00:39:07,144 --> 00:39:07,845 PROMOTE SLEEP. 1159 00:39:07,912 --> 00:39:09,413 SO NOW GIVEN ALL THESE SLEEP 1160 00:39:09,480 --> 00:39:11,048 NEURONS IN THE FOREBRAIN, 1161 00:39:11,115 --> 00:39:13,651 MIDBRAIN AND HINDBRAIN, IN BOTH 1162 00:39:13,718 --> 00:39:16,220 THE AUTONOMIC AND SOMATIC MOTOR 1163 00:39:16,287 --> 00:39:18,289 CIRCLES, IT SEEMS THAT THIS 1164 00:39:18,355 --> 00:39:19,924 TEXTBOOK MODEL WITH A SINGLE 1165 00:39:19,990 --> 00:39:23,327 SLEEP CENTER IS REALLY QUITE 1166 00:39:23,394 --> 00:39:24,328 INADEQUATE. 1167 00:39:24,395 --> 00:39:26,397 INSTEAD IN THE MAMMALIAN BRAIN, 1168 00:39:26,464 --> 00:39:28,265 SLEEP IS REALLY CONTROLLED BY 1169 00:39:28,332 --> 00:39:29,266 MULTIPLE INTERCONNECTED 1170 00:39:29,333 --> 00:39:32,536 POPULATIONS OF NEURONS THAT ARE 1171 00:39:32,603 --> 00:39:34,605 BASICALLY INFILTRATING EVERY 1172 00:39:34,672 --> 00:39:36,474 LEVEL OF THE SOMATIC AND 1173 00:39:36,540 --> 00:39:37,475 AUTONOMIC MOTOR CONTROL 1174 00:39:37,541 --> 00:39:39,810 NETWORKS. 1175 00:39:39,877 --> 00:39:42,079 IN FACT I WOULD EVEN GO ON AND 1176 00:39:42,146 --> 00:39:43,147 SPECULATE A LITTLE BIT, THIS IS 1177 00:39:43,214 --> 00:39:44,281 THE PART I MIGHT GET INTO 1178 00:39:44,348 --> 00:39:44,615 TROUBLE. 1179 00:39:44,682 --> 00:39:46,250 I ACTUALLY THINK THAT FOR 1180 00:39:46,317 --> 00:39:47,885 ANIMALS WITH RELATIVELY SIMPLE 1181 00:39:47,952 --> 00:39:50,654 NERVOUS SYSTEMS, SLEAP IS 1182 00:39:50,721 --> 00:39:52,723 PROBABLY PRIMARILY ABOUT 1183 00:39:52,790 --> 00:39:54,592 SUPPRESSING MOTOR ACTIVITY FOR 1184 00:39:54,658 --> 00:39:55,559 WHATEVER REASON. 1185 00:39:55,626 --> 00:39:57,528 IT'S ONLY FOR ANIMALS WITH MORE 1186 00:39:57,595 --> 00:39:59,096 COMPLEX BRAINS LIKE US, THIS 1187 00:39:59,163 --> 00:40:01,265 KIND OF REDUCTION OF BRAIN 1188 00:40:01,332 --> 00:40:02,266 AROUSAL BECOMES MORE IMPORTANT, 1189 00:40:02,333 --> 00:40:05,035 AND FOR THOSE ANIMALS, BRAIN 1190 00:40:05,102 --> 00:40:07,671 STATES AND MOTOR STATES CAN BE 1191 00:40:07,738 --> 00:40:08,873 COORDINATED BY COLLATERAL 1192 00:40:08,939 --> 00:40:11,375 INNOVATION BY THE SAME SLEEP 1193 00:40:11,442 --> 00:40:13,277 NEURONS THAT KIND OF CONTROL 1194 00:40:13,344 --> 00:40:15,579 BOTH MOTOR ACTIVITY AND BRAIN 1195 00:40:15,646 --> 00:40:17,314 STATES TOGETHER, AND AS WE 1196 00:40:17,381 --> 00:40:20,584 SHOWED IN THE SNR NEURONS. 1197 00:40:20,651 --> 00:40:22,253 OKAY. 1198 00:40:22,319 --> 00:40:23,821 SO NOW I FEEL LIKE WE HAVE A 1199 00:40:23,888 --> 00:40:26,423 PRETTY GOOD HA HANDLE ON THE HOW 1200 00:40:26,490 --> 00:40:26,891 QUESTION. 1201 00:40:26,957 --> 00:40:28,092 I'M SURE THERE ARE A LOT MORE 1202 00:40:28,159 --> 00:40:29,627 DETAILS TO BE FIGURED OUT, 1203 00:40:29,693 --> 00:40:31,262 BECAUSE THESE DIAGRAMS ARE VERY 1204 00:40:31,328 --> 00:40:34,031 CRUDE, RIGHT? 1205 00:40:34,098 --> 00:40:34,799 THERE'S A LOT MORE CIRCUIT 1206 00:40:34,865 --> 00:40:36,667 MAPPING TO BE DONE BUT I SORT OF 1207 00:40:36,734 --> 00:40:38,202 FEEL LIKE WE UNDERSTAND THE 1208 00:40:38,269 --> 00:40:39,737 GENERAL LOGIC OF THE SLEEP 1209 00:40:39,804 --> 00:40:40,304 CONTROL MECHANISM. 1210 00:40:40,371 --> 00:40:41,639 SO WE HAVE SWITCHED OUR 1211 00:40:41,705 --> 00:40:44,341 ATTENTION TO THE WHY QUESTION. 1212 00:40:44,408 --> 00:40:46,544 NOW, WE KNOW THAT SLEEP 1213 00:40:46,610 --> 00:40:49,413 DEPRIVATION CAUSES A LOT OF 1214 00:40:49,480 --> 00:40:49,747 PROBLEMS. 1215 00:40:49,814 --> 00:40:51,515 IN THE BRAIN WE KNOW THAT IT 1216 00:40:51,582 --> 00:40:54,785 CAUSES IMPAIRMENTS OF 1217 00:40:54,852 --> 00:40:57,188 DECISION-MAKING, LEARNING AND 1218 00:40:57,254 --> 00:40:58,622 MEMORY, MEMORY CONSOLIDATION, IT 1219 00:40:58,689 --> 00:41:00,257 PROBABLY SLOWS DOWN WASTE 1220 00:41:00,324 --> 00:41:02,493 COLLECTION THROUGH THE LYMPHATIC 1221 00:41:02,560 --> 00:41:05,763 SYSTEM, IN ADDITION TO COGNITIVE 1222 00:41:05,830 --> 00:41:07,431 AND EMOTIONAL IMPAIRMENT, IT 1223 00:41:07,498 --> 00:41:09,400 CAUSES CARDIOVASCULAR DISEASE, 1224 00:41:09,466 --> 00:41:11,936 HORMONE IMBALANCES, IMMUNE 1225 00:41:12,002 --> 00:41:12,803 PROBLEMS, EVERYTHING, RIGHT? 1226 00:41:12,870 --> 00:41:15,973 SO THAT REALLY INDICATES THAT 1227 00:41:16,040 --> 00:41:17,107 SLEEP BENEFITS ALL OF THESE 1228 00:41:17,174 --> 00:41:18,175 DIFFERENT SYSTEMS. 1229 00:41:18,242 --> 00:41:22,780 BUT HERE IS THE BIG QUESTION. 1230 00:41:22,847 --> 00:41:25,216 DOES SLEEP SUPPORT MULTIPLE 1231 00:41:25,282 --> 00:41:26,417 INDEPENDENT PROCESSES? 1232 00:41:26,483 --> 00:41:28,819 MAYBE EACH UNDERLIE A DIFFERENT 1233 00:41:28,886 --> 00:41:29,386 FUNCTION. 1234 00:41:29,453 --> 00:41:32,122 WE KNOW THERE ARE MULTIPLE 1235 00:41:32,189 --> 00:41:35,759 FUNCTIONS, SOME INSIDE, EACH 1236 00:41:35,826 --> 00:41:37,061 DEPENDS ON THE DIFFERENT PROCESS 1237 00:41:37,127 --> 00:41:38,929 SUPPORTED BY SLEEP, OR IS THERE 1238 00:41:38,996 --> 00:41:40,598 A SINGLE FUNDAMENTAL PROCESS 1239 00:41:40,664 --> 00:41:41,899 THAT UNDERLIES ALL THESE 1240 00:41:41,966 --> 00:41:44,401 DIFFERENT EFFECTS? 1241 00:41:44,468 --> 00:41:47,805 SO THINK ABOUT FEEDING. 1242 00:41:47,872 --> 00:41:49,540 IF YOU'RE FOOD-DEPRIVED FOR 1243 00:41:49,607 --> 00:41:50,574 THREE DAYS, I CAN PROMISE YOU 1244 00:41:50,641 --> 00:41:51,675 IT'S PROBABLY NOT GOING TO KILL 1245 00:41:51,742 --> 00:41:52,977 YOU. 1246 00:41:53,043 --> 00:41:54,211 BUT YOU'RE GOING TO HAVE A LOT 1247 00:41:54,278 --> 00:41:54,645 OF PROBLEMS. 1248 00:41:54,712 --> 00:41:56,747 SOME OF THEM MIGHT EVEN BE 1249 00:41:56,814 --> 00:41:57,014 COGNITIVE. 1250 00:41:57,081 --> 00:41:58,582 IN FACT, I KNOW FROM MY OWN 1251 00:41:58,649 --> 00:42:01,685 EXPERIENCE, I SKIPPED BREAKFAST 1252 00:42:01,752 --> 00:42:04,088 FOR MORE SLEEP, BUT IF I DIDN'T 1253 00:42:04,154 --> 00:42:07,157 MUNCH THE BARS ARIEL GAVE ME, I 1254 00:42:07,224 --> 00:42:09,693 WOULD PROBABLY BE VERY 1255 00:42:09,760 --> 00:42:10,895 COGNITIVELY IMPAIRED TO GIVE 1256 00:42:10,961 --> 00:42:11,762 THIS TALK. 1257 00:42:11,829 --> 00:42:12,463 RIGHT? 1258 00:42:12,529 --> 00:42:14,365 AND YET WE WOULDN'T CONCLUDE 1259 00:42:14,431 --> 00:42:16,066 THAT FEEDING IS FOR COGNITION. 1260 00:42:16,133 --> 00:42:18,602 WE KNOW FEEDING HAS A SINGLE 1261 00:42:18,669 --> 00:42:19,737 FUNDAMENTAL PURPOSE, WHICH IS 1262 00:42:19,803 --> 00:42:21,906 THE INTAKE OF ENERGY AND 1263 00:42:21,972 --> 00:42:23,207 NUTRIENTS, AND YET IF YOU DO 1264 00:42:23,274 --> 00:42:24,408 FOOD DEPRIVATION, YOU HAVE MANY 1265 00:42:24,475 --> 00:42:25,476 PROBLEMS. 1266 00:42:25,542 --> 00:42:25,676 RIGHT? 1267 00:42:25,743 --> 00:42:28,779 SO THE QUESTION IS, IS THERE 1268 00:42:28,846 --> 00:42:29,813 SOMETHING SIMILARLY BASIC FOR 1269 00:42:29,880 --> 00:42:30,247 SLEEP? 1270 00:42:30,314 --> 00:42:32,549 AND IF SO, WHAT COULD THAT BE? 1271 00:42:32,616 --> 00:42:34,218 SO WE DON'T HAVE THE ANSWER TO 1272 00:42:34,285 --> 00:42:37,087 THAT YET, BUT I HAVE A 1273 00:42:37,154 --> 00:42:38,489 HYPOTHESIS. 1274 00:42:38,555 --> 00:42:41,225 SO THAT'S THAT INACTIVATION OF 1275 00:42:41,292 --> 00:42:45,529 CATECHOLAMINE INCLUDING DOPAM 1276 00:42:45,596 --> 00:42:48,365 DOPAMINE, NEUROADREN LEAN AND 1277 00:42:48,432 --> 00:42:50,334 ADREN LEAN SIGNALING MIGHT BE AN 1278 00:42:50,401 --> 00:42:53,871 UNDERLYING PROCESS UNDERLYING 1279 00:42:53,938 --> 00:42:54,805 MULTIPLE ASPECTS OF SLEEP. 1280 00:42:54,872 --> 00:42:56,573 SO WE FOCUSED ON CATECHOLAMINE 1281 00:42:56,640 --> 00:42:57,408 FOR SEVERAL REASONS. 1282 00:42:57,474 --> 00:42:58,909 FIRST IN ADDITION TO BRAIN 1283 00:42:58,976 --> 00:43:00,010 AROUSAL, WE KNOW THAT THEY 1284 00:43:00,077 --> 00:43:01,445 DEFINITELY REGULATE BRAIN 1285 00:43:01,512 --> 00:43:02,413 AROUSAL BIG TIME. 1286 00:43:02,479 --> 00:43:04,715 THEY ALSO REGULATE SOMATIC AND 1287 00:43:04,782 --> 00:43:06,717 AUAUTONOMIC MOTOR ACTIVITY. 1288 00:43:06,784 --> 00:43:08,052 WE KNOW HOW IMPORTANT DOPAMINE 1289 00:43:08,118 --> 00:43:10,688 IS FOR SOMATIC MOTOR ACTIVITY IN 1290 00:43:10,754 --> 00:43:10,854 PD. 1291 00:43:10,921 --> 00:43:17,561 WE ALSO KNOW THAT NEURO 1292 00:43:17,628 --> 00:43:20,431 ADRENALINE -- IN ADDITION TO 1293 00:43:20,497 --> 00:43:23,067 NEURONS IN MUSCLES, 1294 00:43:23,133 --> 00:43:24,835 CATECHOLAMINE SIGNALING ALSO 1295 00:43:24,902 --> 00:43:25,703 REGULATES METABOLISM AND 1296 00:43:25,769 --> 00:43:27,371 REGULATING THE IMMUNE SYSTEM SO 1297 00:43:27,438 --> 00:43:31,742 THIS COULD POTENTIALLY EXPLAIN A 1298 00:43:31,809 --> 00:43:38,182 WIDE RANGE OF SLEEP DEPRIVATION. 1299 00:43:38,248 --> 00:43:39,216 -- BETWEEN THE FUNCTIONS AND 1300 00:43:39,283 --> 00:43:40,417 BENEFITS OF SLEEP AND OUR 1301 00:43:40,484 --> 00:43:41,952 NATURAL DESIRE AND DRIVE FOR 1302 00:43:42,019 --> 00:43:42,953 SLEEP. 1303 00:43:43,020 --> 00:43:45,589 SO TODAY, I'M JUST GOING TO GIVE 1304 00:43:45,656 --> 00:43:47,224 YOU ONE EXAMPLE OF HOW SLEEP IPT 1305 00:43:47,291 --> 00:43:54,598 ACTS INTERACTS WITH THE IMMUNE M 1306 00:43:54,665 --> 00:43:56,667 THROUGH -- SO WE FIRST FOCUSED 1307 00:43:56,734 --> 00:43:58,902 ON MICROGLIA, THE RESIDENT 1308 00:43:58,969 --> 00:43:59,670 IMMUNE CELLS IN THE BRAIN. 1309 00:43:59,737 --> 00:44:03,841 WE KNOW WHEN THERE'S DISEASE AND 1310 00:44:03,907 --> 00:44:07,211 INJURY, THEY SWITCH TO DEFENSE 1311 00:44:07,277 --> 00:44:09,413 MODE, BUT IN A NORMAL HEALTHY 1312 00:44:09,480 --> 00:44:11,281 BRAIN, THEIR MAIN JOB REALLY IS 1313 00:44:11,348 --> 00:44:13,917 TO MAINTAIN BRAIN HOMEOSTASIS. 1314 00:44:13,984 --> 00:44:17,187 AND WE KNOW THAT ONE OF THE MOST 1315 00:44:17,254 --> 00:44:20,491 IMPORTANT MARKERS FOR 1316 00:44:20,557 --> 00:44:26,196 HOMEOSTATIC MICROGLIA IS P I2Y12 1317 00:44:26,263 --> 00:44:28,532 ACTIVATED BY ATP AND ADP 1318 00:44:28,599 --> 00:44:30,501 RELEASED BY NEURONS AND AS CROW 1319 00:44:30,567 --> 00:44:35,439 SIASTROCYTES, TO DECIDE HOW TO 1320 00:44:35,506 --> 00:44:36,974 REACT ACCORDINGLY TO MAINTAIN A 1321 00:44:37,041 --> 00:44:37,474 BALANCE IN THE BRAIN. 1322 00:44:37,541 --> 00:44:38,909 SO THE FIRST EXPERIMENT WE DID 1323 00:44:38,976 --> 00:44:43,814 WAS TO MANIPULATE P2Y12. 1324 00:44:43,881 --> 00:44:47,584 SINCE IT IS A GI COUPLED GPCR, 1325 00:44:47,651 --> 00:44:48,986 THE FIRST EXPERIMENT THEY DID 1326 00:44:49,053 --> 00:44:51,955 WAS TO MANIPULATE MICROGLIA 1327 00:44:52,022 --> 00:44:55,826 CHEMO GENETICALLY USING GIDRED 1328 00:44:55,893 --> 00:44:57,461 SO THEY CROSS THIS HAD SPECIFIC 1329 00:44:57,528 --> 00:45:01,432 DRIVER LINE WITH GIDREADD AND 1330 00:45:01,498 --> 00:45:03,600 THAT ALLOWED US TO LABEL 1331 00:45:03,667 --> 00:45:05,035 MICROGLIA VERY SPECIFICALLY AND 1332 00:45:05,102 --> 00:45:08,105 EFFECTIVELY, ALMOST 100%. 1333 00:45:08,172 --> 00:45:10,207 SO HERE ARE JUST SOME EXAMPLE 1334 00:45:10,274 --> 00:45:10,974 RECORDING EXPERIMENTS. 1335 00:45:11,041 --> 00:45:13,710 WE MEASURED EEG, EMG AND THIS IS 1336 00:45:13,777 --> 00:45:15,279 THE COLOR-CODED BRAIN STATE AND 1337 00:45:15,345 --> 00:45:16,280 HERE'S A POPULATION SUMMARY. 1338 00:45:16,346 --> 00:45:19,550 SO BASICALLY YOU CNO INDUCED 1339 00:45:19,616 --> 00:45:21,785 ACTIVATION OF GI SIGNALING IN 1340 00:45:21,852 --> 00:45:25,189 MICROGLIA CAUSED AN INCREASE IN 1341 00:45:25,255 --> 00:45:26,623 NON-REM SLEEP AND DECREASE IN 1342 00:45:26,690 --> 00:45:28,258 WAKEFULNESS COMPARED TO 1343 00:45:28,325 --> 00:45:29,359 SIGNALING CONTROL. 1344 00:45:29,426 --> 00:45:32,629 WE ALSO DID INACTIVATION OF 1345 00:45:32,696 --> 00:45:35,599 P2Y12 BY INFUSING AN ANTAGONIST, 1346 00:45:35,666 --> 00:45:37,734 AND THAT CAUSED THE OPPOSITE 1347 00:45:37,801 --> 00:45:38,068 EFFECT. 1348 00:45:38,135 --> 00:45:39,770 AND SO WE THINK THAT THIS 1349 00:45:39,837 --> 00:45:41,738 ANTAGONIST SHOULD ONLY AFFECT 1350 00:45:41,805 --> 00:45:43,273 MICROGLIA DIRECTLY IN THE BRAIN, 1351 00:45:43,340 --> 00:45:45,008 BECAUSE WE KNOW THAT WITHIN THE 1352 00:45:45,075 --> 00:45:47,678 CNS, THE CENTRAL NERVOUS SYSTEM, 1353 00:45:47,744 --> 00:45:49,880 P2Y12 IS ONLY EXPRESSED IN 1354 00:45:49,947 --> 00:45:51,115 MICROGLIA AND NOT THE ONLY CELL 1355 00:45:51,181 --> 00:45:53,283 TYPES. 1356 00:45:53,350 --> 00:45:58,755 SO WE ALL KNOW THAT GI, IS TO 1357 00:45:58,822 --> 00:46:02,626 DECREASE CYCLIC EMP BUT THERE'S 1358 00:46:02,693 --> 00:46:04,695 A NON-CANONICAL PATHWAY THAT 1359 00:46:04,761 --> 00:46:05,562 INCREASES CALCIUM, PEOPLE HAVE 1360 00:46:05,629 --> 00:46:07,030 SHOWN THIS IN VITRO BEFORE. 1361 00:46:07,097 --> 00:46:09,633 SO THE ROLE OF CALCIUM SIGNALING 1362 00:46:09,700 --> 00:46:11,068 IN MICROGLIA FUNCTION HAS BEEN 1363 00:46:11,135 --> 00:46:13,170 KIND OF UNDERSTUDIED BUT IT'S 1364 00:46:13,237 --> 00:46:15,372 GETTING A LOT MO MORE ATTENTIONN 1365 00:46:15,439 --> 00:46:15,806 RECENT YEARS. 1366 00:46:15,873 --> 00:46:17,441 SO THE NEXT THING WE DID WAS TO 1367 00:46:17,508 --> 00:46:20,644 DO CALCIUM IMAGING IN VIVO BY 1368 00:46:20,711 --> 00:46:22,846 CROSSING THIS GC ACH M REPORTING 1369 00:46:22,913 --> 00:46:27,251 LINE INTO THE MICROGLIA 1370 00:46:27,317 --> 00:46:29,219 REPORTING LINE. 1371 00:46:29,286 --> 00:46:34,391 SO IF YOU LOOK AT 1 TWH 1 THROU, 1372 00:46:34,458 --> 00:46:39,196 THEY'RE ALL IN PROCESSES. 1373 00:46:39,263 --> 00:46:40,097 THIS IS CONSISTENT WITH THE 1374 00:46:40,164 --> 00:46:49,106 PREVIOUS STUDY DONE, TH SO THEY 1375 00:46:49,173 --> 00:46:50,541 SHOW THAT CALCIUM IS A LOT MORE 1376 00:46:50,607 --> 00:46:53,477 COMMON IN THE PROCESSES. 1377 00:46:53,544 --> 00:46:54,945 AND HERE'S A POPULATION SUMMARY. 1378 00:46:55,012 --> 00:47:00,117 SO COMPARED TO CONTROLS, CAUSED 1379 00:47:00,184 --> 00:47:01,752 INCREASE IN CALCIUM AND THE SAME 1380 00:47:01,818 --> 00:47:04,521 THING IS TRUE IF WE INFUSE THE 1381 00:47:04,588 --> 00:47:07,024 P2Y12 AGONIST. 1382 00:47:07,090 --> 00:47:11,628 SO IT SEEMS THAT P2Y12/GI 1383 00:47:11,695 --> 00:47:13,764 INCREASES CALCIUM IN VIVO, AND 1384 00:47:13,830 --> 00:47:16,633 WE ALSO KNOW THAT THIS PATHWAY 1385 00:47:16,700 --> 00:47:18,135 INCREASES SLEEP, SO A NATURAL 1386 00:47:18,202 --> 00:47:19,469 QUESTION IS WHAT'S THE 1387 00:47:19,536 --> 00:47:21,138 RELATIONSHIP BETWEEN MICROGLIA 1388 00:47:21,205 --> 00:47:22,306 CALCIUM AND SLEEP? 1389 00:47:22,372 --> 00:47:24,174 SO FOR THAT, WE ALREADY HAVE THE 1390 00:47:24,241 --> 00:47:24,541 DATA. 1391 00:47:24,608 --> 00:47:27,077 WE JUST NEED TO LOOK AT THE 1392 00:47:27,144 --> 00:47:29,780 SESSIONS WITHOUT CNO BUT 1393 00:47:29,846 --> 00:47:30,581 COMPARING ACROSS DIFFERENT BRAIN 1394 00:47:30,647 --> 00:47:31,982 STATES. 1395 00:47:32,049 --> 00:47:36,520 SO IN GENERAL, WE SEE THAT A 1396 00:47:36,587 --> 00:47:37,921 MICROGLIA CALCIUM -- ARE HIGHER 1397 00:47:37,988 --> 00:47:41,158 DURING NON-REM SLEEP COMPARED TO 1398 00:47:41,225 --> 00:47:41,491 WAKEFULNESS. 1399 00:47:41,558 --> 00:47:43,126 YOU NOTICE THAT I DIDN'T MENTION 1400 00:47:43,193 --> 00:47:45,028 REM SLEEP AND THAT'S BECAUSE 1401 00:47:45,095 --> 00:47:46,763 HERE'S A DIRTY LITTLE SECRET. 1402 00:47:46,830 --> 00:47:49,199 IF YOU DO FLUORESCENCE IMAGING 1403 00:47:49,266 --> 00:47:53,003 DURING REM SLEEP, WHATEVER YOU 1404 00:47:53,070 --> 00:47:54,304 SEE, DON'T BELIEVE IT RIGHT A 1405 00:47:54,371 --> 00:47:55,439 WAY BECAUSE DURING REM SLEEP, 1406 00:47:55,505 --> 00:47:57,874 ALL THIS KIND OF CRAZY 1407 00:47:57,941 --> 00:47:59,610 CARDIOVASCULAR BLOOD SIGNALS 1408 00:47:59,676 --> 00:48:01,545 JUST MAKES THE IMAGING REALLY 1409 00:48:01,612 --> 00:48:02,946 TRICKY, YOU SEE ALL KINDS OF 1410 00:48:03,013 --> 00:48:04,014 ARTIFACTS, SO WE COULDN'T REALLY 1411 00:48:04,081 --> 00:48:05,616 PIECE APART WHAT'S REAL, WHAT'S 1412 00:48:05,682 --> 00:48:06,917 ARTIFACT SO WE DECIDED NOT TO 1413 00:48:06,984 --> 00:48:08,552 TALK ABOUT REM SLEEP, WHICH 1414 00:48:08,619 --> 00:48:09,686 REVIEWERS GAVE US A REALLY HARD 1415 00:48:09,753 --> 00:48:10,120 TIME. 1416 00:48:10,187 --> 00:48:11,788 AND SAYING I DON'T WANT TO SHOW 1417 00:48:11,855 --> 00:48:13,757 ANYTHING UNRELIABLE, THAT'S WHY. 1418 00:48:13,824 --> 00:48:15,025 ANYWAY, SO BUT AT LEAST WE KNOW 1419 00:48:15,092 --> 00:48:17,761 THAT DURING NON-RECOMMEND SLEEP, 1420 00:48:17,828 --> 00:48:19,062 CALCIUM TRANSIENTS ARE HIGHER. 1421 00:48:19,129 --> 00:48:23,800 OKAY. 1422 00:48:23,867 --> 00:48:25,002 SO MICROGLIA CALCIUM IS 1423 00:48:25,068 --> 00:48:26,436 CORRELATED WITH NATURAL SLEEP. 1424 00:48:26,503 --> 00:48:30,274 THE QUESTION IS, IS IT CAUSAL. 1425 00:48:30,340 --> 00:48:32,709 SO WE HAVE TWO LINES OF EVIDENCE 1426 00:48:32,776 --> 00:48:34,244 SUGGESTING IT PLAYS A CAUSAL 1427 00:48:34,311 --> 00:48:34,578 ROLE. 1428 00:48:34,645 --> 00:48:38,081 FIRST WHEN WE EXPRESS THIS 1429 00:48:38,148 --> 00:48:42,152 IP3 SPONG CALLED P130PH, WE 1430 00:48:42,219 --> 00:48:44,688 ACTUALLY GOT THIS CONSTRUCT FROM 1431 00:48:44,755 --> 00:48:47,557 NIH, SO THIS LARGELY GREATLY 1432 00:48:47,624 --> 00:48:50,027 REDUCED CNO INDREESING CALCIUM, 1433 00:48:50,093 --> 00:48:54,298 SO THE MAGENTA LINE IS WITHOUT A 1434 00:48:54,364 --> 00:48:56,700 SPONG, CAUSING HUGE INCREASE IN 1435 00:48:56,767 --> 00:48:58,101 CALCIUM, BUT WITH THIS SPONG, 1436 00:48:58,168 --> 00:49:01,438 THE CYAN COLORED LINE, THAT'S 1437 00:49:01,505 --> 00:49:03,206 GREATLY REDUCED. 1438 00:49:03,273 --> 00:49:05,375 THE INCREASE IN NON-REM SLEEP IS 1439 00:49:05,442 --> 00:49:06,977 ALSO LARGELY ABOLISHED. 1440 00:49:07,044 --> 00:49:10,247 CONVERSELY WHEN WE INCREASE 1441 00:49:10,314 --> 00:49:17,220 CALCIUM USING G -- WE STILL SAW 1442 00:49:17,287 --> 00:49:19,289 A STRONG EFFECT OF INCREASE IN 1443 00:49:19,356 --> 00:49:21,692 NON-REM SLEEP, SO WE THINK 1444 00:49:21,758 --> 00:49:22,959 PROBABLY MICROGLIA CALCIUM CAN 1445 00:49:23,026 --> 00:49:25,128 CAUSE AN INCREASE IN SLEEP. 1446 00:49:25,195 --> 00:49:27,631 BUT THEN THE QUESTION IS, HOW? 1447 00:49:27,698 --> 00:49:30,534 SO AT SOME POINT MICROGLIA WOULD 1448 00:49:30,600 --> 00:49:32,402 HAVE TO ACT ON NEURONS TO CHANGE 1449 00:49:32,469 --> 00:49:33,403 BRAIN STATES. 1450 00:49:33,470 --> 00:49:36,406 SO ONE OF THE MOST POWERFUL 1451 00:49:36,473 --> 00:49:40,210 WAKE-PROMOTING NEUROMODULATORS 1452 00:49:40,277 --> 00:49:43,413 IS -- ADRENALINE. 1453 00:49:43,480 --> 00:49:44,481 IT'S A VERY SMALL NUMBER OF 1454 00:49:44,548 --> 00:49:46,616 CELLS BUT THEY REALLY SEND THESE 1455 00:49:46,683 --> 00:49:50,120 HUGE AXONS ALL OVER THE BRAIN, 1456 00:49:50,187 --> 00:49:56,059 RELEASING NEUROADRENALINE. 1457 00:49:56,126 --> 00:49:57,928 NEXT WE LOOKED AT THE 1458 00:49:57,994 --> 00:50:01,631 INTERACTION BETWEEN MICROGLIA 1459 00:50:01,698 --> 00:50:03,500 AND NORADRENALINE. 1460 00:50:03,567 --> 00:50:05,869 SO FIRST WE IMAGED NORADRENALINE 1461 00:50:05,936 --> 00:50:10,440 LEVEL USING THE SENSOR DEVELOPED 1462 00:50:10,507 --> 00:50:12,409 BY THE LAB, I'M JUST GOING TO 1463 00:50:12,476 --> 00:50:15,078 USE THE WORD NE SENSOR. 1464 00:50:15,145 --> 00:50:18,348 SO IN GENERAL, THE -- LEVEL IS 1465 00:50:18,415 --> 00:50:21,985 HIGHER DURING WAKEFULNESS THAN 1466 00:50:22,052 --> 00:50:23,387 NON- -- THIS WAS ALL EXPECTED 1467 00:50:23,453 --> 00:50:26,456 BECAUSE WE'VE KNOWN FOR PROBABLY 1468 00:50:26,523 --> 00:50:29,226 60 YEARS THAT THE LOCUS JULIUS 1469 00:50:29,292 --> 00:50:30,327 NEURONS, THEY'RE MUCH MORE 1470 00:50:30,394 --> 00:50:31,928 ACTIVE DURING WAKEFULNESS THAN 1471 00:50:31,995 --> 00:50:35,532 SLEEP SO IT KIND OF MAKES SENSE 1472 00:50:35,599 --> 00:50:37,167 FOR NORADRENALINE TO BE HIGHER 1473 00:50:37,234 --> 00:50:38,402 DURING WAKEFULNESS. 1474 00:50:38,468 --> 00:50:40,837 WHAT'S IMPORTANT IS THAT THE -- 1475 00:50:40,904 --> 00:50:43,006 THEY CHANGE IN OPPOSITE 1476 00:50:43,073 --> 00:50:44,975 DIRECTIONS AT BRAIN STATE 1477 00:50:45,041 --> 00:50:46,576 TRANSITIONS, SO -- LEVEL GOES 1478 00:50:46,643 --> 00:50:50,247 HIGHER WHEN THE ANIMAL WAKES UP 1479 00:50:50,313 --> 00:50:57,554 BUT MY MYOGLIA CALCIUM GOES DOW. 1480 00:50:57,621 --> 00:50:59,856 WHEN WE ACTIVATED MICRO DPLEE YA 1481 00:50:59,923 --> 00:51:03,059 GI USING CNO, IT CAUSED A 1482 00:51:03,126 --> 00:51:04,728 DECREASE IN -- LEVEL, SO THEY'RE 1483 00:51:04,795 --> 00:51:07,230 NOT JUST ANTICORRELATED, IT CAN 1484 00:51:07,297 --> 00:51:09,566 ACTUALLY CAUSE A DECREASE IN NE. 1485 00:51:09,633 --> 00:51:11,535 NOW WE KNOW THE MICROGLIA NOT 1486 00:51:11,601 --> 00:51:14,571 ONLY SENSE APP AND ADP THROUGH 1487 00:51:14,638 --> 00:51:17,240 P2Y12, THEY CAN ALSO HELP TO MA 1488 00:51:17,307 --> 00:51:20,043 TABBIZE ATP AND ADP INTO 1489 00:51:20,110 --> 00:51:21,178 ADENOSINE, AND IN FACT, 1490 00:51:21,244 --> 00:51:22,279 ADENOSINE HAS BEEN KNOWN FOR 1491 00:51:22,345 --> 00:51:24,347 DECADES TO BE A SUBSTANCE THAT 1492 00:51:24,414 --> 00:51:25,415 PROMOTES SLEEP. 1493 00:51:25,482 --> 00:51:28,118 SO PEOPLE TELL YOU TO DRINK A 1494 00:51:28,185 --> 00:51:29,886 GLASS OF MILK BEFORE YOU GO TO 1495 00:51:29,953 --> 00:51:31,955 SLEEP, IT HELPS YOU BECAUSE OF 1496 00:51:32,022 --> 00:51:32,255 ADENOSINE. 1497 00:51:32,322 --> 00:51:34,958 I DON'T KNOW IF THAT'S TRUE, BUT 1498 00:51:35,025 --> 00:51:36,159 ADENOSINE PART IS TRUE. 1499 00:51:36,226 --> 00:51:39,996 SO ADENOSINE DOES PROMOTE SLEEP. 1500 00:51:40,063 --> 00:51:43,533 SO NEXT WE USED ANOTHER SENSOR 1501 00:51:43,600 --> 00:51:46,803 TO MEASURE -- IN THE BRAIN, AND 1502 00:51:46,870 --> 00:51:48,405 INDEED ACTIVATION CAUSED 1503 00:51:48,472 --> 00:51:49,506 INCREASE IN ADENOSINE. 1504 00:51:49,573 --> 00:51:52,108 AND WHEN WE APPLIED AN ADENOSINE 1505 00:51:52,175 --> 00:51:54,444 RECEPTOR AGONIST, IT CAUSED A 1506 00:51:54,511 --> 00:51:55,312 DECREASE IN NE. 1507 00:51:55,378 --> 00:51:57,380 SO WE THINK THAT THE SUPPRESSION 1508 00:51:57,447 --> 00:52:02,052 OF NE LEVEL BY MICROGLIA IS AT 1509 00:52:02,118 --> 00:52:04,120 LEAST PARTLY MEDIATED BY 1510 00:52:04,187 --> 00:52:05,121 ATENNESSEAN. 1511 00:52:05,188 --> 00:52:07,757 NOW WE KNOW THAT NORADRENALINE 1512 00:52:07,824 --> 00:52:08,758 PROMOTES WAKEFULNESS AND 1513 00:52:08,825 --> 00:52:10,060 INHIBITS SLEEP, SO THIS PATHWAY 1514 00:52:10,126 --> 00:52:12,762 THAT WE MAPPED OUT SO FAR IS ONE 1515 00:52:12,829 --> 00:52:14,931 MECHANISM FOR MICROGLIA TO 1516 00:52:14,998 --> 00:52:15,832 PROMOTE SLEEP. 1517 00:52:15,899 --> 00:52:17,267 NOW, WHAT ABOUT INTERACTION IN 1518 00:52:17,334 --> 00:52:18,435 THE OPPOSITE DIRECTION? 1519 00:52:18,502 --> 00:52:20,103 SO WE KNOW THAT MICROGLIA 1520 00:52:20,170 --> 00:52:22,639 EXPRESS A TON OF ADRENERGIC 1521 00:52:22,706 --> 00:52:25,475 RECEPTORS. 1522 00:52:25,542 --> 00:52:27,711 SO WE WENT BACK TO CALCIUM 1523 00:52:27,777 --> 00:52:29,246 IMAGING FOR MICROGLIA AND WHEN 1524 00:52:29,312 --> 00:52:32,916 WE APPLIED A NEW REACC RECEPTOR 1525 00:52:32,983 --> 00:52:33,884 ANTAGONIST, EITHER A COCKTAIL 1526 00:52:33,950 --> 00:52:35,452 THAT BLOCKS MULTIPLE RECEPTORS 1527 00:52:35,519 --> 00:52:38,121 OR SPECIFIC BETA 2 ADRENERGIC 1528 00:52:38,188 --> 00:52:39,189 RECEPTOR ANTAGONIST, IN BOTH 1529 00:52:39,256 --> 00:52:41,825 CASES WE SAW LARGE INCREASE IN 1530 00:52:41,892 --> 00:52:45,662 CALCIUM IN MICROGLIA. 1531 00:52:45,729 --> 00:52:48,365 SO BASICALLY NE ALSO SUPPRESSES 1532 00:52:48,431 --> 00:52:49,232 MICROGLIA CALCIUM AND 1533 00:52:49,299 --> 00:52:50,667 INTERACTIONS ARE MUTUALLY 1534 00:52:50,734 --> 00:52:52,068 ANTAGONISTIC. 1535 00:52:52,135 --> 00:52:53,770 NOW, WE KNOW THE MICROGLIA 1536 00:52:53,837 --> 00:52:55,639 CALCIUM IS IMPORTANT FOR THEIR 1537 00:52:55,705 --> 00:52:58,041 MOTILITY AND ALSO VAGAL SIGH TO 1538 00:52:58,108 --> 00:53:00,944 TICK ACTIVITY, SO THE 1539 00:53:01,011 --> 00:53:02,812 SUPPRESSION BY NE MEANS THAT 1540 00:53:02,879 --> 00:53:05,949 DURING SLEEP DEPRIVATION, WHEN 1541 00:53:06,016 --> 00:53:07,951 THE -- LEVEL IS KEPT HIGH 1542 00:53:08,018 --> 00:53:09,185 ARTIFICIALLY FOR A LONG TIME, 1543 00:53:09,252 --> 00:53:11,388 THAT CAN INTERFERE WITH THE 1544 00:53:11,454 --> 00:53:12,489 FUNCTION, BECAUSE YOU SUPPRESS 1545 00:53:12,556 --> 00:53:15,926 THE CALCIUM AND THAT COULD 1546 00:53:15,992 --> 00:53:18,995 INTERDEER WITH THESE FUNCTIONS 1547 00:53:19,062 --> 00:53:20,297 OF MICROGLIA. 1548 00:53:20,363 --> 00:53:22,065 TO ME THE MOST INTERESTING PART 1549 00:53:22,132 --> 00:53:23,533 IS MICROGLIA CAN ACTUALLY SIGNAL 1550 00:53:23,600 --> 00:53:23,967 BACK. 1551 00:53:24,034 --> 00:53:25,802 SO WE THINK PERHAPS WHEN 1552 00:53:25,869 --> 00:53:26,903 MICROGLIA SENSE THE NEEDS FOR 1553 00:53:26,970 --> 00:53:28,371 THESE HOUSEKEEPING FUNCTIONS, 1554 00:53:28,438 --> 00:53:29,272 THEY BASICALLY CAN TELL THE 1555 00:53:29,339 --> 00:53:31,675 BRAIN TO GO TO SLEEP BY IB 1556 00:53:31,741 --> 00:53:37,247 HIBTI -- BYINHIBITING THIS VERYL 1557 00:53:37,314 --> 00:53:38,014 WAKE-PROMOTING NEUROMODULATOR. 1558 00:53:38,081 --> 00:53:39,049 IN ADDITION TO THE IMMUNE 1559 00:53:39,115 --> 00:53:40,216 SYSTEM, WE ALSO HAVE ANOTHER 1560 00:53:40,283 --> 00:53:41,451 PROJECT LOOKING AT THE 1561 00:53:41,518 --> 00:53:42,419 NEUROENDOCRINE SYSTEM, WHICH I 1562 00:53:42,485 --> 00:53:44,020 WON'T GO INTO THE DATA, I'LL 1563 00:53:44,087 --> 00:53:46,089 JUST SORT OF SUMMARIZE. 1564 00:53:46,156 --> 00:53:47,624 SO SPECIFICALLY WE LOOKED AT 1565 00:53:47,691 --> 00:53:49,259 SLEEP DEPENDENT GROWTH HORMONE 1566 00:53:49,326 --> 00:53:49,826 RELEASE. 1567 00:53:49,893 --> 00:53:52,162 IT TURNS OUT THAT MOST OF OUR 1568 00:53:52,228 --> 00:53:53,630 GROWTH HORMONES ARE RELEASED 1569 00:53:53,697 --> 00:53:54,030 DURING SLEEP. 1570 00:53:54,097 --> 00:53:55,832 SO IN THIS PATHWAY, IT TURNS OUT 1571 00:53:55,899 --> 00:53:57,801 THAT NE IS ALSO PART OF THE 1572 00:53:57,867 --> 00:54:00,537 LOOP. 1573 00:54:00,604 --> 00:54:04,708 SO WE THINK THAT IN ADDITION TO 1574 00:54:04,774 --> 00:54:06,276 REGULATING METABOLISM AND THE 1575 00:54:06,343 --> 00:54:09,546 IMMUNE SYSTEM. 1576 00:54:09,613 --> 00:54:11,748 THE CATECHOLAMINE PATHWAYS, THEY 1577 00:54:11,815 --> 00:54:13,783 CAN ALSO INTEGRATE SIGNALS FROM 1578 00:54:13,850 --> 00:54:15,819 THE IMMUNE SYSTEM AND THE 1579 00:54:15,885 --> 00:54:17,053 ENDOCRINE SYSTEM, AND THEY CAN 1580 00:54:17,120 --> 00:54:19,389 ACTUALLY TELL THE BRAIN WHEN AND 1581 00:54:19,456 --> 00:54:21,257 HOW MUCH SLEEP IS NEEDED, 1582 00:54:21,324 --> 00:54:22,559 BECAUSE SLEEP IS SERVING ALL 1583 00:54:22,626 --> 00:54:25,428 THESE DIFFERENT FUNCTIONS. 1584 00:54:25,495 --> 00:54:26,429 METABOLISM AND THE IMMUNE 1585 00:54:26,496 --> 00:54:27,130 SYSTEM. 1586 00:54:27,197 --> 00:54:30,266 FURTHERMORE, WE THINK THAT 1587 00:54:30,333 --> 00:54:31,034 CATECHOLAMINE SIGNALING CAN 1588 00:54:31,101 --> 00:54:32,702 ACTUALLY TELL THE BRAIN TO GO TO 1589 00:54:32,769 --> 00:54:34,604 SLEEP SIMPLY BY GETTING TIRED 1590 00:54:34,671 --> 00:54:36,139 THEMSELVES. 1591 00:54:36,206 --> 00:54:38,975 SO WE KNOW THAT THE 1592 00:54:39,042 --> 00:54:40,610 CATECHOLAMINE NEURONS ARE 1593 00:54:40,677 --> 00:54:41,778 PARTICULARLY VULNERABLE TO 1594 00:54:41,845 --> 00:54:42,212 METABOLIC STRESS. 1595 00:54:42,278 --> 00:54:43,847 WE KNOW THESE NEURONS DIARILY 1596 00:54:43,913 --> 00:54:45,382 EARLY IN BOTH PARKINSON'S 1597 00:54:45,448 --> 00:54:47,384 DISEASE AND ALZHEIMER'S DISEASE, 1598 00:54:47,450 --> 00:54:49,252 AND WE KNOW THAT SLEEP DEFICITS 1599 00:54:49,319 --> 00:54:52,989 CAN ACTUALLY SPEED UP DISEASE 1600 00:54:53,056 --> 00:54:53,289 PROGRESSION. 1601 00:54:53,356 --> 00:54:55,558 WE ALSO KNOW THAT THESE NEURONS 1602 00:54:55,625 --> 00:54:56,660 STRONGLY PROMOTE WAKEFULNESS, 1603 00:54:56,726 --> 00:54:58,828 THEY'RE ALSO MUCH MORE ACTIVE 1604 00:54:58,895 --> 00:55:00,363 DURING WAKEFULNESS THAN SLEEP. 1605 00:55:00,430 --> 00:55:02,499 SO ONE POSSIBILITY IS THAT SLEEP 1606 00:55:02,565 --> 00:55:03,800 SIMPLY ALLOWS THESE NEURONS TO 1607 00:55:03,867 --> 00:55:07,404 KIND OF TAKE A BREAK AND REST 1608 00:55:07,470 --> 00:55:08,905 AND RECOVER FROM THE HIGH 1609 00:55:08,972 --> 00:55:10,106 METABOLIC STRESS CAUSED BY HIGH 1610 00:55:10,173 --> 00:55:12,175 ACTIVITY DURING WAKEFULNESS. 1611 00:55:12,242 --> 00:55:13,610 SO IN OTHER WORDS, MAYBE 1612 00:55:13,677 --> 00:55:15,078 SHUTTING DOWN THESE NEURONS 1613 00:55:15,145 --> 00:55:18,715 DURING SLEEP ONCE IN A WHILE IS 1614 00:55:18,782 --> 00:55:20,283 IMPORTANT NOT ONLY FOR THEIR OWN 1615 00:55:20,350 --> 00:55:21,551 HEALTH AND WELL-BEING BUT ALSO 1616 00:55:21,618 --> 00:55:23,687 FOR THE OTHER TISSUES AND ORGANS 1617 00:55:23,753 --> 00:55:25,221 THROUGH THEIR INTERACTIONS WITH 1618 00:55:25,288 --> 00:55:26,523 ALL THESE DIFFERENT OTHER 1619 00:55:26,589 --> 00:55:26,990 SYSTEMS. 1620 00:55:27,057 --> 00:55:30,193 SO WE THINK THAT IS QUITE 1621 00:55:30,260 --> 00:55:32,062 PLAUSIBLE THAT CATECHOLAMINE 1622 00:55:32,128 --> 00:55:34,698 INACTIVATION IS A BASIC PROCESS 1623 00:55:34,764 --> 00:55:35,465 UNDERLYING MULTIPLE FUNCTIONS OF 1624 00:55:35,532 --> 00:55:35,865 SLEEP. 1625 00:55:35,932 --> 00:55:41,204 SO THIS IS QUITE SPECULATIVE. 1626 00:55:41,271 --> 00:55:42,072 IT'S STILL EARLY IN THE DAYS BUT 1627 00:55:42,138 --> 00:55:44,307 THIS IS THE CENTRAL HYPOTHESIS 1628 00:55:44,374 --> 00:55:45,642 THAT WE'RE PURSUING RIGHT NOW. 1629 00:55:45,709 --> 00:55:46,643 SO FINALLY, THESE ARE THE PEOPLE 1630 00:55:46,710 --> 00:55:49,079 IN MY LAB, FORMER CURRENT 1631 00:55:49,145 --> 00:55:50,747 TRAINEES, AND SO THE RED ONES 1632 00:55:50,814 --> 00:55:52,048 ARE THE ONES THAT ARE 1633 00:55:52,115 --> 00:55:53,349 RESPONSIBLE FOR THE DATA I 1634 00:55:53,416 --> 00:55:56,686 SHOWED YOU TODAY. 1635 00:55:56,753 --> 00:55:57,787 ACTUALLY MOST OF THEM ARE NOW 1636 00:55:57,854 --> 00:55:58,988 RUNNING THEIR OWN LABS. 1637 00:55:59,055 --> 00:55:59,889 SO WE THANK YOU FOR YOUR 1638 00:55:59,956 --> 00:56:00,256 ATTENTION. 1639 00:56:00,323 --> 00:56:10,500 [APPLAUSE] 1640 00:56:21,244 --> 00:56:22,612 >> HI, HOW ARE YOU? 1641 00:56:22,679 --> 00:56:23,012 >> HI. 1642 00:56:23,079 --> 00:56:25,048 >> REALLY FANTASTIC TALK. 1643 00:56:25,115 --> 00:56:26,282 SO I HAVE A QUICK QUESTION AND 1644 00:56:26,349 --> 00:56:28,051 MAYBE A LONG QUESTION. 1645 00:56:28,118 --> 00:56:33,022 SO THE QUICK QUESTION IS, THE 1646 00:56:33,089 --> 00:56:35,125 RETICULATA NEURONS, THE 1647 00:56:35,191 --> 00:56:36,326 GOOD2 KRELTS ARE INCREASED 1648 00:56:36,392 --> 00:56:39,863 DURING WAKEFULNESS BUT ALSO THE 1649 00:56:39,929 --> 00:56:42,832 LOCUS -- HOW EXACTLY DOES THAT 1650 00:56:42,899 --> 00:56:43,066 HAPPEN? 1651 00:56:43,133 --> 00:56:46,269 >> THE LOCUS JULIUS NEURONS ARE 1652 00:56:46,336 --> 00:56:48,571 MORE ACTIVE DURING WAKEFULNESS. 1653 00:56:48,638 --> 00:56:49,672 THE OTHERS ARE MORE ACTIVE 1654 00:56:49,739 --> 00:56:50,106 DURING SLEEP. 1655 00:56:50,173 --> 00:56:51,441 >> SORRY, I GOT THAT MIXED UP. 1656 00:56:51,508 --> 00:56:52,575 >> YEAH, YEAH. 1657 00:56:52,642 --> 00:56:55,745 SO THE SNR NEURONS PROJECT TO 1658 00:56:55,812 --> 00:56:59,182 THE OSM C, SO WE CAN SAY THE OC 1659 00:56:59,249 --> 00:57:00,950 NEWER OPS ARE LESS ACTIVE DURING 1660 00:57:01,017 --> 00:57:02,185 SLEEP BECAUSE THEY'RE INHIBITED 1661 00:57:02,252 --> 00:57:03,052 BY SNR. 1662 00:57:03,119 --> 00:57:04,721 THEY'RE PROBABLY INHIBITED BY 1663 00:57:04,788 --> 00:57:05,922 MANY OTHER CELLS, BUT AT LEAST 1664 00:57:05,989 --> 00:57:08,258 THAT PATHWAY CONTRIBUTES IN A 1665 00:57:08,324 --> 00:57:08,658 POSITIVE WAY. 1666 00:57:08,725 --> 00:57:09,926 >> ALL RIGHT, I MIXED THAT UP. 1667 00:57:09,993 --> 00:57:10,827 THANKS FOR THAT. 1668 00:57:10,894 --> 00:57:13,897 BUT THEN -- SO YOU MENTIONED 1669 00:57:13,963 --> 00:57:15,632 THIS, ONE OF THE EARLIEST -- YOU 1670 00:57:15,698 --> 00:57:17,033 KNOW THIS, ONE OF THE EARLIEST 1671 00:57:17,100 --> 00:57:18,735 SIGNS IN PD IS YOU GET THIS SORT 1672 00:57:18,802 --> 00:57:22,872 OF -- THINKING OUT YOUR DREAMS. 1673 00:57:22,939 --> 00:57:25,508 I GUESS NOW LOOKING AT YOUR 1674 00:57:25,575 --> 00:57:26,943 TALK, OR I GUESS I HAD ALWAYS 1675 00:57:27,010 --> 00:57:30,180 THOUGHT THIS, THE LOCUS -- 1676 00:57:30,246 --> 00:57:30,947 DEGENERATION IS PROBABLY 1677 00:57:31,014 --> 00:57:32,448 CONTRIBUTING TO THAT, TO A LARGE 1678 00:57:32,515 --> 00:57:36,152 EXTENT, BUT HOW MUCH OF THE 1679 00:57:36,219 --> 00:57:37,353 DOPAMINE SYSTEM SORT OF IS 1680 00:57:37,420 --> 00:57:39,222 INVOLVED IN THAT? 1681 00:57:39,289 --> 00:57:42,025 OF COURSE THEY REGULATE THE 1682 00:57:42,091 --> 00:57:42,559 RETICULATA NEURONS. 1683 00:57:42,625 --> 00:57:43,660 JUST KIND OF YOUR IDEAS. 1684 00:57:43,726 --> 00:57:44,961 I KNOW YOU'RE STUDYING THIS, 1685 00:57:45,028 --> 00:57:45,161 BUT -- 1686 00:57:45,228 --> 00:57:47,130 >> SO WE JUST SAW EACH OTHER IN 1687 00:57:47,197 --> 00:57:49,766 ROME A COUPLE MONTHS AGO IN THIS 1688 00:57:49,833 --> 00:57:51,701 ASAP MEETING, SO MY LAB GOT INTO 1689 00:57:51,768 --> 00:57:53,203 PD WHICH IS THE MOST EXCITING 1690 00:57:53,269 --> 00:57:54,504 EVENT IN MY LIFE FOR THE PAST 1691 00:57:54,571 --> 00:57:55,138 FEW YEARS. 1692 00:57:55,205 --> 00:57:57,540 SO ANYWAY, SO WE KNOW THAT THE 1693 00:57:57,607 --> 00:57:59,576 DOPAMINE NEURONS PLAY A BIG ROLE 1694 00:57:59,642 --> 00:58:01,878 BECAUSE THE MICE THAT WE'RE 1695 00:58:01,945 --> 00:58:04,581 STUDYING, IT'S A DOPAMINE NEURON 1696 00:58:04,647 --> 00:58:05,048 SPECIFIC MANIPULATION. 1697 00:58:05,114 --> 00:58:08,518 SO IN THAT MOUSE MODEL, WE ONLY 1698 00:58:08,585 --> 00:58:10,854 CROSS TO THE -- CRE MICE SO THE 1699 00:58:10,920 --> 00:58:12,088 LC NEURONS ARE SPARED. 1700 00:58:12,155 --> 00:58:14,357 SO IN THAT EXPERIMENT, WE KNOW 1701 00:58:14,424 --> 00:58:15,959 THE DOPAMINE NEURONS DEFINITELY 1702 00:58:16,025 --> 00:58:17,293 PLAY A ROLE BECAUSE THOSE MICE, 1703 00:58:17,360 --> 00:58:20,463 THEIR SLEEP IS REALLY MESSED UP. 1704 00:58:20,530 --> 00:58:23,032 BUT WE HAVEN'T DONE THE CONVERSE 1705 00:58:23,099 --> 00:58:23,499 EXPERIMENTS. 1706 00:58:23,566 --> 00:58:25,034 IF YOU ONLY SPECIFICALLY 1707 00:58:25,101 --> 00:58:26,436 MANIPULATE THE OC NEURONS. 1708 00:58:26,502 --> 00:58:27,503 ACTUALLY WE HAVE A LITTLE BIT OF 1709 00:58:27,570 --> 00:58:28,705 DATA, IT'S NOT PUBLISHED. 1710 00:58:28,771 --> 00:58:30,106 SO IF YOU MESS WITH THE OC 1711 00:58:30,173 --> 00:58:31,841 NEURONS, NOT ONLY THE OC NEURONS 1712 00:58:31,908 --> 00:58:33,610 BUT THE ADRENERGIC NEURONS 1713 00:58:33,676 --> 00:58:35,345 BECAUSE THIS IS -- CRE MICE, 1714 00:58:35,411 --> 00:58:36,713 THEN THE SLEEP IS ALSO AFFECTED 1715 00:58:36,779 --> 00:58:40,550 AND ACTUALLY NOT AS STRONGLY AS 1716 00:58:40,617 --> 00:58:42,719 THE BAD CRE, BUT MORE NEEDS TO 1717 00:58:42,785 --> 00:58:43,152 BE DONE. 1718 00:58:43,219 --> 00:58:46,923 >> OKAY. 1719 00:58:46,990 --> 00:58:47,657 >> HI. 1720 00:58:47,724 --> 00:58:48,725 SO I WANT TO GO BACK TO 1721 00:58:48,791 --> 00:58:50,293 SOMETHING YOU MENTIONED EARLIER, 1722 00:58:50,360 --> 00:58:53,930 SO A LOT OF THESE SLOPE 1723 00:58:53,997 --> 00:58:55,498 PROMOTING NEURONS OR REGIONS 1724 00:58:55,565 --> 00:58:56,799 THAT YOU'VE MAPPED OUT AS YOU 1725 00:58:56,866 --> 00:58:58,001 MENTIONED EARLIER ALSO TAKE PART 1726 00:58:58,067 --> 00:59:00,570 IN CONTROLLING FEAR-RELATED 1727 00:59:00,637 --> 00:59:02,338 BEHAVIORS, PARENTAL BEHAVIORS, 1728 00:59:02,405 --> 00:59:07,043 SO MY QUESTION WAS, IS THE SLEEP 1729 00:59:07,110 --> 00:59:08,077 PROMOTING FUNCTION, ARE THESE 1730 00:59:08,144 --> 00:59:09,312 LABELS LINES, MAYBE THERE'S 1731 00:59:09,379 --> 00:59:10,179 SEPARATE SETS OF NEURONS THAT 1732 00:59:10,246 --> 00:59:12,115 ARE DOING THESE THINGS, OR IS 1733 00:59:12,181 --> 00:59:15,184 THIS SOME SORT OF INTERACTION 1734 00:59:15,251 --> 00:59:17,353 WITH THE STATE AND SORT OF 1735 00:59:17,420 --> 00:59:18,788 RELATED TO THAT WHAT I WANTED TO 1736 00:59:18,855 --> 00:59:20,690 ASK, WHEN YOU DO THE OPTOGENETIC 1737 00:59:20,757 --> 00:59:21,591 EXPERIMENTS AND YOU SEE THE 1738 00:59:21,658 --> 00:59:22,892 STATE CHANGES, YOU KNOW, WHEN 1739 00:59:22,959 --> 00:59:24,327 YOU DO THE STIMULATION, YOU SEE 1740 00:59:24,394 --> 00:59:24,994 THE STATE CHANGE. 1741 00:59:25,061 --> 00:59:26,162 WHEN YOU STOP THE STIMULATION, 1742 00:59:26,229 --> 00:59:29,999 DOES THE ANIMAL CONTINUE DOWN 1743 00:59:30,066 --> 00:59:34,370 THAT PATH FROM SMALL MOVEMENT TO 1744 00:59:34,437 --> 00:59:36,873 QUIET WAKEFULNESS, OR DOES IT 1745 00:59:36,940 --> 00:59:42,512 STAY THERE AND FRUK T AND FLUCTT 1746 00:59:42,578 --> 00:59:42,845 BACK UP? 1747 00:59:42,912 --> 00:59:43,813 >> IT VARIES. 1748 00:59:43,880 --> 00:59:45,248 IN SOME CASES IT ONLY -- AND IN 1749 00:59:45,315 --> 00:59:47,183 MOST CASES, THE EFFECT IS THE 1750 00:59:47,250 --> 00:59:48,284 STRONGEST DURING STIMULATION. 1751 00:59:48,351 --> 00:59:50,787 SO WHEN YOU STOP STIMULATION, 1752 00:59:50,853 --> 00:59:52,655 SOMETIMES YOU SEE THE EFFECT 1753 00:59:52,722 --> 00:59:55,358 GRADUALLY KIND OF, YOU KNOW, HAS 1754 00:59:55,425 --> 00:59:57,126 SOME LASTING EFFECT, BUT IT'S 1755 00:59:57,193 --> 00:59:57,660 WEAKER. 1756 00:59:57,727 --> 00:59:59,529 BUT IN OTHER CASES, YOU ACTUALLY 1757 00:59:59,595 --> 01:00:00,463 SEE A STRONG REBOUND. 1758 01:00:00,530 --> 01:00:01,664 BUT I THINK THAT, YOU KNOW, PART 1759 01:00:01,731 --> 01:00:05,835 OF THAT COULD BE YOU KNOW 1760 01:00:05,902 --> 01:00:07,337 WHEN -- SOME CELLS YOU STOP 1761 01:00:07,403 --> 01:00:08,204 ACTIVATING, THEY GO BACK TO 1762 01:00:08,271 --> 01:00:08,871 BASELINE. 1763 01:00:08,938 --> 01:00:09,939 SOME CELLS YOU SEE THIS REBOUND. 1764 01:00:10,006 --> 01:00:12,008 SO I THINK THE PART OF THAT 1765 01:00:12,075 --> 01:00:13,276 DIFFERENT EFFECTS, BEHAVIORAL 1766 01:00:13,343 --> 01:00:14,610 EFFECTS COULD BE DEPENDENT ON 1767 01:00:14,677 --> 01:00:15,545 THE BIOPHYSICAL PROPERTIES OF 1768 01:00:15,611 --> 01:00:17,080 THE NEURONS THAT WE ACTIVATED. 1769 01:00:17,146 --> 01:00:20,149 OF COURSE ALSO CIRCUIT. 1770 01:00:20,216 --> 01:00:23,753 SO THAT VARIES BUT WE HAVE NEVER 1771 01:00:23,820 --> 01:00:26,356 SEEN A CASE WHERE YOU START THE 1772 01:00:26,422 --> 01:00:29,759 CASE CADE, YOU LEAVE IT ALONE 1773 01:00:29,826 --> 01:00:32,061 AND THE EFFECT GETS STRONGER AND 1774 01:00:32,128 --> 01:00:32,795 STRONGER. 1775 01:00:32,862 --> 01:00:34,097 THAT RARELY HAPPENS. 1776 01:00:34,163 --> 01:00:34,964 YOUR FIRST QUESTION IS BROADER 1777 01:00:35,031 --> 01:00:35,965 BUT I THINK IT'S A GREAT 1778 01:00:36,032 --> 01:00:36,599 QUESTION, IN FACT, IT'S 1779 01:00:36,666 --> 01:00:37,467 SOMETHING THAT I'M SORT OF 1780 01:00:37,533 --> 01:00:41,804 TRYING TO SAY, I THINK THAT 1781 01:00:41,871 --> 01:00:43,573 WE'RE ALL -- YOU CAN BE STUDYING 1782 01:00:43,639 --> 01:00:44,374 PARENTAL BEHAVIOR AND THAT'S THE 1783 01:00:44,440 --> 01:00:46,609 ONLY THING YOU STUDY, YOU CAN BE 1784 01:00:46,676 --> 01:00:49,112 STUDYING FEAR AND IT'S THE ONLY 1785 01:00:49,178 --> 01:00:50,213 THING YOU STUDY. 1786 01:00:50,279 --> 01:00:51,514 WE TALK ABOUT SLEEP, IT'S JUST 1787 01:00:51,581 --> 01:00:52,949 ONE STAGE. 1788 01:00:53,016 --> 01:00:54,050 YEAH, WAKE, WHAT ELSE DO YOU 1789 01:00:54,117 --> 01:00:55,418 CARE ABOUT, RIGHT? 1790 01:00:55,485 --> 01:00:56,886 BUT OF COURSE WAKEFULNESS IS NOT 1791 01:00:56,953 --> 01:00:57,754 A SINGLE STATE. 1792 01:00:57,820 --> 01:01:00,023 THEY DO ALL THESE DIFFERENT 1793 01:01:00,089 --> 01:01:00,690 THINGS. 1794 01:01:00,757 --> 01:01:01,958 SO I THINK THE PART OF THE POINT 1795 01:01:02,025 --> 01:01:03,393 THAT I REALIZED, I'M TRYING TO 1796 01:01:03,459 --> 01:01:04,694 PREACH, IS THAT WE NEED TO START 1797 01:01:04,761 --> 01:01:07,230 TALKING TO EACH OTHER. 1798 01:01:07,296 --> 01:01:09,265 BECAUSE THE MOUSE BRAIN IS 1799 01:01:09,332 --> 01:01:09,932 PRETTY SMALL. 1800 01:01:09,999 --> 01:01:11,434 SOONER OR LATER YOU HIT THE SAME 1801 01:01:11,501 --> 01:01:13,503 POPULATION OF NEURONS, YOU CLAIM 1802 01:01:13,569 --> 01:01:14,804 THAT'S MOTOR NEURON, I CLAIM 1803 01:01:14,871 --> 01:01:15,905 IT'S A SLEEP NEURON. 1804 01:01:15,972 --> 01:01:17,540 I'M RIGHT, OF COURSE YOU SAY 1805 01:01:17,607 --> 01:01:19,042 YOU'RE RIGHT BUT THEY'RE 1806 01:01:19,108 --> 01:01:19,275 RELATED. 1807 01:01:19,342 --> 01:01:21,477 SO I THINK YOUR QUESTION -- I 1808 01:01:21,544 --> 01:01:22,979 MEAN, AT LEAST I THINK THAT THE 1809 01:01:23,046 --> 01:01:26,449 WAKE NEURONS, I'VE BEEN SAYING 1810 01:01:26,516 --> 01:01:28,217 THIS LIKE FOREVER, I DON'T THINK 1811 01:01:28,284 --> 01:01:29,419 THEIR ONLY PURPOSE IS TO WAKE UP 1812 01:01:29,485 --> 01:01:30,253 THE BRAIN. 1813 01:01:30,319 --> 01:01:32,455 THEY'RE INVOLVED IN DIFFERENT 1814 01:01:32,522 --> 01:01:33,756 WAKE BEHAVIORS, YET WHEN YOU 1815 01:01:33,823 --> 01:01:35,691 ACTIVATE THEM, THEY ALSO PROMOTE 1816 01:01:35,758 --> 01:01:37,527 AROUSAL, BECAUSE A LOT OF THE 1817 01:01:37,593 --> 01:01:38,628 BEHAVIORS, YOU NEED TO BE 1818 01:01:38,694 --> 01:01:41,264 AROUSED IN ORDER TO DO THEM. 1819 01:01:41,330 --> 01:01:42,899 I THINK THAT THE SLEEP NEURONS 1820 01:01:42,965 --> 01:01:43,833 ALSO, THEY KIND OF PUSH THINGS 1821 01:01:43,900 --> 01:01:46,135 IN THE OPPOSITE DIRECTION, 1822 01:01:46,202 --> 01:01:46,502 RIGHT? 1823 01:01:46,569 --> 01:01:48,337 THEY WANT YOU TO REDUCE YOUR 1824 01:01:48,404 --> 01:01:49,305 AROUSAL, REDUCE YOUR MOTOR 1825 01:01:49,372 --> 01:01:50,440 ACTIVITY, AND IF YOU HAPPEN TO 1826 01:01:50,506 --> 01:01:52,442 BE STUDYING SOME PARENTAL 1827 01:01:52,508 --> 01:01:55,211 BEHAVIOR, IF THAT BEHAVIOR 1828 01:01:55,278 --> 01:01:57,713 REQUIRES A LESS AROUSED STATE 1829 01:01:57,780 --> 01:01:58,681 THAN YOU'RE FIGHTING WITH 1830 01:01:58,748 --> 01:01:59,649 SOMEBODY, YOU MIGHT PROMOTE 1831 01:01:59,715 --> 01:02:02,151 THAT, BUT IT'S ALSO RELATED TO 1832 01:02:02,218 --> 01:02:03,686 THIS GENERAL STATE CHANGE, OR 1833 01:02:03,753 --> 01:02:04,787 EMOTIONAL STATE CHANGE RATHER 1834 01:02:04,854 --> 01:02:06,489 THAN JUST A VERY SPECIFIC 1835 01:02:06,556 --> 01:02:06,756 BEHAVIOR. 1836 01:02:06,823 --> 01:02:08,791 >> PERHAPS, I MEAN, RELATED TO 1837 01:02:08,858 --> 01:02:11,494 WHAT YOU SAID ABOUT NEUROTENSIN, 1838 01:02:11,561 --> 01:02:13,696 I DON'T KNOW IF YOU GUYS TRIED 1839 01:02:13,763 --> 01:02:14,897 DIFFERENT STIMULATION 1840 01:02:14,964 --> 01:02:16,432 PARAMETERS, PERHAPS IT'S ABOUT 1841 01:02:16,499 --> 01:02:18,167 THE CANONICAL TRANSMITTER THAT 1842 01:02:18,234 --> 01:02:21,037 THESE CELLS ARE USING, GLUTAMATE 1843 01:02:21,104 --> 01:02:23,272 OR GABA, PERHAPS THE PEPTIDES 1844 01:02:23,339 --> 01:02:24,240 PLAY A DIFFERENT ROLE YOU AND 1845 01:02:24,307 --> 01:02:25,108 NEED A DIFFERENT KIND OF 1846 01:02:25,174 --> 01:02:27,477 ACTIVITY TO GET THAT -- 1847 01:02:27,543 --> 01:02:31,747 >> SO THE NEUROTENSIN STUDY, WE 1848 01:02:31,814 --> 01:02:34,283 USED CRISPR TO KNOCK OUT EITHER 1849 01:02:34,350 --> 01:02:41,824 THE GABA OR NEUROTENSIN -- YOU 1850 01:02:41,891 --> 01:02:43,326 KNOCK OUT ONE OF THEM, YOU DON'T 1851 01:02:43,392 --> 01:02:45,495 REDUCE BY HALF, YOU REDUCE BY 1852 01:02:45,561 --> 01:02:46,129 LIKE 80%. 1853 01:02:46,195 --> 01:02:47,930 BUT HOW THEY SYNERGISTICALLY 1854 01:02:47,997 --> 01:02:51,467 WORK WITH EACH OA WE DO OTHER, T 1855 01:02:51,534 --> 01:02:52,802 KNOW BECAUSE WE HAVEN'T BEEN 1856 01:02:52,869 --> 01:02:54,837 DOING A LOT OF SLICE RECORDINGS 1857 01:02:54,904 --> 01:02:56,038 TO FIGURE OUT THE DETAIL SORT OF 1858 01:02:56,105 --> 01:02:57,573 CIRCUIT STUFF, BUT BEHAVIORALLY, 1859 01:02:57,640 --> 01:02:58,508 WE KNOW THAT THEY'RE BOTH 1860 01:02:58,574 --> 01:02:58,774 IMPORTANT. 1861 01:02:58,841 --> 01:03:00,943 AND WE DON'T EVEN KNOW IF 1862 01:03:01,010 --> 01:03:05,314 THEY'RE RELEASED FIRST VERSUS -- 1863 01:03:05,381 --> 01:03:07,683 SPIKES, DIFFERENTIAL RELEASE, 1864 01:03:07,750 --> 01:03:09,886 PEOPLE SAY THAT BUT WE HAVE 1865 01:03:09,952 --> 01:03:11,420 NEVER MEASURED IT, AND WHETHER 1866 01:03:11,487 --> 01:03:14,123 THEY'RE RELEASED AT THE SAME 1867 01:03:14,190 --> 01:03:15,858 SYNAPSIS, THERE ARE CASES WHERE 1868 01:03:15,925 --> 01:03:18,094 PEPTIDE IS RELEASED IN ONE 1869 01:03:18,161 --> 01:03:19,862 PLACE, TRADITIONAL TRANSMITTER 1870 01:03:19,929 --> 01:03:20,997 RELEASED IN OTHER PLACES. 1871 01:03:21,063 --> 01:03:24,300 WE DON'T KNOW ANY OF THAT SO I 1872 01:03:24,367 --> 01:03:26,002 THINK THERE'S A LOT MORE TO BE 1873 01:03:26,068 --> 01:03:26,335 FIGURED OUT. 1874 01:03:26,402 --> 01:03:26,903 >> HI. 1875 01:03:26,969 --> 01:03:28,304 THANKS FOR A REALLY GREAT TALK. 1876 01:03:28,371 --> 01:03:29,839 I MAY HAVE MISSED IT AS YOU WERE 1877 01:03:29,906 --> 01:03:31,774 GOING THROUGH, THERE WAS SO MUCH 1878 01:03:31,841 --> 01:03:32,875 BEAUTIFUL DATA THERE, BUT I 1879 01:03:32,942 --> 01:03:33,976 NOTICED IN THE FIRST PART THAT 1880 01:03:34,043 --> 01:03:35,545 MOST OF THE MANIPULATIONS MAY 1881 01:03:35,611 --> 01:03:37,780 NOT HAVE CHANGED REM SLEEP, AND 1882 01:03:37,847 --> 01:03:39,415 I'M WONDERING, IS THAT BECAUSE 1883 01:03:39,482 --> 01:03:40,850 THE MOTOR GAIT IS ALREADY THERE 1884 01:03:40,917 --> 01:03:45,321 AND YOU'RE NOT REALLY -- SORT OF 1885 01:03:45,388 --> 01:03:45,588 BEHAVIOR? 1886 01:03:45,655 --> 01:03:46,956 >> IT'S A GREAT QUESTION. 1887 01:03:47,023 --> 01:03:48,925 SO REM SLEEP IS QUITE DIFFERENT. 1888 01:03:48,991 --> 01:03:50,993 MY PERSONAL OPINION IS THAT REM 1889 01:03:51,060 --> 01:03:54,597 SLEEP, THE CIRCUIT IS SMALLER. 1890 01:03:54,664 --> 01:03:57,200 SO MICHELLE JUVE, WHO'S THIS 1891 01:03:57,266 --> 01:03:58,067 FANTASTIC SCIENTIST WHO DIED A 1892 01:03:58,134 --> 01:04:00,369 FEW YEARS AGO, HE DID A LOT OF 1893 01:04:00,436 --> 01:04:02,672 WORK ON REM SLEEP, SO HE 1894 01:04:02,738 --> 01:04:06,142 ACTUALLY -- HIS EARLY WORK DID 1895 01:04:06,209 --> 01:04:07,543 DIFFERENT TRANSECTIONS IN 1896 01:04:07,610 --> 01:04:09,412 DIFFERENT PARTS OF THE BRAIN, HE 1897 01:04:09,478 --> 01:04:10,613 PRETTY MUCH SHOWED YOU JUST NEED 1898 01:04:10,680 --> 01:04:13,583 A BRAINSTEM FOR REM SLEEP 1899 01:04:13,649 --> 01:04:14,984 GENERATION BECAUSE YOU CAN THROW 1900 01:04:15,051 --> 01:04:16,852 AWAY THE FOREBRAIN AND REM SLEEP 1901 01:04:16,919 --> 01:04:17,486 STILL HAPPENS. 1902 01:04:17,553 --> 01:04:19,555 SO WE HAVE FOUND PUBLISHED -- 1903 01:04:19,622 --> 01:04:22,191 OTHER PEOPLE HAVE FOUND GLUTE 1904 01:04:22,258 --> 01:04:23,392 MANNER JIK NEURONS BUT MY 1905 01:04:23,459 --> 01:04:25,027 OPINION IS THAT PROBABLY TWO OR 1906 01:04:25,094 --> 01:04:26,329 THREE POPULATIONS IN THE 1907 01:04:26,395 --> 01:04:28,164 BRAINSTEM, THEY FORM A LOOP AND 1908 01:04:28,231 --> 01:04:30,233 THAT'S PROBABLY SUFFICIENT FOR 1909 01:04:30,299 --> 01:04:31,667 MOST OF REM. 1910 01:04:31,734 --> 01:04:32,735 PEOPLE FOUND SOME THAT REGULATE 1911 01:04:32,802 --> 01:04:34,270 REM BUT MY OPINION IS THAT THOSE 1912 01:04:34,337 --> 01:04:36,872 ARE MORE LIKE MODULATORY RATHER 1913 01:04:36,939 --> 01:04:38,474 THAN DIRECTLY CONTROLLING REM 1914 01:04:38,541 --> 01:04:39,308 SLEEP. 1915 01:04:39,375 --> 01:04:42,812 SO REM SLEEP IS A VERY DIFFERENT 1916 01:04:42,878 --> 01:04:43,212 THING. 1917 01:04:43,279 --> 01:04:44,981 SO NORMALLY, GOING FROM 1918 01:04:45,047 --> 01:04:46,115 WAKEFULNESS WE FIRST NEED TO GO 1919 01:04:46,182 --> 01:04:48,918 INTO NON-REM SLEEP AND THEN YOU 1920 01:04:48,985 --> 01:04:50,987 CAN GO INTO REM SLEEP FOR NORMAL 1921 01:04:51,053 --> 01:04:53,789 SUBJECTS, UNLESS YOU'RE NARK 1922 01:04:53,856 --> 01:04:54,991 HELP TICK. 1923 01:04:55,057 --> 01:04:56,459 SO NORMAL TRANSITION IS THAT 1924 01:04:56,525 --> 01:04:57,960 FIRST YOU DECIDE DO YOU SLEAP OR 1925 01:04:58,027 --> 01:04:58,628 NOT SLEEP. 1926 01:04:58,694 --> 01:05:00,796 AND THEN THE FIRST STATE IS 1927 01:05:00,863 --> 01:05:01,130 NON-REM. 1928 01:05:01,197 --> 01:05:04,500 THEN YOU MAKE A DECISION, DO YOU 1929 01:05:04,567 --> 01:05:06,469 GO INTO REM SLEEP OR DO YOU STAY 1930 01:05:06,535 --> 01:05:08,771 IN NON-REM SLEEP? 1931 01:05:08,838 --> 01:05:10,273 >> THANK YOU FOR YOUR GREAT 1932 01:05:10,339 --> 01:05:11,507 TALK. 1933 01:05:11,574 --> 01:05:18,281 SO I'M VERY INTERESTED ABOUT 1934 01:05:18,347 --> 01:05:21,651 THE -- SO THING IS, I MEAN, 1935 01:05:21,717 --> 01:05:25,788 BESIDES THE -- THERE'S ALSO -- 1936 01:05:25,855 --> 01:05:36,499 [INAUDIBLE] ALSO PRODUCE -- AND 1937 01:05:36,565 --> 01:05:43,773 ALSO -- 1938 01:05:43,839 --> 01:05:46,876 >> SO THIS IS WHAT I READ IN 1939 01:05:46,942 --> 01:05:48,744 REVIEW PAPERS, PEOPLE SAY THAT 1940 01:05:48,811 --> 01:05:53,983 FOR THE FOREBRAIN, THE MAIN OR 1941 01:05:54,050 --> 01:05:58,854 SOLE SOURCE OF NORADRENALINE IS 1942 01:05:58,921 --> 01:05:59,989 FROM THE LOCUS JULIUS. 1943 01:06:00,056 --> 01:06:04,927 THERE ARE OTHER SOURCES BUT THE 1944 01:06:04,994 --> 01:06:06,329 ADRENAL GLAND IS ALSO USED AS A 1945 01:06:06,395 --> 01:06:09,365 MORE MOANHORMONE. 1946 01:06:09,432 --> 01:06:10,366 MY UNDERSTANDING IS THAT DOES 1947 01:06:10,433 --> 01:06:13,102 NOT GO THROUGH THE BLOOD BRAIN 1948 01:06:13,169 --> 01:06:13,402 BARRIER. 1949 01:06:13,469 --> 01:06:16,472 >> NOREPINEPHRINE, I MEAN THE 1950 01:06:16,539 --> 01:06:18,641 ADRENAL GLAND CAN ALSO PRODUCE 1951 01:06:18,708 --> 01:06:19,008 NOREPINEPHRINE. 1952 01:06:19,075 --> 01:06:20,810 >> I DON'T KNOW FOR SURE BUT MY 1953 01:06:20,876 --> 01:06:21,677 UNDERSTANDING IS THAT THAT'S 1954 01:06:21,744 --> 01:06:22,678 ONLY IN THE CIRCULATION. 1955 01:06:22,745 --> 01:06:23,879 IT DOESN'T GO INTO -- IT DOESN'T 1956 01:06:23,946 --> 01:06:25,081 GO THROUGH THE BLOOD BRAIN 1957 01:06:25,147 --> 01:06:26,349 BARRIER. 1958 01:06:26,415 --> 01:06:27,717 BUT OF COURSE, YOU KNOW, YOU CAN 1959 01:06:27,783 --> 01:06:29,752 CHANGE THE BLOOD LEVELS WITH 1960 01:06:29,819 --> 01:06:30,986 THAT SYSTEM, I'M SURE IT DOES, 1961 01:06:31,053 --> 01:06:32,254 RIGHT? 1962 01:06:32,321 --> 01:06:33,923 AND OF COURSE FOR 1963 01:06:33,989 --> 01:06:35,458 NEUROSCIENTISTS, WE TEND NOT TO 1964 01:06:35,524 --> 01:06:37,026 THICK ABOUT THE BLOOD VESSELS, 1965 01:06:37,093 --> 01:06:38,260 THOSE ARE BORING, JUST THE 1966 01:06:38,327 --> 01:06:40,129 BLOOD, BUT THEY CHANGE THE BRAIN 1967 01:06:40,196 --> 01:06:41,664 IN A HUGE WAY, RIGHT? 1968 01:06:41,731 --> 01:06:43,532 YOU CHANGE BLOOD FLOW TO THE 1969 01:06:43,599 --> 01:06:46,202 BRAIN, EVERYTHING CHANGES, RIG 1970 01:06:46,268 --> 01:06:46,469 RIGHT? 1971 01:06:46,535 --> 01:06:47,670 WHICH WE TEND TO IGNORE, WHICH 1972 01:06:47,737 --> 01:06:50,439 IS A MISTAKE, I THINK. 1973 01:06:50,506 --> 01:06:52,141 >> I GUESS IF I CAN ASK ONE 1974 01:06:52,208 --> 01:06:52,742 QUESTION. 1975 01:06:52,808 --> 01:06:53,776 REALLY NICE TALK, I REALLY 1976 01:06:53,843 --> 01:06:54,543 ENJOYED IT. 1977 01:06:54,610 --> 01:06:56,612 I WAS REALLY INTERESTED FROM THE 1978 01:06:56,679 --> 01:06:57,713 BOTTOM UPPER SPECULATIVE 1979 01:06:57,780 --> 01:06:59,115 THINKING ABOUT THE MUSCULATURE 1980 01:06:59,181 --> 01:07:02,051 FEEDING BACK TO THE BRAIN TO 1981 01:07:02,118 --> 01:07:02,618 DICTATE BRAIN STATE. 1982 01:07:02,685 --> 01:07:03,819 HAVE YOU EVER TRIED ANYTHING 1983 01:07:03,886 --> 01:07:06,188 WHERE YOU MANIPULATED MUSCLE 1984 01:07:06,255 --> 01:07:07,189 TONE PERIPHERALLY BUT TRIED TO 1985 01:07:07,256 --> 01:07:09,358 KEEP THE ANIMAL AT THE SAME 1986 01:07:09,425 --> 01:07:10,926 CONSCIOUS STATE, OR THOUGHT 1987 01:07:10,993 --> 01:07:14,263 ABOUT KIND OF THE HIGH 1988 01:07:14,330 --> 01:07:14,930 DIMENSIONAL DATA THAT YOU GET 1989 01:07:14,997 --> 01:07:16,365 FROM ALL THE INDIVIDUAL MUSCLES 1990 01:07:16,432 --> 01:07:18,000 AND THEN HOW THAT FEEDS BACK 1991 01:07:18,067 --> 01:07:19,869 INTO THE BRAIN STATE, BECAUSE 1992 01:07:19,935 --> 01:07:22,371 YOU'RE THINKING ABOUT LIKE 1993 01:07:22,438 --> 01:07:24,774 REALLY HIGH ENERGY LOCOMOTION, 1994 01:07:24,840 --> 01:07:28,477 THERE'S COORDINATED CONTRACTION 1995 01:07:28,544 --> 01:07:30,146 OF HIND LIMBS, FORELIMBS VERSUS 1996 01:07:30,212 --> 01:07:30,880 LIKE GROOMING. 1997 01:07:30,946 --> 01:07:32,114 >> SO THE WAY THAT WE'RE 1998 01:07:32,181 --> 01:07:35,317 THINKING ABOUT IT RIGHT NOW IS 1999 01:07:35,384 --> 01:07:37,286 THE RELATIONSHIP BETWEEN THE 2000 01:07:37,353 --> 01:07:39,121 MUSCULAR ACTIVITY AND THE BRAIN 2001 01:07:39,188 --> 01:07:41,757 STATE IS MORE LIKE THE NEURONS, 2002 01:07:41,824 --> 01:07:43,259 THE SAME NEURONS CONTROLLING 2003 01:07:43,325 --> 01:07:44,827 BOTH. 2004 01:07:44,894 --> 01:07:46,162 BUT OF COURSE -- BUT I THINK 2005 01:07:46,228 --> 01:07:48,931 THAT WHAT YOU'RE SAYING IS THAT 2006 01:07:48,998 --> 01:07:50,065 COULD THERE BE FEEDBACK. 2007 01:07:50,132 --> 01:07:52,568 IF YOU LEAVE THE NEURONS ALONE 2008 01:07:52,635 --> 01:07:57,039 BUT YOU PAIR PL -- YOU PARALYZEE 2009 01:07:57,106 --> 01:07:57,907 MUSCLES, WHAT'S GOING TO HAPPEN. 2010 01:07:57,973 --> 01:07:59,241 I THINK IT'S HARD TO PREDICT 2011 01:07:59,308 --> 01:08:01,310 BECAUSE WHEN WE'RE MAKING 2012 01:08:01,377 --> 01:08:02,611 MOVEMENTS, CONSTANT FEEDBACK 2013 01:08:02,678 --> 01:08:04,780 PLACE A HUGE ROLE IN OUR NEXT 2014 01:08:04,847 --> 01:08:04,980 STEP. 2015 01:08:05,047 --> 01:08:06,115 IF I TOUCH SOMETHING, I DON'T 2016 01:08:06,182 --> 01:08:07,316 SENSE I'M TOUCHING SOMETHING, I 2017 01:08:07,383 --> 01:08:08,284 MIGHT BE DOING DIFFERENT THINGS. 2018 01:08:08,350 --> 01:08:09,919 SO I THINK -- I'LL BET IF YOU DO 2019 01:08:09,985 --> 01:08:11,187 THAT EXPERIMENT, YOU WILL SEE 2020 01:08:11,253 --> 01:08:12,521 THAT THE FEEDBACK SIGNAL IS 2021 01:08:12,588 --> 01:08:12,955 THERE. 2022 01:08:13,022 --> 01:08:16,125 BUT WE JUST HAVEN'T GOTTEN INTO 2023 01:08:16,192 --> 01:08:16,592 THAT YET. 2024 01:08:16,659 --> 01:08:17,960 THAT'S WHY EVEN WHEN I THOUGHT 2025 01:08:18,027 --> 01:08:19,295 THE IMMUNE SYSTEM WAS SUPER 2026 01:08:19,361 --> 01:08:21,931 IMPORTANT, WHAT DID I DO WITH 2027 01:08:21,997 --> 01:08:22,798 MICROGLIA, BECAUSE THEY'RE 2028 01:08:22,865 --> 01:08:23,332 INSIDE THE BRAIN. 2029 01:08:23,399 --> 01:08:24,767 ONCE I GET OUTSIDE THE BRAIN, I 2030 01:08:24,834 --> 01:08:30,139 DON'T KNOW WHAT TO DO. 2031 01:08:30,206 --> 01:08:31,640 >> THANK YOU FOR YOUR TALK. 2032 01:08:31,707 --> 01:08:32,608 QUICK QUESTION ABOUT THE 2033 01:08:32,675 --> 01:08:33,709 COGNITIVE IMPLICATIONS OF SLEEP. 2034 01:08:33,776 --> 01:08:34,910 SO WE KNOW IT'S IMPORTANT FOR 2035 01:08:34,977 --> 01:08:36,312 MEMORY CONSOLIDATION AND OTHER 2036 01:08:36,378 --> 01:08:37,947 COGNITIVE FUNCTION. 2037 01:08:38,013 --> 01:08:40,783 HOW DOES THIS CAT C CATECHOLAMIE 2038 01:08:40,850 --> 01:08:42,785 HYPOTHESIS FIT INTO THIS STUDY? 2039 01:08:42,852 --> 01:08:47,223 >> CA CATECHOLAMINE REGULATES 2040 01:08:47,289 --> 01:08:49,425 MEMORY PLASTICITY BIG TIME. 2041 01:08:49,492 --> 01:08:51,594 I'M NOT SUPER FAMILIAR WITH THE 2042 01:08:51,660 --> 01:08:53,896 LITERATURE. 2043 01:08:53,963 --> 01:08:56,198 I KNOW THERE ARE A LOT OF PAPERS 2044 01:08:56,265 --> 01:08:57,600 STUDYING THOSE BUT I CAN'T GIVE 2045 01:08:57,666 --> 01:08:58,901 YOU A COHERENT STUDY ON EXACTLY 2046 01:08:58,968 --> 01:09:00,336 WHAT THEY DO, BUT I KNOW THEY 2047 01:09:00,402 --> 01:09:01,437 HAVE BIG EFFECTS DEPENDING ON 2048 01:09:01,504 --> 01:09:03,639 THE CIRCUITS. 2049 01:09:03,706 --> 01:09:05,140 >> HI. 2050 01:09:05,207 --> 01:09:07,109 I HAVE -- REGARDING THE 2051 01:09:07,176 --> 01:09:09,945 DIFFERENT -- BETWEEN THE PATTERN 2052 01:09:10,012 --> 01:09:13,048 OF DIE EURNL AND NOCTURNAL 2053 01:09:13,115 --> 01:09:13,616 SPECIES. 2054 01:09:13,682 --> 01:09:15,751 DO YOU KNOW IF THE 2055 01:09:15,818 --> 01:09:17,720 SUBPOPULATIONS YOU SHOWED, ARE 2056 01:09:17,786 --> 01:09:20,122 THEY ACTIVATED IN THE SAME WAY? 2057 01:09:20,189 --> 01:09:21,457 >> -- WOULD BE THE GUY TO 2058 01:09:21,524 --> 01:09:22,291 ANSWER THAT QUESTION, RIGHT? 2059 01:09:22,358 --> 01:09:24,393 I DON'T. 2060 01:09:24,460 --> 01:09:25,594 SO UNFORTUNATELY WE'RE LIMITED 2061 01:09:25,661 --> 01:09:27,129 TO MICE. 2062 01:09:27,196 --> 01:09:32,101 WE HAVEN'T STUDIED ANY DIURNAL 2063 01:09:32,167 --> 01:09:32,334 ANIMALS. 2064 01:09:32,401 --> 01:09:33,903 >> DO YOU KNOW IF THE SNR IS 2065 01:09:33,969 --> 01:09:36,972 RECEIVING ANY INPUTS FROM -- 2066 01:09:37,039 --> 01:09:38,274 REGIONS OF THE BRAIN? 2067 01:09:38,340 --> 01:09:47,783 >> NOT THAT I'M AWARE OF, RIGHT? 2068 01:09:47,850 --> 01:09:58,027 [APPLAUSE]