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1、大脑与节律大脑与节律Biological RhythmsAlmost all land animals coordinate their behavior according to circadian rhythms - the daily cycles of daylight and darkness that result from the spin of the Earth. (The term is from the Latin circa, “approximately,” and dies,“day.”) In humans, there is an approximately i
2、nverse relationship between the propensity（倾向、习性倾向、习性） to sleep and body temperatureHuman Circadian Time StructureEnvironmentalLight IntensityPlasma MelatoninConcentrationSleep-Wake CycleTime of DayBody TemperaturePlasma CortisolConcentrationWhen the cycles of daylight and darkness are removed - cir
3、cadian rhythms continue on more or less the same schedule - the primary clocks for circadian rhythms are not astronomical (the sun and earth) but biological, in the brain.Brain clocks are imperfect and require occasional resettingExternal stimuli, such as light and dark, or daily temperature changes
4、, help adjust the brains clocks to keep them synchronized with the coming and going of the sunlight. Brain clocks are an interesting example of the link between the activity of specific neurons and behavior.Biological clockThe first evidence, a brainless organism - the mimosa plant that raises leave
5、s during the day and lowers them at night: reacts to sunlight, in some kind of reflex movement? In 1729, French physicist de Mairan: mimosa plants continued to raise and lower their leaves in darkness, still sensing the suns movements? 100 yrs later, Swiss botanist de Candolle: a similar plant in th
6、e darkness moved its leaves up and down every 22, rather than 24, hrs, implying the plant was not responding to the sun and very likely had an internal biological clock.Zeitgeber: a stimulus that resets the biological clock (eg. bright light, exercise, temperature) What sets the Clock?The strongest
7、zeitgeber, for both plants and animals, is light. Non-photic zeitgebers include temperature, social interactions, pharmacological manipulation, exercise, and eating/drinking patterns.Biological clockBiological clock overrides （重写、无视重写、无视）most environmental cues.To maintain clock-environment synchron
8、y, zeitgebers induce changes in the concentrations of the molecular components of the clock to levels consistent with the appropriate stage in the 24-hr cycle, a process termed entrainment.In the presence of zeitgebers, animals become entrained to the day-night rhythm and maintain an activity cycle
9、of exactly 24 hrs. Deprivation of zeitgebers: free-runningEven small, consistent errors of timing could not be tolerated for long - a 24.5-hour cycle would, within 3 weeks, completely shift an animal from daytime to nighttime activity. When mammals are completely deprived of zeitgebers, they settle
10、into an activity-rest rhythm often with a period more or less than 24 hrs, in which case their rhythms are said to freerun （自由运转自由运转）In mice, the natural free-running period is about 23 hrs; hamsters, 24 hrs; humans, 24.525.5 hrsBiological clockDifficult to separate a human from all possible zeitgeb
11、ers: deep caves, the sites for several isolation studiesWhen people in caves are allowed to set their own schedules of activity for months on endwaking and sleeping, turning lights on and off, and eating when they choosethey initially settle into roughly a 25-hr rhythm. But after days to weeks, thei
12、r activity may begin to free-run with a surprisingly long period of 3036 hrs: staying awake for about 20 hrs straight, then sleep for about 12 hrs, and this pattern seems perfectly normal to them at the time.Biological clockIn isolation experiments, behavior and physiology do not always continue to
13、cycle together: the rhythms of temperature and sleeping-waking, which are normally synchronized to a 24-hr period, become desynchronized. One implication of this desynchronization is that the body has more than one biological clock, uncoupled from one another. Desynchronization may occur temporarily
14、 - when we travel and force our bodies suddenly into a new sleep-wake cycle: jet lag, and the best cure is bright light, which helps resynchronize our biological clock.LightBecause behavior is normally synchronized with light-dark cycles, there must also be a photosensitive mechanism for resetting t
15、he brain clock. Mammals have a tiny pair of neuron clusters in the hypothalamus that serves as a biological clock: the suprachiasmatic nuclei (SCN), retinal ganglion cells send direct projections to the SCN, i.e. the retinohypothalamic tract, which provides information about light to the SCN light c
16、an also alter blood-borne factors SCN is highly vascularizedWhat Reset the Clock?Melatonin secreted from the pineal gland increased levels of melatonin: one feels sleepy melatonin can act on receptors in the SCN to phase-advance the biological clockWhat Reset the Clock?The circadian timing systemSup
17、erior cervicalganglion Axons from ganglion cells in the retina synapse directly on the dendrites of SCN neurons. This input from the retina is necessary and sufficient to entrain sleeping and waking cycles to night and day. Pineal gland (to birds?) is unimportant to humans, but melatonin may be impo
18、rtant.Biological clockWhen the SCN is stimulated electrically, circadian rhythms can be shifted in a predictable wayRemoval of both nuclei abolishes the circadian rhythmicity of physical activity, sleeping and waking, and feeding and drinking.In hamsters, the transplantation of a new SCN can restore
19、 rhythms within 24 weeks. The brains internal rhythms never return without an SCN. SCNBiological clockA biological clock producing circadian rhythms consists of several components:Light-sensitive input pathway Clock Output pathwayOne or more input pathways are sensitive to light and dark; the clock
20、itself continues to run and keep its basic rhythm even when the input pathway is removed. Output pathways from the clock allow it to control certain brain and body functions according to the timing of the clock.Biological clockThe retinal cells synchronizing the SCN are neither rods nor cones -Eyele
21、ss mice cannot use light to reset their clocks, but mutant mice with intact retinas that lack rods and cones can! David Berson et al. discovered a new photoreceptor in the retina that was not at all like rods and cones but was, remarkably, a very specialized type of ganglion cell. The light-sensitiv
22、e ganglion cells express a newly recognized type of photopigment called melanopsin（视黑素视黑素）, which is not present in rods and cones, and are very slowly excited by light, their axons sending a signal directly to the SCN that can reset the circadian clock that resides there.?Biological clockOutput axo
23、ns of the SCN mainly innervate nearby parts of the hypothalamus, but some also go to the midbrain and other parts of the diencephalon Because almost all SCN neurons use GABA as their primary neurotransmitter, presumably they inhibit the neurons they innervate.In addition to the axonal output pathway
24、s, SCN neurons may rhythmically secrete the peptide neuromodulator vasopressinHow do neurons of the SCN keep time? no complete answer at the molecular level, but its clear that each SCN cell is a minuscule（极小的） clock.Biological clockRemove SCN neurons of an animal and grow them alone in a tissue cul
25、ture dish - their rates of action potential firing, glucose utilization, vasopressin production, and protein synthesis continue to vary with rhythms of about 24 hrs, just as they do in the intact brain. Circadian rhythms of the SCN isolated from the rest of the brain. The activity of a clock gene wa
26、s monitored in 100 individual SCN neurons maintained in tissue culture. Each neuron generates a strong circadian rhythm that is well coordinated with the neurons. (Fig 19.22)Biological clockSCN cells in culture can no longer be entrained to light-dark cycles (input from the eyes is necessary for thi
27、s), but their basic rhythmicity remains intact and expresses itself just as it does when an animal is deprived of zeitgebers.SCN cells communicate their rhythmic message to the rest of the brain through efferent axons, using action potentials (APs) in the usual way, and rates of SCN cell firing vary
28、 with a circadian rhythm.However, APs are unnecessary for SCN neurons to maintain their rhythm - When tetrodotoxin (TTX，河豚毒河豚毒), a blocker of sodium channels, is applied to SCN cells, it blocks their APs but has no effect on the rhythmicity of their metabolism and biochemical functions. Biological c
29、lockWhen the TTX is removed, APs resume （重新开始重新开始）firing with the same phase and frequency they had originally - the SCN clock keeps running even without APs. SCN APs are like the hands of a clock; removing the clocks hands does not stop the clock from working, but it does make it very difficult to
30、read the time. It is a molecular cycle based on gene expression, which in humans is very similar to those found in mice, fruit flies (Drosophila), and bread mold: in Drosophila and mice, the system involves clock genes known as period (per), timeless (tim), and clock. Biological clockAlthough the de
31、tails vary across species, the basic scheme is a negative feedback loop. Joseph Takahashi et al. at Northwestern University named the clock gene (an acronym for circadian locomotor output cycles kaput). A clock gene is transcribed to produce mRNA that is then translated into proteins. After a delay,
32、 the newly manufactured proteins send feedback and somehow interact with the transcription mechanism, causing a decrease in gene expression - less protein is produced, and gene expression again increases to start the cycle anew. This entire cycle takes about 24 hrs, and thus it is a circadian rhythm
33、Biological clockClock genes. In the SCN, clock genes produce proteins that inhibit further transcription.Gene transcription and the firing rate of individual SCN neurons cycle up and down over 24 hrs.The cycles of many cells are synchronized by light exposure (input from theretina) and by interactio
34、ns of the SCN neurons.(Figure 19.23).Biological clockThere must be a mechanism to coordinate the thousands of cellular clocks so that the SCN as a whole transmits a single, clear message about time to the rest of the brain. Light information from the retina serves to reset the clocks in the SCN neur
35、ons each day, but the SCN neurons also communicate directly with each other and seems to be independent of APs and normal synaptic transmission: TTX does not block them. Also, the SCN of the very young rat brain coordinates circadian rhythms perfectly well, even before it has developed any chemical
36、synapses. In addition to classical chemical synapses, it may include other chemical signals, gap junctions, or the participation of glia.Types of RhythmsCircadian fluctuate dailySleep-wake, temperature, hormones, urine production, gastrointestinal activityCognitive and motor performance levelsInfrad
37、ian less than once a dayHibernation, ovulationUltradian more than once a daySleep cycles (REM and other sleep stages)Multiple PacemakersSCN cycles (affected by environment):Sleep-wake cyclesSkin temperatureHormones in blood, calcium in urine.Cycles independent of SCN:Sleep cycles (REM)Internal body
38、temperatureCortisol in blood, potassium in urine.Rhythms and DisturbanceEpilepsyExtreme synchronous behavior in which many neurons fire at once.Localized or globalUpsets balance of excitation and inhibition among neuronsDelayed sleep-phase insomniaSeasonal depressionDesynchronization between circadi
39、an rhythms, sleep and emotion states may result in depression.Depression is almost invariably cyclic.Many depressed people enter REM sleep earlier than normal.Sleep deprivation may ease depression temporarily.Alzheimers diseaseAlzheimers disease Randomized Clinical trial:Light & Melatonin 3.5 yr in
40、up to 189 subjects in 12 homes for the elderly, placebo-controlled.- nocturnal restlessness - 22% by light & melatonin- enhanced rhythms (activity, melatonin)- 12% less depressive symptoms- attenuated cognitive decline (3 MMSE points after 3.5 yearsMMSE changeRiemersma et al., JAMA,299, 2642-2655, 2008
