Lecture 10 - Synaptic Circuitry Regulating Sleep-Wake Cycles PDF

1 LECTURE 10: NEURAL CIRCUITRY REGULATING SLEEP-WAKE STATES PROF. JUNIOR STEININGER 2 WHY SHOULD WE CARE ABOUT THE NEURAL CIRCUITRY CONTROLLING SLEEP? 3 EFFECTS OF SLEEP DEPRIVATION OR POOR SLEEP QUALITY 4 WHAT IS SLEEP? 5 REGULATION OF THE SLEEP-WAKE CY...

1 LECTURE 10: NEURAL CIRCUITRY REGULATING SLEEP-WAKE STATES PROF. JUNIOR STEININGER 2 WHY SHOULD WE CARE ABOUT THE NEURAL CIRCUITRY CONTROLLING SLEEP? 3 EFFECTS OF SLEEP DEPRIVATION OR POOR SLEEP QUALITY 4 WHAT IS SLEEP? 5 REGULATION OF THE SLEEP-WAKE CYCLE IS CONTROLLED BY TWO DISTINCT PROCESSES 6 WE LIVE IN A HIGHLY RHYTHMIC WORLD THESE RHYTHMS IMPACT THE AVAILABILITY OF OUR RESOURCES AND SHOULD INFLUENCE BEHAVIOURAL DECISIONS 7 WE’VE DEVELOPED MEANS TO HELP TRACK THE PASSAGE OF TIME 8 But what did we do before clocks? How do animals and plants track time? 9 THERE MUST BE AN INTERNAL BIOLOGICAL MECHANISM THAT CAN KEEP RELIABLE TIME, WITHOUT ACTUAL CLOCKS 10 CIRCADIAN RHYTHMS REFER TO OSCILLATIONS IN OUR BEHAVIOUR AND PHYSIOLOGY THROUGHOUT THE DAY (24-HR CYCLE) 11 MOST PHYSIOLOGICAL AND BIOCHEMICAL PROCESSES RISE AND FALL WITH CIRCADIAN RHYTHMS, INCLUDING SLEEP/WAKE CYCLES 12 THE SUPRACHIASMATIC NUCLEUS SERVES AS AN INTERNAL BIOLOGICAL CLOCK -> MASTER CLOCK Necessary components of a biological clock: Light sensor -> tracks time -> Output The SCN is both necessary and sufficient for normal sleep‐wake cycles and other circadian rhythms 13 CENTRAL CLOCK NEURONS GENERATE CIRCADIAN RHYTHMS IN ELECTRICAL ACTIVITY THAT ARE STABLE AND SELF-SUSTAINED 14 CENTRAL CLOCK NEURONS GENERATE CIRCADIAN RHYTHMS IN ELECTRICAL ACTIVITY THAT ARE STABLE AND SELF-SUSTAINED 15 CLOCK GENES FUNCTION VIA AN AUTOREGULATION, NEGATIVE FEEDBACK LOOP THAT TAKES ~24HR TO COMPLETE ONE CYCLE 16 CONSEQUENCE OF LIGHT-EXPOSURE ON THE MOLECULAR CLOCKWORK OF THE SCN Light -> melanopsin‐expressing retinal ganglion cells RHT -> SCN neurons Glutamate and a neuropeptide (PACAP) are released Increased intracellular Ca2+ Phosphorylated CREB leads to increased transcription of Per1 and Per2 Can result in adjustments of SCN circadian activity and shifts in subjective day and night 17 REGULATION OF THE SLEEP-WAKE CYCLE IS CONTROLLED BY TWO DISTINCT PROCESSES 18 FOR SLEEP HOMEOSTASIS, WHAT COULD BE SERVING THE ROLE OF THE “SAND” IN THE HOURGLASS? Criteria for being a Sleep Regulatory Substance: Should be something that enhances a sleep phenotype Inhibition of the SRS should reduce sleep Levels of the SRS should correlate with sleep propensity The SRS should act on putative sleep regulatory circuits The SRS levels in disease should correlate with sleepiness What is it? We have no Idea….. But there are some candidates…. 19 FOR SLEEP HOMEOSTASIS, WHAT COULD BE SERVING THE ROLE OF THE “SAND” IN THE HOURGLASS? Accumulation of adenosine during wake hours Nitric Oxide (NO) Cytokines (interleukin-1, TNF) Some other metabolite? DNA damage? A change to overall synaptic strength of many neural circuits Not much is known about the genetic and circuit basis for sleep homeostasis 20 HOW DO WE MEASURE SLEEP- WAKE STATES? 21 DIFFERENTIATING BEHAVIOURAL STATES OF WAKE, NREM SLEEP AND REM SLEEP 22 AN EEG ELECTRODE DETECTS SMALL ELECTRICAL FIELDS GENERATED BY SYNAPTIC CURRENTS IN CORTICAL PYRAMIDAL CELLS 23 THE SIZE OF EEG SIGNALS TELLS US HOW WELL SYNCHRONIZED ACTIVITY IN CORTICAL PYRAMIDAL CELLS ARE 24 AMPLITUDE AND SYNCHRONY MEASUREMENTS OF EEG RHYTHMS DISTINGUISH THE DIFFERENT STAGES OF SLEEP 25 RECALL: THALAMIC RELAY NEURONS DISPLAY DIFFERENT MODES OF VOLTAGE-DEPENDENT FIRING: “TONIC” OR “BURST” ACTIVITY 26 A HYPNOGRAM REPRESENTS THE IDENTIFIED STAGES OF SLEEP AS A FUNCTION OF TIME, REFERRED TO AS “SLEEP ARCHITECTURE” 27 NEURAL CIRCUITRY REGULATING SLEEP-WAKE STATES 28 EARLY INSIGHT INTO THE NEURAL CIRCUITRY UNDERLYING SLEEP AND WAKEFULNESS 29 BRAIN TRANSECTIONS AND ELECTRICAL STIMULATION EXPERIMENTS INDICATE IMPORTANCE OF THE MEDULLA AND PONS 30 BRAIN TRANSECTIONS AND ELECTRICAL STIMULATION EXPERIMENTS INDICATE IMPORTANCE OF THE MEDULLA AND PONS 31 BRAIN TRANSECTIONS AND ELECTRICAL STIMULATION EXPERIMENTS INDICATE IMPORTANCE OF THE MEDULLA AND PONS 32 THE BIG QUESTIONS BEING ASKED 1. Which regions are active during sleep and wake states? 2. Is activity in this region sufficient or necessary for promoting sleep or wake states? Technological advancements are always striving to improve precision, sensitivity, specificity, and being able to study under natural and ethologically-relevant conditions 33 CURRENT METHODS FOR NEURONAL MANIPULATIONS 34 CURRENT METHODS FOR MEASURING NEURAL ACTIVITY 35 CURRENT METHODS FOR MEASURING NEURAL ACTIVITY 36 CURRENT METHODS FOR MEASURING NEURAL ACTIVITY 37 NEURAL CIRCUITRY REGULATING SLEEP-WAKE STATES 38 SEVERAL NEUROCHEMICALLY DISTINCT SYSTEMS HELP PROMOTE WAKEFULNESS -> ASCENDING RETICULAR AROUSAL SYSTEM 39 THE MONOAMINERGIC NEURONS SHOW SIMILAR FIRING PATTERNS: HIGH DURING WAKE, LOW DURING NREM, ABSENT DURING REM 40 THE BASAL FOREBRAIN CHOLINERGIC NEURONS ARE ACTIVE DURING WAKE AND REM, RESPONSIBLE FOR FAST CORTICAL EEG 41 MANY OF THE WAKE- PROMOTING NEUROMODULATORS INDUCE TONIC FIRING IN THALAMIC RELAY NEURONS (I.E., “AWAKE” STATE) 42 WHAT ARE SOME POTENTIAL CAVEATS/COMPLICATIONS WHEN TRYING TO INVESTIGATE THE NEURAL REGULATION OF WAKEFULNESS? There are a lot of areas promoting wakefulness. Is this secondary to engagement of other pathways? Are different cell groups organized hierarchically, in recurrent loops, or work in parallel to control different aspects of wake/sleep? Heterogeneity of cell types and their projections within one area. Do they all play the same role? Understanding the mechanisms and conditions of co‐release and neuropeptides (a limitation of optogenetics). 43 WHAT ARE SOME POTENTIAL CAVEATS/COMPLICATIONS WHEN TRYING TO INVESTIGATE THE NEURAL REGULATION OF WAKEFULNESS? Redundancy of function and potential for compensation (differences with acute vs chronic effects of lesions). Emergent behavioural states likely reflect the summated activity across all of these neurons. What does it even mean to stimulate/inhibit just one circuit? Do changes in firing rate actually have a casual role in triggering/maintaining the state transition? Disentangling fundamental wake‐promoting roles from their other functions (e.g. mood, attention, reward, locomotion, thermoregulation) 44 LH NEURONS RELEASING OREXIN EXCITE NEURONS IN CORTEX, THALAMUS, AND ALL WAKE-PROMOTING BRAIN REGIONS 45 ACTIVATION OF OREXIN NEURONS WAKE ANIMALS FROM SLEEP AND SUPPRESSES REM SLEEP 46 LOSS OF OREXIN NEURONS DOES NOT CHANGE TOTAL AMOUNTS OF SLEEP- WAKE, BUT INCREASES TRANSITIONS BETWEEN STATES 47 FOCAL RESTORATION OF TMN AND LC SUBSTANTIALLY IMPROVES ABILITY TO MAINTAIN WAKEFULNESS AFTER OREXIN LOSS 48 INHIBITION OF LC BLOCKS THE AWAKENING EFFECT OF STIMULATING OREXIN NEURONS DURING SLEEP 49 BUT LESIONS TO THE LATERAL HYPOTHALAMUS CAUSE MORE SEVERE SLEEPINESS SYMPTOMS THAN SELECTIVE LOSS OF OREXIN NEURONS 50 NEURAL CIRCUITRY REGULATING SLEEP-WAKE STATES 51 GABAERGIC NEURONS IN VLPO+MNPO PROMOTE NREM SLEEP BY INHIBITING THE WAKE-PROMOTING NEURONS 52 THE BASAL FOREBRAIN ALSO CONTAINS GABAERGIC SLEEP- ACTIVE NEURONS THAT MAY PROMOTE SLEEP 53 GABAERGIC NEURONS IN THE PARAFACIAL ZONE MAY PROMOTE SLEEP BY INHIBITING THE PARABRACHIAL NUCLEUS 54 THERE ARE ALSO SOME NREM SLEEP-ACTIVE NEURONS IN CORTEX CONTAINING BOTH GABA AND NITRIC OXIDE SYNTHASE 55 DIFFERENT NEURAL CIRCUITRY UNDERLIES REM SLEEP 56 GLUTAMATERGIC NEURONS IN THE SUBLATERODORSAL (SLD) NUCLEUS PLAY A CRITICAL ROLE IN GENERATING REM SLEEP 57 SLD ACTIVITY LEADS TO INHIBITION OF SPINAL MOTOR NEURONS, ALLOWING MUSCLE PARALYSIS DURING REM SLEEP 58 CHOLINERGIC NEURONS IN PPT/LDT MAY HELP DRIVE THE FAST EEG TYPICAL OF REM BY ACTIVATING THE BASAL FOREBRAIN 59 DURING WAKE AND NREM, GABAERGIC NEURONS WITHIN THE LC, DR, AND VLPAG INHIBIT THE SLD 60 MCH-RELEASING NEURONS IN THE LATERAL HYPOTHALAMUS PROMOTE REM SLEEP INDUCTION AND DURATION 61 NEURAL CIRCUITRY REGULATING SLEEP-WAKE STATES 62 THE SLEEP- WAKE “FLIP- FLOP” SWITCH 63 THE SLEEP-WAKE “FLIP-FLOP” SWITCH Setup by mutually inhibitory neurons 64 THE REM- NREM SLEEP “FLIP-FLOP” SWITCH 2 POPULATIONS OF MUTUALLY INHIBITORY NEURONS 65 THE REM- NREM SLEEP “FLIP-FLOP” SWITCH OTHER KEY PLAYERS ACT TO ALTER THE BALANCE OF THE SWITCH 66 RECIPROCAL BISTABLE FIRING PATTERNS BETWEEN SLEEP PROMOTING AND WAKE-PROMOTING NEURONS 67 CASCADING WAKE-SLEEP AND REM-NREM SWITCHES 68 CASCADING WAKE- SLEEP AND REM- NREM SWITCHES ARE STABILIZED BY OREXIN NEURONS 69 LOSS OF OREXIN IN NARCOLEPSY CONSISTENT WITH SYMPTOMS OF A DESTABILIZED SWITCHING MECHANISM 70 CIRCADIAN INFLUENCES ON THE SLEEP/WAKE CIRCUITS