NEURAL MECHANISMS OF SLEEP (p.1) (Rev. 3/21/07) 1. Revisitation of Bremer s 1936 Isolated Brain Studies Transected the brain: a. Cut between the medulla and the spinal cord ( encephale isole ) Note: recall that in the 1930s the passive brain being driven into W was the major hypothesis By cutting the CNS at this level, still have 4 of the 5 major senses still coming into the brain via cranial nerves so Cat s brain should still show what re. Sleep (REM&SWS) & Wake? And, what did it show? b. Cut between the inferior and superior colliculi ( cerveau isole ) By cutting the CNS at this level, would only have 2 of the 5 senses still coming into the brain via cranial nerves so Cat s brain should show what re. Sleep & Wake? And, what did it show?... What was Bremer s (incorrect) interpretation of these data? That indeed the brain was passive, was driven into W by incoming sensory stimulation, w/o which brain lapses into sleep But what if there was another explanation?.. What if there were a brain center just posterior to cut made in midbrain and just anterior to cut made in hindbrain, and what if that center generated wakefulness (and REM)? 2. Reticular Activating System W This structures generates wakefulness, alerting Discovered in late 1940s by UCLA researchers Moruzzi & Magoun Core of diffuse neurons lying midbrain+hindbrain Receives information from many incoming sensory pathways Sends axons to many areas of forebrain (incl. thalamus, basal ganglia, and basal forebrain) If stimulate RAS while S is asleep?
NEURAL MECHANISMS OF SLEEP (p.2) 2. Reticular Activating System (cont.) If stimulate RAS while S is awake? If lesion the RAS? What happens if you cut all the incoming sensory signals to the RAS but leave the RAS itself intact?... Thus, sleep and wake are active processes that are generated from within the brain itself, independent of (although affected by) sensory stimuli Sleep and wake are not passive processes as once thought Why does RAS send so much output to: Basal ganglia? Thalamus? Basal forebrain? What NTs does RAS use? RAS (in midbrain) & Pontomesencephalic system (pons & midbrain) Receive sensory input from many ascending pathways Send inputs to thalamus and basal forebrain Releases ACh & Glutamate ( EPSEs) increased arousal & W e.g. nicotine (ACh agonist) increased W and alertness e.g. if basal forebrain damaged (e.g. Alzheimer s Disease) poor attentional focus, impaired alertness, increased S (esp. SWS) 3. Turning Off Arousal and Turning On Sleep How do we transition out of high arousal and into sleep? Basal Forebrain Region & Anterior Hypothalamus Both of these regions are together implicated in initiating sleep Tumors/lesions in this area difficulty initiating sleep, no more SWS If stimulate BFR/AH increased SWS Neurons in this area are active only during sleep Adenosine (a peptide NT) levels increase with prolonged W, and decrease With S Adenosine inhibits ACh neurons of the basal forebrain less arousal Adenosine may play a primary role in the onset/control of sleep
Neural Mechanisms of Sleep (p.3) Turning Off Arousal & Turning on Sleep (cont.) Why do we need to turn off wakefulness every so often? Maybe cells need to replenish energy supplies Other neurotransmitters that may have something to do with going from W S: Histamine, GABA, and Orexin/Hypocretin There are neurons that run from the hypothalamus to the basal forebrain that use histamine as their NT histamine increased arousal histamine antagonist drugs ( anti-histamines ) less arousal, drowsiness e.g. Benadryl (blocks H1 RS) histaminergic neurons are very active during W, very inactive during S (both during NREM and REM) Cells in the basal forebrain and the hypothalamus also increase the release of GABA increased IPSPs (inhibition) in brain activity decreased Arousal increased likelihood of S (esp. NREM and SWS) GABA agonist drugs (e.g. sedative-hypnotics) (alcohol, barbiturates, BZDs) decreased arousal & increased likelihood of sleep Role of orexin/hypocretin Humans with a sleep disorder called narcolepsy have a great deal of difficulty remaining awake & keep lapsing into sleep At birth they have normal wake and sleep, but begin developing severe EDS in adolescence typically The onset of these symptoms coincide with the dying off of neurons in their lateral hypothalamus that normally produce orexin (also called hypocretin) Is orexin/hypocretin a NT that promotes wakefulness?
Neural Mechanisms of Sleep (p.4) 4. Once Asleep, What Controls Sleep Stages? ( sleep architecture ) Raphe Nuclei Must be inactive for REM to occur These are midline structures in the brainstem (near pontine/medullary RF) Neurons are the major source of serotonin/5ht in the brain These 5HT neurons are most active W, decrease their activity as become sleepy, and then enter sleep Almost no activity during REM except for the first seconds of REM sleep when they are very active (even > than in W) Give PCPA (parachlorophenylalanine) totally blocks synthesis of 5HT decreased cortical arousal Activity in Raphe neurons seems to inhibit REM Nuclei in Pons/Medulla that Control REM Sleep If transect brain anterior to pons no REM If transect brain posterior to pons still see REM (alternating with SWS) PGO spikes precede the onset of REM sleep (Pons, lateral Geniculate nucleus, Occipital lobe) At the start of REM, each PGO spike correlates with a single REM (rapid eye movement) Locus coeruleus (in dorsal pons region): Like the Raphe nucleus, neurons in LC must be inactive for REM to occur LC neurons most active in W, decrease their activity before SO, inactive in REM Is the major source of nor-epinephrine NT If stimulate just ventral to LC abolishes REM sleep If lesion LC induces/prolongs REM sleep Neurons in LC are inactive during REM sleep
NEURAL MECHANISMS OF SLEEP (cont., p.5) Neurons that control REM use ACh (acetylcholine) Cholinergic agonists induces/prolong REM sleep (e.g. muscarine) Cholinergic antagonists reduce/block REM sleep (e.g. antidepressants) Specialized nuclei in area of pons & medulla that control various aspects of REM sleep: To generate PGO spikes To produce cortical EEG desynchronization (peribrachial area) To generate hippocampal theta waves (5-8 Hz) To produce muscle twitches in face, extremeties To produce REMs To produce skeletal muscle atonia (just ventral to LC)(subcoerulear nucleus) To produce SNS arousal (cardiorespiratory irregularities) If lesion subcoerulear nucleus abolishes muscle atonia normally seen in REM Jouvet s cats got up and acted out their dreams (presumably) If stimulate SN profound atonia (descending axons in spinal cord terminate on interneurons (Renshaw cells) that then inhibit alpha motor neurons skeletal muscle paralysis) Note: this system uses nor-epinephrine as a NT Peribrachial area sends axons to RF which, in turn, sends axons to basal forebrain (using ACh) desynchronous beta EEG in cortex PB area also PGO spikes and REMs PB area also activates the SN muscle atonia Suprachiasmatic Nucleus of Hypothalamus area in brain of circadian timing mechanism nucleus contains neurons that exhibit circadian cycles of electrical activity, metabolic activity, etc. (even when isolated from the rest of the brain) neurons exhibit endogenous rhythm Ss can be selectively bred to have shorter or longer rhythms Transplant data light on signals from SCN pineal gland (suppresses melatonin production) light off signals from SCN pineal gland produces melatonin Underlies the C-drive of sleep
Neural Mechanisms of Sleep (p.6) SCN receives major inputs from retina (signaling L&D), major zeitgeber is light Note: SCN is not the only brain area that can do this circadian timing, because after lesioning the SCN Ss can still entrain to food or water availability (although can no longer do so to L/D) General Summary of some NTs: In Wake ACh, NE and 5HT are all in high amounts; glutamate & histamine high Orexin/hypocretin high; adenosine accumulates In NREM ACh is low, and both NE and 5HT may be high; GABA high In REM ACh is high, and both NE and 5HT are low