Brain Rhythms and Sleep Study Guide Exam 3 PDF
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This document is a study guide for a neuroscience exam, focusing on brain rhythms and sleep. It defines EEG, discusses different brain rhythms, and their correlations to behavioral states (e.g. alertness).
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Brain Rhythms and Sleep 1. E EG: principle of method, why is it used, which part of the CNS creates the oscillations. How does the amplitude of the EEG trace depend on the activity of the underlying neurons? a. EEG- electroencephalogram: classica...
Brain Rhythms and Sleep 1. E EG: principle of method, why is it used, which part of the CNS creates the oscillations. How does the amplitude of the EEG trace depend on the activity of the underlying neurons? a. EEG- electroencephalogram: classical method of recordingbrain rhythms from the cerebral cortex, measurement of generalized cortical activity i. Thecerebral cortexproduces a range of electricalrhythms that are easily measured and reflect intriguing behaviors ii. Is noninvasive and painless - wires are taped on the skull for low resistance interaction. Wires have fixed positions. b. Why it is used -diagnosis neurological conditionssuch as seizures, epilepsy, sleep disorders, and for research c. Recording the waves -electrodes are placed on theirstandard positions, and connected to banks of amplifiers and recording devices. i. Small voltage fluctuations are measured in microvolts between pairs of electrodes in the different brain regions (difference between electrodes) d. Creating the oscillations- EEG measures voltagesgenerated by currents that flow during excitation of dendrites of pyramidal cortical neurons. It is an extracellular recording of multiple neurons i. The signal must pass through several layers of non neural tissue, such as the meninges, skull, and CSF (causes loss of some electricity) ii. thousands/millions of activated neurons are needed to observe a change in EEG e. Amplitude- associated with synchronous vs irregularfiring. Depends on firing interval i. Synchronous - inputs fire at all the same interval. Upon summation, the EEG has a LOW firing frequency and HIGH amplitude ii. Irregular - inputs fire at different intervals. Upon summation, the EEG reading has a HIGH frequency and LOW amplitude. 2. EEG rhythms are categorized based on their frequency; how do they correlate with the different behavioral states? What purpose do they serve according to current hypotheses? a. Gamma - Beta- lowest amplitude, highest frequency. i. Concentration, activated cortex,higher mental activity,problem solving, fear, arousal, cognition ii. Evident in someone highly attention, afraid, or stressed b. Alpha i. Relaxation, quiet, waking state ii. Evident in someone awake but with their eyes closed c. Theta i. Dreams, deep meditation, REM sleep ii. Small decrease in amplitude and increase in frequency d. Delta -highest amplitude, lowest frequency i. Deep dreamless sleep, loss of body awareness e. Functions of rhythms according to hypothesis i. Sleep hypothesis -brain's way of disconnecting cortexfrom sensory input. Slow rhythm to relay info, no sensory info from thalamus to the cortex so we fall asleep ii. Walter freeman hypothesis- neural rhythms coordinateactivity, synchronize oscillation, bind together 1. Playing basketball → ball is thrown at you → different groups of cells respond to different factors of the the ball → brain oscillates to create pattern of generalized activity to work together → becomes a perception 3. Which are the mechanisms by which a large group of neurons may produce synchronized oscillations? What is the role of the thalamus in this process? a. Mechanisms of synchronous rhythms i. Pacemaker - central clock 1. Coordinated rhythms then pass to the cortex through the thalamocortical axons ii. Collective behavior - sharing/distribution of timing function among neurons 1. Some rhythms of the cortex do not depend on the thalamus but on cortical interconnections b. Thalamus- massive cortical input; pacemaker neurons→ cortex i. Generation of rhythmic action potential discharges of cortex (special set of voltage gated channels) ii. Fires without an external stimulus → channels activate whenever . Which are the three functional states of the brain and which are their characteristics (i.e. 4 awake, NREM sleep, REM sleep)? awake NREM REM EEG Low voltage, fast High voltage, slow Low voltage, fast sensation ivid, externally V Dull or absent ivid, internally V generated generated thought Logical, progressive Logical, repetitive Vivid, illogical, bizarre movement Continuous, voluntary O ccasional, uschel paralysis, M involuntary movement commanded by brain but not carried out - REM atonia Rapid eye movement often rare often 5. D efine sleep and describe in detail the sleep cycle. What physiological alterations occur during NREM versus REM sleep? How do EEG rhythms vary during the different stages of sleep? a. Sleep -readily reversible state of reduced responsivenessto, and interaction with, the environment i. Universal among higher vertebrates, ⅓ of life is spent asleep, deprivation can be devastating b. Sleep cycle- every night sleep begins with a periodof NREM sleep. The cycle is NREM period interrupted by REM sleep i. NREM is roughly 75% of total sleep time interrupted by REM 1. NREM is the first part of sleep ii. NREM → REM → NREM (cycle 90 min - ultradian rhythms) 1. Ultradian rhythms - short period 2. As the night progresses the depth of NREM decreases ( decrease 3-4 stages) and REM duration increases 3. Half of the night’s REM sleep during the last third → longest REM cycle 30-50 min (obligatory refractory period of 30 min NREM sleep c. NREM- period of rest for body & brain i. Body rests - muscle tension throughout the body is reduced and movement is minimal ii. Brain rests - rate of energy demands and firing rate at the lower point of the day iii. Usually not complex dreams (when awakened only vague thoughts), not same as REM dream iv. Increased parasympathetic system, so decreased HR and RR v. Dominant large slow EEG rhythms d. REM- rapid eye movement; brain looks more awake thansleep i. Muscle paralysis - atonia, loss of skeletal muscle tone 1. Eyes move - could be due to decreased brain temp by 1 degrees so eyes move fast to increase ii. O2 consumption greater than that of an awake brain that concentrates on complex calculus iii. If awakened after REM, lifelike, vivid, and bizarre dreams are reported iv. Increased sympathetic activity, so increased HR and RR, clitoris and penis become engorged with blood v. EEG looks almost indistinguishable from that in wakefulness, fast low voltage oscillations → paradoxical e. EEG rhythms during stages of sleep i. Awake -beta and gamma waves ii. Stage 1 - transitional sleep (eyes rolling movements - few min - easy awakening) -theta waves iii. Stage 2 - deeper (5-15 min eye movements almost cease), preparing for deeper sleep . Spindles from the thalamic pacemaker 1 2. K complex - sharp dispersed waves iv. Stage 3 - slow delta waves begin to emerge v. Stage 4 - deepest stage of sleep, higher frequency delta waves vi. REM sleep (eye movements), beta and gamma rhythms 6. What hypotheses have been put forward to explain why humans sleep and how do some dolphins sleep? a. Restoration hypothesis -sleep to rest and recover,prepare to be awaken again b. Adaptation - sleep to keep out of trouble, hide frompredators, conserve energy c. Dolphins i. Have evolved to sleep w/ one hemisphere at a time ii. Spend 2h w/ left hemisphere asleep → 1 hour with both awake → 2 h w/ right hemisphere asleep d. Only mammals and birds have REM sleep 7. Should REM sleep and dreams be considered synonymous? Why do we say that “the body craves for REM sleep”? a. Dreams and REM are not synonymous b. We would rather focus on REM sleep in order to take objective measurements (but also NREM) c. Body craves for REM - Dement’s experience i. He would hook subjects up to EEGs and would wake them up when they would enter REM ii. He found that overtime when the subjects fell back to sleep they would enter REM quicker iii. Shows when the body is deprived of REM, it finds it quicker. However deprivation is not harmful d. Psychological interpretation- unconscious way toexpress forbidden secual/aggressive desires and to conquer anxiety - Freud 8. Biological interpretation of dreams: what does the activation-synthesis hypothesis support? a. Activation synthesis hypothesis -dreams are the associationsand memories of the cerebral cortex elicited by random discharges of the pons during REM sleep i. Neurons in the pons fire semi randomly → randomly activates the thalamus → thalamus randomly activates cortex → cortex synthesizes images into dreams 1. Since they are random, that's why dreams don’t make sense b. REM, dreams and memory- REM deprivation impairs learning,increased REM after intense learning experience, sleep learning 9. Neural mechanisms of sleep: critical neurons, brain regions and mechanisms involved in the regulation of wakefulness, NREM and REM sleep (REM on/off cells); why don’t we act-out our dreams? Define REM sleep behavior. a. Critical neurons -diffuse modulatory neurotransmittersystems i. NA and 5-HT neurons → fire during waking state ii. ch neurons → enhance REM events, others active during waking A iii. Ascending branches of the diffuse modulatory system control rhythmic behaviors of thalamus that in turn controls cortical EEG iv. Descending branches of diffuse modulatory systems also involved in sleep 1. Provide sending pathway to thalamus → go to spinal cord → mediate REM atonia spinal cord reflexes b. Wakefulness and the ascending reticular activating system (ARAS) -During arousal or wakefulness neurons of the ARAS increase their firing i. NA, 5-HT, ACH, Histamine, hypocretin (orexin) → collectively synapse on thalamus/cortex → depolarization, suppression of rhythmic firing 1. Orexin - regulates appetite, for those in narcolepsy they go straight into REM and fall right asleep. In this case the neurons that produced orexin have died. 2. Orexin promotes wakefulness, so when we lose it we go into REM c. Falling asleep and NREM state i. Decreased in firing rates of most brain stem modulatory neurons using NE, 5-HT, ACh → EEG sleep spindles in early stages (rhythmicity of thalamic neurons) → spindles disappear and replaced by slow delta rhythms ii. Neuron firing slows down as you get drowsy d. Mechanisms of REM sleep - striate cortex i. Internally generated explosion in extrastriate activity (not induced by primary visual cortex) ii. Limbic activation → emotional component of dreams iii. Reduced activity of frontal lobes → reduced integration/interpretation of extrastriate visual images (bizarre) e. REM On/off cells i. REM-ON - cholinergic neurons in the pons that fire at the onset of REM sleep 1. Increase firing at onset ii. REM-OFF - serotonergic (raphe), and noradrenergic (LC) neurons fire before the end of REM sleep 1. Reach nadir at REM onset, silent during NREM and beginning of REM f. Why don’t we act out our dreams? i. Because descending pathways from the diffuse modulatory systems of the brainstem suppress spinal motor neurons ii. REM atonia keeps us from moving because the brain commands movement but the atonia prevents it iii. REM sleep behavior disorder 1. Adaptive process → avoid self harm 2. Sleepwalking - NREM stage 3 & 4 not REM, act out the dream, do not enter sleep atonia, midbrain systems that mediate REM atonia Neurobiology of Learning and Memory I 1. P hineas Gage, Karl Lashley, Wilder Penfield, Henry Molaison (H.M. patient), Brenda Milner, N.A.patient, John O’Keefe, Edvard/May Britt Moser: contributions in neuroscience? a. Phineas Gage -a railroad construction worker whowas in an accident and ended up with an iron rod piercing through his skull and frontal lobe. Survived 12 years after the accident, but he was not the same after. Had major personality, mood, and emotion changes. Gave first insight that different regions of the brain are associated with learning and memory. b. Karl Lashley -studied learning and memory in ratsusing experimental ablation to see how the cortex was associated in learning and memory. Concluded that all cortex areas are equipotential to learning and memory. Later research confirmed that this isn’t true, not all cortex areas are equipotential. Declarative memories reside in the neocortex but in order to get there they need to pass through structures in the medial temporal lobe, important for consolidation/storage c. Wilder Penfield -used electrical stimulation of partsof the brain as part of a surgical treatment for severe epilepsy. This showed that the temporal lobe has a special role in memory storage, as seen by the direct stimulation of the region with an electrode. d. H.M. -had surgery to remove his medial temporal lobe;left with anterograde amnesia and could not form new declarative memories. Showed that the medial temporal lobe is critical for declarative memory consolidation, and that working and procedural memories use distinct brain structures e. Brenda Milner -doctor that worked with H.M. for over50 years, and had to reintroduce herself everytime she met with him. She is the person that tilted the scale that the hippocampus is the most important region in learning and memory f. N. A. patient -his roommate’s fencing foil went throughhis right nostril and damaged left dorsomedial thalamus. Left with severe anterograde amnesia and retrograde amnesia for the last 2 years of declarative memory (but less severe than H.M’s. Showedmedial temporal and diencephalicregions - interconnected regions that form a system of memory consolidation. g. John O’Keefe -discovered place cells, which are neuronsin the hippocampus that selectively respond when the animal is in a particular position in its environment. h. Edvard/May Britt Moser -discovered grid cells, whichare neurons in the entorhinal cortex that selectively respond when the animal is placed at multiple locations that form a hexagonal grid 2. Which are the basic types of procedural memory? What is habituation and sensitization? a. Types of procedural memory i. Nonassociative learning- change in behavior responsethat occurs over time in response to stimulus 1. Habituation- learn to ignore a meaningless stimulus.Response decreases as the stimulus becomes habituated. 2. S ensitization- learn to intensify response to stimulus. Ex - lights out and you hear footsteps would cause a magnified response bc footsteps in daylight isn’t as scary ii. Associative learning 1. Classical conditioning -Association of stimulus thatevokes a response with a second stimulus that normally does not evoke a response. 2. Instrumental conditioning -association of responsewith a meaningful stimulus (reward), complex neural circuits 3. Pavlov’s dogs and classical conditioning: what do US, CS, UR and CR stand for? a. Classical conditioning- association of a stimulusthat evokes a response with a second stimulus that normally does not evoke a response i. Unconditioned stimulus (US)- evokes an unconditionedresponse (UR). no conditioning/training is required ii. Conditioned stimulus (CS)- normally does not evokea response. Training is required before it yields the conditioned response (CR) b. Pavlov’s experiment i. The unconditioned stimulus is the food the dog is presented with. The unconditioned response is for the dog to salivate. ii. When the unconditioned stimulus is paired with a bell ringing, then the dog will begin to associate the bell with the unconditioned stimulus. The bell becomes the conditioned response. iii. When the dog hears the conditioned stimulus even without the unconditioned stimulus of the food, the dog will begin to salivate. The conditioned stimulus of the bell leads to the conditioned response of being salivated. iv. The conditioned stimulus must be presented before the unconditioned stimulus close together. If they are too far apart then the association becomes weaker depending on when the stimulus is present. 1. Shorter time = greater association . Types of declarative memory: how is working memory different from short-term memory 4 and how can it be assessed in the clinic? Which brain regions are implicated in working memory? a. Definition -explicit memories - facts (semantic)and life events (episodic). Assessed for conscious recollection, results from conscious effort, easy to form and more easily forgotten b. Types of declarative memory- long term memories andshort term memories i. Long term- can be recalled for days, months, yearsfollowing initial storage. Usually important events ii. Short term- last from sec to hours and are vulnerableto disruption. Trying to recall what you ate for dinner last night and then how many nights before c. W orking memory -temporary storage between sensory information and short term memory. Has a very limited capacity, short duration (several seconds), and requires repetition to be kept alive. (remembering a phone number read off) i. Assessed in the clinic 1. digital span test -person sits in front of screen,is shown a list of numbers for a few seconds and then asked to recall as many numbers as they can; score of 7+/- 2 means working memory capacity is normal 2. Wisconsin card sorting task -a person is asked tosort a deck of cards having a variable number of colored geometric shapes. Person is not told the pattern, only if the card they place is right or wrong so they have to try and figure out the criteria (color, number, shape). After 4 correct placements, the criteria changes again. Assesses both working memory and prefrontal cortex function ii. Implicated brain regions -neocortex, specificallyneocortex of prefrontal cortex 5. Define anterograde, retrograde and dissociative amnesia and describe transient global amnesia. a. Amnesia -serious loss of memory and/or ability tolearn. Caused by concussions, alcoholism, encephalitis, brain tumor, stroke, epilepsy. i. Anterograde -inability to form new memories aftertrauma. Person will retain their old declarative memories but is unable to form new ones. (this is what happens in 50 first dates!!!) ii. Retrograde -memory loss for events before a trauma.A person will lose their more recent declarative memories, but may remember old declarative memories from childhood, etc. in severe cases they lose all declarative memories. iii. Dissociated amnesia -amnesia caused by no other cognitivedeficit. For example alzheimer’s wouldn’t count because it has a cognitive component iv. Transient global amnesia -an attack of anterogradeamnesia that lasts for a short period and often includes retrograde amnesia for recent events. 1. Symptoms -A person may feel disorientated, ask thesame questions repeatedly, and can’t form new memories for a short period of time. 2. Attacks subside in a matter of hours, and they are left with a permanent memory gap 3. Causes -brief cerebral ischemia/decrease in bloodflow to memory regions, concussions, seizures, stress, sex, cold shows, and the antidiarrheal drug Clioquinol. . How did Karl Lashley reach the conclusion that the engrams are widely distributed in the 6 cerebral cortex? Are all cortical areas equipotential to learning and memory? a. K arl Lashleystudied learning and memory in rats using experimental ablation to see how the cortex was associated in learning and memory b. Experiment -He trained rats to run through a mazeto get a food reward at the end. After the rats were trained, he used ablation to create bilateral lesions in the rats’ cortexes. i. Lesions before learning the maze -interfered withthe ability to learn, and made it harder for the rats to learn the task and took them more time. ii. Lesions after learning the maze -damaged memory formation,so the rats couldn’t remember what they already learned, like the maze path. c. His conclusions -the larger the lesion, the moredamage, so he concluded that all cortex areas are equipotential to learning and memory. i. However, later research confirmed that this isn’t true, not all cortex areas are equipotential. But Karl was right that engrams are widely distributed throughout the cerebral cortex d. Declarative memories reside in the neocortex but in order to get there they need to pass through structures in the medial temporal lobe, important for consolidation/storage 7. Describe the basic anatomy of the medial temporal lobe. How did Wilder Penfield show that the temporal lobe plays a role in declarative memory storage? What do you know about the extraordinary case of H.M.? a. Anatomy -medial temporal lobe sits right below thetemporal lobe, and contains: i. Hippocampus ii. Three cortical regions surrounding the rhinal sulcus -Entorhinal cortex, perirhinal cortex, and parahippocampal cortex b. Information flows through the lobe- responsible forconsolidation of declarative memory. i. Cortical association areas project sensory info to mid temporal lobe → parahippocampal and rhinal cortical areas receive the sensory information → hippocampus → fornix loops around → mammillary bodies of hypothalamus → thalamus c. Wilder Penfield -neurosurgeon; used electrical stimulationof parts of the brain as part of a surgical treatment for severe epilepsy i. He found that if the temporal lobe was stimulated, the patient would experience complex sensations, hallucinations, and recollection of past experiences. Patients on the table could remember their mother talking to them as a child, remembering an old carnival. This showed that the temporal lobe has a special role in memory storage, as seen by the direct stimulation of the region with an electrode. d. H. M.- Henry Molaison was in a bicycle accident andthen suffered from epilepsy from age 10 and as he aged the condition became more severe. i. In 1953 when he was 27 years old, he had surgery to remove 8 centimeters of the medial temporal lobe (cortex, amygdala, and anterior two thirds of hippocampus) ii. he surgery stopped his seizures, and did not affect perception T intelligence or personality, but left him with extreme anterograde amnesia iii. He could not form new declarative memories, but his working memory and procedural memory were ok. He also developed partial retrograde amnesia and was able to form a few new declarative memories. iv. Conclusions -based on H.M.’s amnesia, the medialtemporal lobe is critical for declarative memory consolidation, and that working and procedural memories use distinct brain structures 8. How is the diencephalon implicated in memory storage? Lessons learned from the N.A. patient and the Korsakoff syndrome. a. Regions of the diencephalon implicated -damage inthese regions can cause amnesia. Flow of info from hippocampus → fornix → mammillary bodies → anterior nucleus of thalamus i. Thalamus -anterior and dorsomedial nuclei ii. Hypothalamus -mammillary bodies b. N. A. patient -his roommate’s fencing foil went throughhis right nostril and damaged left dorsomedial thalamus. i. Left with severe anterograde amnesia and retrograde amnesia for the last 2 years of declarative memory (but less severe than H.M’s ii. Conclusions -medial temporal and diencephalic regions- interconnected regions that form a system of memory consolidation c. Korsakoff’s syndrome -syndrome from chronic alcoholism,deficiency of thiamine. i. Early symptoms of thiamine deficiency: tremors, loss of balance, abnormal eye movement ii. Treated with supplemental thiamine. If untreated, structural changes and lesions can occur in the diencephalon that lead to Korsakoff’s syndrome iii. If left untreated, becomes Korsakoff’s syndrome, and the patient experiences anterograde amnesia, retrograde amnesia, confabulations (inverted memories due to memory gaps), and apathy 9. Place cells and grid cells: function and localization in the rat brain. a. Place cells -neurons in the hippocampus that selectivelyrespond when the animal is in a particular position in its environment. They would fire APs when the animal is in a specific environment, and use microelectrodes to impair a single neuron. Specific neurons fire at specific positions. i. Discovered by John O’ Keefe b. Grid cell -neurons in the entorhinal cortex thatselectively respond when the animal is placed at multiple locations that form a hexagonal grid i. Discovered by Edvard and May Britt Moser c. Conclusion -snow importance of hippocampus in spatiallearning and memory 10.Which experimental studies proved that the striatum is implicated in procedural memory? a. Radial arm maze test i. tandard version -mouse in a maze with 8 arms, some with food some S without, the rat had to locate the food through trial and error. Caused the rat to use declarative memory, therefore depending on hippocampus ii. Light version -light above arm with food - used ofprocedural memory forms a habit based on light food association 1. Found that lesions in the striatum (caudate nucleus and putamen) caused poor performance, but lesions in hippocampus did not 2. Therefore procedural memory depends on the striatum, and the striatum is not crucial for declarative Neurobiology of Learning and Memory II 1. W hich experiments shed light to the molecular and cellular processes underlying habituation and sensitization of the gill-withdrawal reflex in Aplysia Californica? Why did Eric Kandel use this animal model system? a. Eric Kandel -interested in cellular mechanisms ofmemory, wanted to record signals from the hippocampus. Wanted to study neurons during a simple memory. i. UsedAplysia California, the marine snail, becausethe rat brain was too complex and he wanted to study a simple reflex controlled by large and accessible neurons. This was the first model to understand molecular mechanisms of learning and memory. b. The gill withdrawal reflex -when a small amount ofwater is placed on the siphon of aplysia, the aplysia withdraws its gill. c. Habituation of gill withdrawal i. He observed that this reflex displays habituation up repeating the action (responsiveness decreases) ii. Reflex pathway- a bundle of neurons enter the abdominalganglion → one sensory neuron axon from the siphon skin synapses with a motor neuron called L7 → motor neuron innervates the gill to contract the muscle iii. Location of habituation -realized it had to be eitherat the sensory, motor, or synapse. He tried blocking both the sensory neuron and motor neuron and found no change in the response no matter the amount of stimulation, so he concluded that habituation had to occur at the synapse. iv. The synapse -glutaminergic; he impaled the presynapticneuron with a stimulating and recording electrode, and impaled the postsynaptic neuron with a recording electrode to record the EPSPs (reflex level of activation). 1. Found that repeated electrical stimulation of the sensory neuron leads to a progressively smaller EPSP in the postsynaptic motor neuron. 2. How does this occur -voltage gated Ca2+ channelsin the presynaptic terminal become less effective, resulting in a decrease of neurotransmitter released by the sensory neuron d. S ensitization of gill withdrawal -Kandel applied a brief electrical shock to the tail of Aplysia, which responded in an exaggerated gill withdrawal response in response to siphon stimulation i. Synapses is an axoaxonic synapse with sensory neuron -sensory info from the shock converges on the serotonergic L29 neuron, which in turn synapses with the sensory neuron that activates motor neuron L7 1. Sensitizing stimulus to another body part causes indirect activation of L29 interneurons ii. Chemical pathway -release of serotonin from L29 →acts on serotonergic metabotropic receptors on membrane of sensory neuron → activate AC to produce cAMP → cAMP activates PKA → PKA phosphorylates K+ channel on sensory neuron membrane and channel closes → cell keeps depolarizing → more Ca2+ channels open and more NT released onto motor neuron so larger response iii. Short term memory -if one shock on the tail, sensitizationlasts a few hours. 1. Caused by secondary messengers acting on pre existing proteins (transient alterations in existing synaptic proteins) iv. Long term memory -If 4 shocks over 5 days, lastsa few weeks 1. Caused by gene transcription/protein synthesis. Caused by persistent synthesis of new proteins v. Lessons -learning and memory results from modificationsof synaptic transmission. Synaptic modification can be triggered by conversion of neural activity into intracellular second messengers 2. Be able to describe in detail the molecular/cellular and neurophysiological mechanisms underlying LTP/LTD in the hippocampus (brain slice studies). What appears to be the maximum duration of LTP according to in vivo rat studies? a. Brain slice studies- Slices of hippocampus have microcircuits i. Pathway - input from entorhinal cortex → form synapses with DG → DG axons synapse with CA3 → CA3 axons branch to fornix or CA1 region 1. Schaffer collateral - CA3 → CA1. many experiments for learning and memory here ii. Bliss and Lomo - cut hippocampus in thin slices and kept alive in CSF. impaled cells w/ electrodes to record response. Found that brief high frequency electrical stimulation of perforant path synapses on DG neurons induced long lasting strengthening of stimulated synapses - LTP b. Long term potentiation- form of synaptic modification.Neurons that fire together wire together! If an active presynaptic neuron synapses with an active postsynaptic neuron then the synapse will be stronger i. Modification of synapses so that they are more effective. Presynaptic neurons stimulated with a burst of high frequency stimulation that increased the EPSPs. More EPSPs = more activation ii. Maximum duration -high frequency stimulation canproduce LTP in the rat hippocampus (in vivo) that lasts more than a year c. L ong term depression- opposite of LTP. Neurons that fire out of synch lose their link! An active presynaptic neuron that synapses with a weak postsynaptic neuron will form a weak synapse i. Under persistent weak synaptic stimulation active synapses undergo LTD. presynaptic neurons are stimulated weakly and the EPSPs responses are now weaker → less effective 3. Early versus late alterations that result in long-lasting changes in synaptic transmission during LTP. a. Early phase mechanism of LTP in CA1 -early phasesof LTP induction are on pre existing molecules i. Excitatory synaptic transmission in the hippocampus is mediated by glutamate ii. CA1 neurons have NMDA receipts that are activated upon AMPA dependent depolarization of the postsynaptic cell → increased Ca2+ mediates the strength of elimination of the synapse → activates PKC and CaMKII 1. PKC → directly phosphorylates AMPA to stay opens more Na+ can enter to increase depolarization 2. CaMKII → insertion of new AMPARs in the postsynaptic membrane. CaMKII mobilizes vesicles w/ AMPA receptors to membrane, vesicles fuse and receptors join the membrane making the spine larger. iii. Prevention- LTP is prevented by NMDA receptor antagonists,Ca2+ chelators inhibiting rise in postsynaptic Ca2+, and pharmacological inhibition of PKC/CaMKII b. Long term LTP -induces changes in synaptic structures,the spine size increases. . Which pharmacological experiments suggested that NMDA receptor activation, calcium 4 and CamKII/PKC are needed for the induction of LTP? a. Experimental evidence i. attractive mechanistic models → synaptic plasticity can contribute to formation of declarative memories. How synapses are strengthened following high frequency stimulation ii. NMDAR dependent plasticity also in other brain regions → same mechanism iii. The genetic knockout mice for CaMKII (a) → deficits in hippocampal LTP and memory. Don’t perform well on memory tasks b. Synaptic transmission is modified by altering the phosphorylation status of certain synaptic proteins 5. LTP and LTD represent two opposite forms of synaptic plasticity, and both are triggered by calcium; please explain how this happens. a. The level of NMDA activation determines the amount of Ca2+ which triggers the LTP/LTD i. LTP 1. S trong depolarization → complete displacement of Mg2+ (all NMDAs open at the same time) and activation of kinases → large elevation of Ca2+ (phosphorylation) ii. LTD 1. Weak depolarization → partial blockage by Mg2+ (not all NMDAs open) and activation of phosphatases → small elevation of Ca2+ (dephosphorylation) 6. Which in vivo experimental studies suggested that hippocampal LTP is indeed implicated in learning and memory (hint: water maze, transgenic mice, inhibitory avoidance studies)? a. Water maze i. Intrahippocampal injection of NMDAR blocker in rats during training in the water maze. ii. Rats placed in a bucket with opaque water, swam until they found the platform. They got there quicker and quicker with each test. 1. If the blocker was injected the rats performed poorly on the test even if they knew where the platform was before. 2. Ablation of NMDA receptors → rats could not learn the task b. Transgenic mice i. Genetic knockout mice for CaMKII (a) → deficits in hippocampal LTP and memory, don’t perform as well on the tests ii. Mice that overexpress NMDArs display enhanced learning ability in some learning tasks (appear to have photographic memory) c. Inhibitory avoidance studies i. Rodents love the dark, so a sliding door opens and the mouse in the light runs to the dark, but the mouse gets shocked in the dark. ii. After the first shock, the mouse is reintroduced to the compartment to see if they try to go in the dark again. Measure latency it takes the mouse to go from light to dark. 1. High latency if they remember the shock iii. Learning induces LTP at hippocampal synapses. At the end, observed LTP in CA1 neurons, induced LTP due to the training. . Molecular basis of memory consolidation: CREB, protein synthesis and synaptogenesis. 7 Which experiments gave us insights into the mechanisms of memory consolidation (hint: protein synthesis inhibition studies) a. Protein synthesis- required during memory consolidation,for short term memory to become long term memory i. Intracerebral injection of protein synthesis inhibitors 1. Injection during or shortly after training: the animals may learn the task but cannot remember when tested some days later. Doesn’t affect short term, but won’t remember it afterward 2. Memories become increasingly resistant if the interval between training and protein synthesis inhibition increases b. Regulation of protein synthesis is by transcription factors i. nter nucleus → bind to DNA →regulate synthesis E ii. CREB- a transcription factor. Creb is phosphorylationby kinase → activated and goes into the nucleus and displaces CREB2 1. cyclic AMP response element binding protein binds to specific genome elements → binds to CREB response elements (CREs) on DNA 2. CREB 1 -activator of gene expression 3. CREB 2 -repressor of gene expression c. Synaptogenesis i. Ca2+ activates calmodulin and protein kinase → effects in late phase making of dendritic spines → long term memory ii. Early phase 1. Ca2+ released into synapse → binds to NMDA receptors → activates calmodulin → activates protein kinase → activates AMPA receptors 2. Protein kinases convert ATP to cAMP and activate PKA → CREB activated and transcription regulators → activate synapse growth proteins which causes growth -Late phase 8. Be able to define/discuss the significance of the following terms: a. gill-withdrawal reflex -from the aphasia snail, showedthe habituation and sensitization studies b. perforant pathway -entorhinal cortex → DG. hippocampalmicrocircuit c. mossy fibers -DG → CA3. part of hippocampal microcircuit d. Schaffer collateral -from CA3 → CA1, many experimentsfor learning and memory. Part of hippocampal microcircuits e. NMDA/AMPA receptor regulation -AMPA opens immediatelyafter Glu binds and allows Na+ to enter and depolarize the membrane. Depolarization causes the Mg2+ in the NMDA receptors to pop out, to allow more Na+ and Ca2+ to enter cell f. AMPLIfication -insertion of new AMPA receptors intothe membrane, caused by increased in Ca2+ g. PKC -phosphorylates AMPA to stay open and becomemore effective so more Na+ in cell increasing depolarization h. CamKII -mobilizes vesicles w/ AMPA receptors to membraneand inserts new receptors to join membrane and make spine longer i. CREB -transcription factor, binds to CREB responseelements on DNA. activate or repress gene expression j. inhibitory avoidance task -showed learning inducesLTP at hippocampal synapses Neurobiology of Disease: Schizophrenia 1. S chizophrenia: DSM symptoms, disease progression, main neuroanatomical abnormalities, and pathogenetic factors (genes versus environment). a. DSM symptoms i. Positive (psychotic) symptoms - excess in normal functions 1. Hallucinations - perceptions not elicited by appropriate sensory stimulus a. Auditory (hearing voices, music), bully, derogatory, issue commands, thought echo (hearing your thoughts spoken aloud in your head) 2. Delusions - distortion of reality a. Thought withdrawal (entity takes away their thoughts), thought insertion (controlled by another entity), thought broadcasting (everyone hears your thoughts), paranoid delusions (being plotted against, special powers), delusions of reference (thinks their getting a message to do something) 3. Agitation - talking moving all the time 4. Disorganized speech ii. Negative symptoms - reduction in normal functions 1. Lack of interest, blunted affect, social withdrawal, passivity iii. Cognitive symptoms - cognitive impairment, learning and memory deficits, attentional deficits 1. Can’t be treated with antipsychotics b. Disease progression 1. Stage 1 - asymptomatic period 2. Stage 2 - prodromal phase → odd/ eccentric behavior, mild negative symptoms. Mild and still functionable. (15-20 years) 3. Stage 3 - acute phase of disease → positive symptoms, psychotic episodes remission, relapses a. Downhill functionality that patients never regain 4. Stage 4 - prominent negative and cognitive symptoms, “burnout” phase of disability. Decreased positive symptoms but more disability . Main neuroanatomical abnormalities c i. Pronounced reduction in cortical gray matter (plus amygdala and hippocampus) in frontal and temporal regions 1. Synaptic pruning in amygdala and hippocampus, frontal, temporal 2. Loss of gray matter resulting from loss of synaptic contact rather than loss of cells ii. Deficits in working memory - dorsolateral prefrontal cortex shows less activity 1. Decreased dendritic spine density in dorsolateral PFC iii. Cell death in thalamus 1. Cell death in thalamus that forms a synapse w/ neuron in cortex and thalamic axon → synapse died because neurons in thalamus died → issues with sensory relay → no filter → no nothing can be filtered out → experienced at once which can cause symptoms iv. Enlarged third and lateral ventricles in schizophrenia 1. Cortex is thinning → gray matter loss → counterbalance brian matter loss v. Anterior part of left hippocampus is smaller (CA1) vi. Disorganized hippocampal network d. Pathogenetic factors i. 50/50 genetics vs environment. If one identical twin develops it, there is a 50% chance that the other twin will ii. Environmental factors -pregnancy complications, viralinfections, unwanted pregnancy iii. Urbanization, psychosocial factors 2. Describe in detail the extended dopaminergic hypothesis of schizophrenia. Which dopaminergic pathways are affected in this disorder and how is this related to the emergence of symptoms? a. Dopaminergic synapse i. Tyrosine → TH converts to DOPA → DDC converts to dopamine → packed in vesicles and fuse to membrane → released in synapse → act on DA receptors ii. Dopaminergic receptors 1. D1 like -D1, D5; coupled to Gs and increase cAMP 2. D2 like -D2, D3, D4: coupled to Gi and decrease cAMP b. Mesolimbic pathway - OVERACTIVITY i. VTA → NA/amygdala/hippocampus ii. Positive symptoms of schizophrenia iii. The increased dopamine gives the positive symptoms c. Mesocortical pathway - HYPOACTIVITY i. VTA → frontal cortex ii. Negative symptoms of schizophrenia d. Normal vs schizophrenia state i. Normal -cortex gives negative feedback to dopaminergicneurons in the VTA to control the dopamine release ii. Schizophrenia- The VTA neurons stop working well,so no good negative feedback. The neurons become disinhibited, so the mesolimbic pathway becomes OVERACTIVE to account for the lack of negative feedback from the cortex . What evidence suggests that alterations in the glutamatergic neurochemical system are 3 also implicated in the pathogenesis of schizophrenia? (hint: ketamine/PCP) a. Glutamatergic hypothesis- PCP and Ketamine produceeffects on behavior that resemble symptoms of schizophrenia (toxic delirium) i. High doses increase psychotic like symptoms ii. Post mortem studies shows a decrease in NMDA receptors in the frontal cortex of schizophrenic patients iii. Glutamatergic projections are hypoactivated 4. D iscuss the differences between typical and atypical antipsychotics regarding their mechanism of action, their therapeutic effects and adverse effect profile. a. Typical -chlorpromazine, haloperidol i. Mechanism of action -strong DOPA 2 antagonists, D3&4affinity 1. Dirty - bind to a bunch of receptors ii. Therapeutic effects 1. Will decrease the dopamine in the mesolimbic pathway, causing alleviation of positive symptoms 2. Will target all the dopaminergic pathways iii. Adverse effects 1. H1 - weight gain and drowsiness, a1 - hypotension and dizziness, M1 - anticholinergic effects, dry mouth, constipation 2. Worsening of negative symptoms because it will decrease dopamine even more 3. Causes mirroring of parkinson’s due to nigrostriatal pathway becoming affected a. Tardive dyskinesia - motor problems and erratic movements. Can be reversed if drug stopped early enough 4. Hyperprolactinemia - mirrors postpartum bc it also reduces dopamine in the tuberoinfundibular pathway, sexual dysfunction, infertility b. Atypical -clozapine, risperidone, olanzapine i. Mechanism of action -target serotonergic receptorsbecause D2 affinity isn’t great enough 1. Dirty - antihistaminic effects, anti a1 and M1 2. Serotonergic system modulates the Dopaminergic system - acts on DA neurons ii. Therapeutic effects 1. Improvement of negative symptoms 2. Decreases tardive dyskinesias 3. Less motor effects bc on small target of D2 receptors iii. Adverse effects 1. Metabolic effects - diabetes, weight gain, insulin resistance, drowsiness, cardiovascular, dyslipidemia 5. A schizophrenic patient is treated with atypical antipsychotic: discuss how administration of this drug may affect the different dopaminergic pathways of the brain. a. The serotonergic system modulates the dopaminergic system i. Improves the negative symptoms because it doesn’t just decrease dopamine throughout all ii. Not a D2 antagonist so it won’t block all? 6. Arvid Carlsson, John Nash, Emil Kraepelin, Eugen Bleuler, Henri Laborit: contributions to neuroscience? a. A rvid Carlsson -discovered relationship between D2 antagonists and parkinsons. Saw schizophrenic patients in mental hospitals before the invention of antipsychotics. b. John Nash -a scientist, discovered game theory. Hadschizophrenia and slowly lost his mind. “A beautiful mind” c. Emil Kraepelin -1887: defined schizophrenia as “dementiapraecox → early age onset (deterioration of intellect) d. Eugen Bleuler -1911; coined the term schizophrenia(splitting of the mind), cognition split off from volition and emotion e. Henri Laborit -found that chlorpromazine could reducethe psychotic symptoms in schizophrenic patients, eventually concluded the disease could be due to an increase in dopamine because chlorpromazine was a D2 receptor antagonist Neurobiology of Disease: Major Depression 1. M ajor depression (MD): DSM symptoms, critical brain regions implicated in MD pathogenesis and symptomology, and treatment strategies (e.g. pharmacotherapy, ECT, psychotherapy). a. DSM symptoms i. To be diagnosed - must have 5 or more of the 9 symptoms present nearly every day during the same 2 week period. 1 symptom must be either depressed mood or loss of interest or pleasure 1. Depressed mood or anhedonia (loss of pleasure/interest) 2. Fatigue, diminished ability to think/cocnentrate, feelings of worthlessness/self loathing/guilt, recurrent thoughts of death/suicidal thoughts, psychomotor agitation/retardation, insomnia or hypersomnia, weight loss/gain b. Critical brain regions i. MDD is caused by decrease in serotonin, NA, DA ii. Neuronal pathways implicated in depression include the limbic system, reward system and many other cortical and subcortical brain regions iii. Depressed mood - NA, DA, 5-HT iv. Guilt and worthlessness, suicidal ideation - 5-HT v. Appetite and weight - hypothalamus and serotonin vi. Fatigue - NA, DA 1. Somatic fatigue in striatum - decreased dopamine → decreased NA in spinal cord c. Treatment strategies i. Antidepressants ii. ECT -electrical currents passing through two electrodeson scalp → induce localized seizure discharge but anesthesia and muscle relaxants 1. Effective in about 85% of severe depression and produced rapid relief, can accompany some memory loss for patients that do not respond to therapy and high sucide risk iii. sychotherapy -overcome negative views of life, themselves, future. P 30%/placebo effect effective 2. Mechanism of action of MAOIs, TCAs, SSRIs (adverse effects?): do the conventional antidepressant drugs/placebo treatment work in all depressed patients? Please discuss. PS: you need to know the drugs mentioned in the lecture. a. MAOIs -monoamine oxidase inhibitors keep serotoninin the cleft i. Phenelzine b. TCAs -tricyclic antidepressants are reuptake inhibitorsfor NA and DA i. Imipramine, clomipramine, desipramine, nortriptyline ii. Therapeutic effects - NET and SERT iii. adverse effects - can inhibit potassium channels in heart and brain c. SSRIs -block reuptake of serotonin so it stays inthe cleft i. Boos 5-HT levles ii. Fluoxetine (most prescribed drug in the 90s iii. Fluvoxamine, sertraline, paroxetine, citalopram, escitalopram iv. Adverse effects -anxiety, motor effects, sleep disturbance,nausea, vomiting, GI effects, sexual dysfunction . Describe the monoamine and the monoaminergic receptor hypotheses for MD: which 3 experimental evidence supports these theories? Criticisms? a. Monoamine hypothesis -depression associated withreduced levels of 5-HT, NA and DA i. Antidepressants induce acute increase of monoamine levels 1. Reserpine - depletes monoamines → depression ii. Decrease 5-HIAA levels in the CSF of depressed patients with suicidal ideation.less metabolite in CSF → so less serotonin metabolized iii. Criticism -administration of antidepressant drugsinduces only an acute increase of monoamine levels but significant improvement in patients symptomatology evidenced after 3-4 weeks of chronic antidepressant treatment (prolonged clinical antidepressant) 1. Correcting level of monoamines does not fix the issue that fast b. Monoaminergic hypothesis -depression induces upregulationof postsynaptic monoaminergic receptors i. Post mortem studies showed an increase of postsynaptic 5-HT receptors in the prefrontal cortex of depressed patients ii. Criticism -change in receptor number/sensitivityfollowing antidepressant treatment takes only some days 4. Neuroendocrine (i.e. HPA stress axis) and neuroplasticity hypotheses for MD: which experimental evidence supports these theories? a. Neuroendocrine theory i. Depression can be induced by chronic stress/adverse life events; patient loses ability to cope with it ii. As a result, depression precipitates due to deregulation of body’s stress response iii. PA axis:stress → hypothalamus releases CRH → pituitary releases H ACTH → adrenal cortex releases cortisol → cortisol is an immunosuppressant and does negative feedback on hypothalamus, binds to glucocorticoid receptors iv. Deregulation of HPA axis 1. Non effective negative feedback in depressed patients, so they can’t completely turn it off so depressed patients have higher levels of cortisol in the blood → reduced number of glucocorticoid receptors 2. Too much cortisol can affect the hippocampus, and high levels can kill neurons, glial cells, spines, synapse b. Neuroplasticity i. Prefrontal cortex is sensitive to stress ii. Decrease in volume of structures due to neuron, spine, and glial cell death 1. Reduction of hippocampal volume (3.3 to 2) iii. PFC and hippocampus are usually resistant but chronic death can affect them iv. Brain derived neurotrophic factor (BDNF) - sustains viability of neurons and synaptogenesis 1. Depression → decreased BDNF → apoptosis of neurons and decrease of synapses in the hippocampus 5. Ketamine is the prototype rapid-acting antidepressant: please describe its theorized mechanism of action. a. Ketamine - non competitive NMDA receptor antagonist b. A single dose of ketamine → rapid (2h) and sustained (1 week) antidepressant responses in treatment resistant depressed patients c. Induces neurogenesis d. Upregulation of GLU neurotransmitters, acts regularly on GABAergic neurons that normally inhibit the glutamatergic neuron → GABA activity decreases e. Induce synaptogenesis of spines within a month on ketamine i. GLU released from neurons into cleft, binds to postsynaptic AMDAs ii. Glutamate burst → molecular synaptic plasticity pathways → rapid synaptogenesis . What is the forced swim test (FST) and how can we implement it in preclinical research 6 to screen for putative antidepressant drugs? a. Measures immobility levels to determine behavioral despair (depressive like behavior) b. Antidepressant drugs reduce immobility duration/learned helplessness 7. Be able to define/describe the following terms: a. BDNF -depression decreases it causing apoptosis ofneurons and decrease of synapses in hippocampus b. ketamine-induced “glutamate burst” -disinhibitedGABAergic → glutamate burst → molecular synaptic plasticity pathways → rapid synaptogenesis . R c eceptor -what a neurotransmitter binds to on the postsynaptic cell d. up/down-regulation -postsynaptic tells presynapticthat much is released, so it will internalize receptors. Altered rate of receptor synthesis or function e. Iproniazid -used to treat TB but also elevates apatient’s mood,enhances monoamines serotonin, NA< and DA in the brain. f. Melancholy -what hippocrates called depression g. Mood -if it goes below dysthymia its double depression h. Affect -the result of a drug?? i. Anhedonia -loss of interest or pleasure j. psychomotor agitation -can’t stand still or stopmoving Neurobiology of Disease: Alzheimer’s Disease, Parkinson’s Disease 1. A lois Alzheimer, Auguste Deter, James Parkinson, Friedrich Lewy: contributions to neuroscience? a. Alois Alzheimer -diagnosed first patient, performedthe autopsy and found prominent neuropathological alterations b. Auguste Deter -Alzheimer’s patient, first describedpatient with AD. had memory deficits and progressive loss of cognitive abilities. Around 50 when presenting with symptoms and died 5 years later c. James Parkinson d. Friedrich Lewy 2. Alzheimer’s Disease (AD): disease progression, neuropathological hallmarks. Aging of the healthy elderly brain? a. AD -most common cause of dementia in people over65, 6th leading cause of death b. Disease progression -usually 7-10 years could befast or slow i. Early stage - loss of memory for recent events, repeat themselves, cannot grasp new ideas, confusion, poor judgment - looks like normal aging ii. Middle stage - confusion about where they are, walk off and become lost, mix up night and day, forgetfulness, odd behavior, hallucinations 1. This is where diagnosis usually occurs iii. Late stage - totally dependent on caregivers, degeneration of motor neurons, inability to recognize familiar objects or surroundings, confined to bed or a wheelchair, trouble swallowing or eating, weight loss, incontinence, loss of speech c. Neuropathological hallmarks i. Brain atrophy - narrowed gyri, widened sulci, decreased brain weight, enlarged ventricles, death of neurons → neurodegenerative disorder ii. Amyloid rich senile plaques - extracellular plaques of dense material (amyloid, surrounded by swollen axons and dendrites, associated with astrocytic process and microglia iii. eurofibrillary tangles - filamentous inclusions in the cell bodies and N dendrites of affected but still alive neurons, abnormal polymers of hyperphosphorylated tau protein iv. Hippocampus, entorhinal cortex, neocortex, nucleus basalis of meynert 1. Basal nucleus is one of first to die in Alzheimers, decreased in acetylcholine in AD d. Aging of healthy brain i. Usually variable decline in mental agility ii. MCI - memory impairment that is alarming but does not affect daily life 1. 50% of those with MCI will get denial dementia - progressive impairment of memory and cognitive function e. Treatment -only can treat symptoms not cure i. Ach inhibitors to increase ACh by inhibiting its breakdown - bc basal nucleus is the first to go so try and boost ACh and slow cognitive decline 3. Senile plaques and amyloid beta (Aβ) peptides: are they causally related to AD pathogenesis? a. Composition -Senile plaques are made of toxic ABpeptides → AB40, AB42 i. AB2 are the more toxic, key component in amyloid plaques b. Precursor -amyloid precursor protein (APP) - transmembraneprotein we don’t really know c. APP processing i. B and y secretase cleave APP to make 3 fragments 1. Middle and extracellular fragment cleaved by B - extracellular fragment (amino terminal fragment) travels to extracellular space 2. Middle fragment is nucleated and forms the amyloid plaques that
