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Biopsychology of Memory What is Memory? The storage of information about our experiences Major Research Questions • What is the biological substrate(s) of memory? • Where are memories stored in the brain? • How are memories accessed during recall? • What is the mechanism of forgetting? Early Hypotheses about the Brain Substrates of Memory • Two prominent psychologists - Karl Lashley - Donald Hebb Karl Lashley • Studied memory of complex maze learning in rats • Design: -train lesions of the cortex test their memory • Results: - only large lesions of the cortex produced deficits - similar deficits were obtained no matter where the cortical lesion was located Lashley’s Two Principles 1. Principle of Mass Action ~ Memories for complex tasks are stored diffusely throughout the neocortex. 2. Principle of Equipotentiality ~ All parts of the neocortex play an equal role in the storage of memories for complex tasks. IMPORTANT POINT: Lashley’s research discouraged thinking about localized regions important for memory Donald Hebb - 1949ff • Two memory systems - short-term storage system - long-term storage system • Short-term storage = reverberatory activity • Long term storage = structural change • Different substrates for short- vs. long-term storage • Transfer from short- to long-term storage = CONSOLIDATION OF MEMORY The Evidence for Hebb’s Consolidation Theory • RETROGRADE AMNESIA Russell and Nathan - 1949 - World War II concussions - Short-term or recent memory was vulnerable - Long-term or older memory was resistant CONSOLIDATION MODEL OF MEMORY Long-term (older) Short-term (recent) memory memory Consolidation process (resistant) (vulnerable) Experimental Evidence for Consolidation Theory Pinel (1969) Water bottle niche Pinel (1969) • Design: Days 1-5 Exploration of Box, no water present Day 6 1. Water present, rats drink 2. Electroconvulsive shock (ECS) given at various times after drinking Day 7 Retention Test - count niche explorations Squire et al. 1975 • ECS treatments in depressed humans • Two memory tests - one before, one after ECS treatments - pick from a list of T.V. shows those that played for only one season - some shows were from 1-3 years before ECS, some from 4-5, 6-7, 8-9, and 10-17 years previously. • RESULTS: - Retrograde amnesia for events that occurred from 1-3 years prior to ECS - consolidation of memory can continue for a long time period The Case of H.M. • • • • Epileptic seizures William Scoville, 1953 – Neurosurgeon Bilateral medial temporal lobectomy Brenda Milner – Neuropsychologist H.M.’s Memory Deficit Retrograde Amnesia - Loss of some memories for information learned before (3 years) the surgery Anterograde Amnesia – Inability to form enduring memories for events occurring after the surgery Intact short-term memory H.M. - Formal Testing for LTM Long-term Memory Tests – Deficient • Digit Span + 1 test • Matching to Sample • Maze Learning Perceptual Tests - Normal • Gollin Incomplete Pictures Test • Mooney Face Perception Test Long-term Memory Tests – Normal • Mirror drawing • Rotary pursuit • Pavlovian trace eyeblink conditioning • Gollin incomplete pictures • Tower of Hanoi Puzzle Digit Span + 1 Test • • • • 1,3,2,7,9 1,3,2,7,9,6, 1,3,2,7,9,6,4 etc. Explicit Memory(Declarative) • Memory that is directly accessible to conscious recollection • Memory of facts, events - “knowing that” something happened • Memory with record • Impaired with medial temporal lobe damage Implicit Memory(Procedural) • Memory not accessible as specific facts or data • Memory that is contained within learned skills or cognitive operations -“knowing how” • Expressed only in performance - motor skill learning - cognitive skill learning • Not impaired with medial temporal lobe damage What has H.M. taught us about the neural substrates of memory? • The importance of the medial temporal lobes • There is localization of function for memory • Different brain structures for short- and long-term memory • Medial temporal lobes contribute to memory consolidation • Memories are not permanently stored in the medial temporal lobes • Different brain structures for “explicit” vs. “implicit” memory H.M.’s MRI Scans The Contribution of the Hippocampus • Corsi – 1970 • Case R.B. - 1986 Zola-Morgan et al. (1986) • Case R. B. • Severe ischemic episode hypoxia • Extensive memory tests - Story recall - Paired associates recall ~ 10 pairs of words Dog – Umbrella Car – Face Mask - Pencil - Diagram recall Zola-Morgan et al. - cont • R.B. died in 1983 • Obtained brain 4 hours after death • Brain Pathology - Hippocampus 1. CA1 subfield gone 2. 4.6 million neurons missing • Little, if any, damage to other brain areas HIPPOCAMPAL ANATOMY Rempel-Clower et al. (1996) • Three additional cases • GD, LM, WH • All suffered from cardiovascular problems - hypotension - ischemia during surgery - seizures with respiratory distress Patient GD • Bilateral cell loss in hippocampal CA1 subfield • Other hippocampal subfields intact • Extra-hippocampal cell loss - small region of the left amygdala - small region of the left fornix - region in the right globus pallidus Patient LM • Bilateral cell loss in hippocampal CA1, CA2, CA3 subfields and dentate gyrus • Extra-hippocampal cell loss - Entorhinal cortex (layers II and III) – major source of input to hippocampus - minor cell loss in areas of cortex and cerebellum Patient WH • Bilateral cell loss in hippocampal CA1, CA2, CA3 subfields, dentate gyrus • Extra-hippocampal cell loss - entorhinal cortex - subiculum - fornix, striatum, pons Important implications for the effects of cardiac arrest and cardiovascular disease on brain integrity Two Questions • How does ischemia/hypoxia damage the hippocampus? • Why the selective damage (e.g., CA1 damage) in some cases? Animal Models of Ischemia • Davis – 1986 - Radial arm maze to assess spatial memory in rats - Design: 1. 30 min. ischemic period (carotid artery clamp) 2. 30 day recovery period 3. Maze training - Results: 1. ischemic rats demonstrate memory impairments 2. cell loss in hippocampal CA1 subfield How Does Ischemia/Hypoxia Cause Hippocampal Damage? • Microdialysis: - ischemia elevates glutamate in the hippocampus • How? ischemia/hypoxia anoxic depolarization of glutamate bouton 1. Excessive glutamate release 2. Reversal of the glutamate reuptake system additional glutamate release Two Effects of Excess Glutamate on the Postsynaptic Hippocampal Neuron • Early, immediate effect • Delayed effect over a 24 hour period Early, Immediate Effect of Glutamate Excess glutamate release Extended period of depolarization in postsynaptic cell Excessive Na+ influx Water pulled osmotically into neuron Neurons swell and burst Delayed Effect of Glutamate • Neurons demonstrate morphological and biochemical signs of disintegration over 24 hour period • Dependent on the presence of CA++ in the extracellular fluid • Glutamate receptors: Kainate receptor AMPA “ NMDA “ mGlu “ class The Glutamate NMDA Receptor (N-methyl-D-aspartate) • Associated with Ca++ ion channel • At rest, Ca++ channel blocked by magnesium ion • Sufficient depolarization from Na+ influx thru’ kainate and AMPA receptor Na+ channels ejects magnesium ion permits Ca++ flow into soma activation of numerous enzymes, 2nd messengers The NMDA Receptor – cont. Abnormally excessive glutamate release Prolonged period of Ca++ influx Excessive activation of enzymes Delayed cellular disintegration What Evidence Points to the NMDA Receptor in Ischemia? • Gill et al. (1987) 1. ischemia elevates glutamate in hippocampus 2. lesion of perforant pathway (major glutamate input pathway to hippocampus) prevents ischemia cell death in CA1 region 3. MK – 801, a glutamate receptor antagonist Protects against ischemic cell death in CA1 region HIPPOCAMPAL ANATOMY Why the selective damage to the CA1 region in some humans? • Probable Answer(?) The CA1 region has the highest concentration of glutamate receptors in the brain. Animal Models of Medial Temporal Lobe Amnesia • Tests of Memory Monkey: - Nonrecurring-Items Delayed Nonmatching-toSample Test (DNMS) - Explicit memory - Delayed Response Task - Explicit memory - Barrier Motor-Skill Task - Implicit memory - Lifesaver Motor-Skill Task – Implicit memory Rats: - Mumby Box - Explicit memory Characteristics of Human Amnesia Produced by MTL lesions in Monkeys • Memory impaired on several tasks including ones identical to those failed by human patients. • Memory impairment exacerbated by increasing the retention delay. • Memory impairment is not limited to one sensory modality. • Memory impairment is enduring. • Skill-based memory is spared. • Immediate memory is spared. What Areas in the Temporal Lobe Contribute to Memory Consolidation? • Hippocampus • Neocortex • Amygdala Zola-Morgan et al. (1980s-1990s) • Is the hippocampus the only medial temporal lobe structure important for memory consolidation? • Compared DNMS scores across experiments: -Hippocampal plus surrounding cortex lesions (H+) -Hippocampal plus amygdala plus all surrounding cortex lesions (H+A+) 1. The medial temporal lobectomy monkey Result: The H+A+ lesion produces the greatest deficit. Why does H+A+ lesion produce more memory impairment than the H+ lesion? • Possibilities: 1. The amygdala contributes to explicit memory OR 2. The cortex surrounding the amygdala contributes to explicit memory Zola-Morgan et al. • Five groups of monkeys 1. Group A amygdala lesion, spared the cortex 2. Group H+ hippo. lesion plus surrounding cortex 3. Group H+A hippo. lesion plus surrounding cortex plus amygdala lesion 4. Group H+A+ Hippo. plus surrounding cortex plus amygdala plus surrounding cortex lesion 5. Group N Unoperated Control Zola-Morgan et al. • Results: Group A no deficit Group H+A similar deficits Group H+ Group H+A+ worse than all other groups Conclude: 1. Amygdala doesn’t contribute to explicit memory 2. Cortex surrounding the amygdala may contribute A Dissociation of Hippocampal vs. Amygdala Memory Function in Humans Declarative (Explicit Memory) (Hippocampal Function) versus Emotional Memory (Amygdala Function) Bechara et al. (1995) Three patients: - one with bilateral hippocampal damage (H+) - one with bilateral amygdala damage due to Urbach-Wiethe Disease (A) - one with bilateral medial temporal lobe damage (H+A+) Normal control group: no brain damage (n=4) Bechara et al. - cont. • Pavlovian Conditioning Task • Procedure: - present green, blue, yellow and red slides Blue slide 100 decibel boat horn (Conditioned Stimulus) (Unconditioned Stimulus) Skin Conductance Response (Unconditioned Response) (Sympath. Nerv. System Activation) Bechara et al. – cont. • Pavlovian Conditioning: - Over repeated slide presentations (trials): Subject learns that blue slide predicts aversive US Blue slide elicits learned anticipatory anxiety indicated by the SCR Conditioned Response • Five minutes following conditioning trials: - subjects asked four questions to assess declarative memory (memory for facts) Bechara et al. - cont. Four Questions: 1. How many different colors did you see? 2. Tell me the names of the colors? 3. How many different colors were followed by the horn? 4. Tell me the name(s) of the colors that were followed by the horn? Bechara et al - cont. • Results: • Normal group • Amygdala lesion • Hippo. lesion • MTL lesion conditioned SCR good declarative memory no conditioned SCR normal declarative memory normal conditioned SCR no declarative memory no conditioned SCR no declarative memory Bechara et al. - cont. Conclusion: • A Double Dissociation • Amygdala contributes to the formation of emotional memories (fear, anxiety) • Hippocampus contributes to the formation of explicit (declarative) memories Amygdala vs. Hippocampal Damage in Monkeys • A double dissociation similar to humans Why does the H+A+ lesion produce a more severe impairment than the H+A or H+ lesion? • Is it do to damage to cortex which surrounds the amygdala? • What is the cortex? Perirhinal and Parahippocampal Cortex Entorhinal Cortex Hippocampus Zola-Morgan et al. • DNMS Task • Three groups: 1. Group N 2. Group H+A+ 3. Group PRPH perirhinal/parahippocampal lesion Result: PRPH Group severe deficits comparable to H+A+ Group Conclude: The critical area may reside in PRPH cortex What about the hippocampus by itself? Murray and Mishkin (1998) • Compared AH vs. perirhinal (Rh) cortical lesions in monkeys • DNMS Test • Result: - Absolutely no effect of the AH lesion - Severe deficit with Rh lesion • Important point: - Rh lesions do not produce retrograde amnesia Mumby and Pinel (1994) • Compared AH lesions vs. perirhinal cortex lesions in rats • Mumby Box Test • Results: - Little effect of AH lesion - Significant effect of perirhinal cortex lesion But…..What about R.B.and G.D.??? • Rather selective damage to hippocampal CA1 subfield produced substantial anterograde memory impairments • The Problem: Why does limited damage to the hippocampal subfields produce significant memory deficits whereas only minimal or no deficits occur with total removal of the hippocampus??? Mumby et al. (1996) • Three groups of rats: 1. Ischemia 1 hr. Sham lesion 2. Ischemia 1 hr. Hippo. lesion 3. Ischemia 1 wk. Hippo. Lesion Mumby box Mumby box Mumby box Result?? - Group 2 demonstrated normal memory - Group 3 demonstrated severe memory deficit Cort. Mumby Ischemia Hypothesis Cortical glutamate neuron Perforant path Excess glutamate release CA1 Hippocampal CA1 neuron (becomes hyperactive and dies) Excess glutamic acid Cort. Cortical neurons (become dysfunctional) memory impairment Is There a Function for the Hippocampus in Memory? The Evidence for a Function: Selective hippocampal lesions in rats Deficits: 1. Morris Water Maze 2. Radial Arm Maze A Contribution for the hippocampus in spatial memory A Hippocampal Function in Memory? – cont. Additional evidence for a role in spatial memory: Hippocampal size in different species of birds - Homing pigeons have a larger hippocampus - Birds that store seeds in wide-spread caches have a larger hippocampus than non-seed storing species - Black-capped chicadee: hippocampal size increases in the fall A Hippocampal Function in Memory? • London Taxi Drivers - posterior hippocampal region enlarged compared to comparison group - anterior hippocampal region reduced in size - drivers with more experience have a larger posterior, but smaller anterior, hippocampus than less experienced drivers Suggests: - the experience of navigating may have led to the enlargement Can the Adult Brain Generate New Neurons? Gage and colleagues (1997ff.) • Stem cells - adult mouse hippocampal dentate gyrus - versatile cells - resemble stem cells in the developing embryo - continuously divide - many die soon after division - some mature into dentate gyrus granule cells - the process of neurogenesis • QUESTION: How can neurogenesis be enhanced? Gage et al. (1997) • Adult mice – two genetically identical groups • Two living conditions for 40 days - standard laboratory cages - enriched living condition - complex environment • Results: - enriched mice 1. larger dentate gyrus (young adult) 2. 15% more dentate gyrus granule cells 3. significantly faster learning in Morris water maze Gage et al. (1999) • Adult mice • Two living conditions: - standard cage - standard cage plus running wheel (4.78 km/day) Result: Runners - enhanced neurogenesis - enhanced performance in Morris Water maze when tested 30 days into housing condition POSSIBILITY: New neurons may contribute to improved memory??? What About Neurogenesis in the Primate Brain? Gould et al. (1998) • Adult Monkeys - neurogenesis in the adult dentate gyrus • Stress and neurogenesis: adult males placed in unfamilar colony 1. subjected to aggression/stress by dominant males 2. reduced number of developing dentate granule cells 3. Glucocorticoids inhibit hippocampal neurogenesis Does Neurogenesis Occur in the Human Brain? • Erickson et al. (1998) - made use of DNA marker (BrdU) used in mice - only labels DNA in cells (i.e., stem cells) preparing to divide - marker inherited by daughter cells and future descendants of original dividing cell - BrdU will be observed in mature neurons - given to certain cancer patients to monitor tumor growth rate Erickson et al. - cont. - examined hippocampus of five deceased patients - each displayed new dentate gyrus granule cells A Hippocampal Function in Memory?? • Hippocampal place cells - respond when the rat is in a particular place its environment - their place response takes several minutes to develop while the rat explores a new environment CONCLUSIONS: One specific function of the hippocampus is the storage of memories for spatial location MEDIAL TEMPORAL LOBE VS. DIENCEPHALIC AMNESIA • Korsakoff’s Syndrome - chronic alchoholism - anterograde Amnesia - severe retrograde amnesia - damage to the diencephalon - thiamin (vitamin B1) deficiency 1. mammillary bodies (hypothalamus) 2. thalamic mediodorsal nucleus - Case N.A. MEDIAL TEMPORAL LOBE VS. DIENCEPHALIC AMNESIA • Diencephalic Amnesia • Medial temporal lobe amnesia Similar Memory Dysfunctions • The mammilary bodies, mediodorsal thalamus and temporal lobe structures which contribute to memory may be components of the same circuit What are the physiological/structural changes that form the substrate for memory? A focus on the hippocampus Long-term Potentiation (LTP) • The enduring facilitation of transmission across a synapse as a function of repeated activation • First observed in the hippocampus – 1973 • Occurs at several different hippocampal synapses • Occurs in numerous brain areas • Can be induced in a matter of seconds • Can last for months • Can be studied in the hippocampal slice preparation LTP: TWO CONDITIONS REQUIRED Dentate Gyrus Neuron 1 –Transmitter Release Perforant path Stimulate here 2 - Depolarization of Sufficient Magnitude Entorhinal Cortex Neuron 1. 1 and 2 must occur concurrently. 2. Both occur with high frequency stimulation (tetanus) of the entorhinal cortex LTP from concurrent activation of two different inputs 2. Depolarization 1. Transmitter release Perforant path Unconditioned Stimulus LTP occurs here Conditioned Stimulus 1. 1 and 2 must occur concurrently. Conditioned Response LTP: MECHANISM EXPERIMENT 1: • Hippocampal slice • Apply NMDA receptor antagonist • Apply high frequency stimulation to induce LTP in dentate gyrus neurons RESULT: LTP IS BLOCKED CONCLUSION: 1. Glutamate is necessary for LTP to occur 2. NMDA receptor activation is also necessary LTP: MECHANISM EXPERIMENT 2.: • Hippocampal slice • Apply high frequency stimulation to induce LTP in dentate gyrus neurons • Reduce Ca++ activity in the post-synaptic neuron RESULT: 1. LTP is blocked CONCLUSION: 2. Ca++ is necessary for LTP LTP: MECHANISM CONCLUSIONS: 1. NMDA receptors are necessary for LTP 2. Ca++ is necessary for LTP What is the Role of Calcium? CA++ enters via NMDA Receptors activates CA++ dependent enzymes protein synthesis Structural changes (post-synaptic cell) nitric oxide synthesis (retrograde transmitter) Structural changes (pre-synaptic cell) What are the structural changes produced by LTP that lead to enhanced synaptic transmission? 1. Increased Receptors or Receptor Sensitivity 2. Increased Transmitter Release 3. Increased Number of Synapses 4. Structural Change of Dendritic Spine LTP: Mechanism – cont. • LTP blocked by inhibition of protein synthesis • LTP blocked by blocking nitric oxide synthesis Is There a Relationship Between LTP and Memory? • Several lines of evidence point to one 1. NMDA receptor antagonists injected into the hippocampus or amygdala produce learning/memory deficits in different tasks Some controversy in the results 2. LTP develops in the hippocampus or amygdala during different forms of learning 3. Genetic alterations of LTP mechanisms The Relationship Between LTP and Memory during Fear Conditioning? • Rogan et al. (1997) - Pavlovian fear conditioning in rats - Tone (CS) footshock(US) (paired trials) - Tone comes to elicit fear reflected in freezing (CR) over trials - Lesions of the lateral amygdala block freezing CR Rogan et al. – cont. Design: - two groups of rats: 1. Group 1 Paired trials 2. Group 2. Unpaired trials - recorded population response to tone from lateral amygdala - three phases of the conditioning procedure 1. Pre-training– recorded response to tone alone 2. Training – recorded response during paired and unpaired trials 3. Test phase (1 day later) – recorded response to tone alone Rogan et al. - cont Results: - Population response became larger in rats receiving paired trials than in rats receiving unpaired trials - Larger population response was present in rats receiving paired trials during the test phase 24 hrs. after training Conclude: - Response of lateral amygdala neurons to tone is enhanced as a function of learning - Suggests that an LTP mechanism may be the substrate for the enhancement Genetic Alterations of LTP Mechanisms and Effects on Learning • The “Knock-out” mouse model - mice deficient in the genes necessary for the production of NMDA receptors, CA++ - dependent enzymes, etc. Recall: 1. CA++ enters the NMDA receptor channel 2. CA++ activates enzymes Structural changes LTP Tsien et al. (1996) • Created a “knockout mouse” - deficient in gene responsible for an essential subunit of hippocampal CA1 NMDA receptors - renders the CA1 NMDA receptors non-functional Results: - deficient in LTP at CA1 synapses - deficient in learning in Morris water maze What happens if you increase the function of NMDA receptors? Will you facilitate LTP and learning? Tang et al. (1999) • Created a mouse with a type of NMDA receptor that stays open longer More CA++ influx - the Doogie mouse - new receptor is located in various brain regions • Result: Compared to control mice Doogie mice demonstrate - enhanced hippocampal LTP - enhanced fear memory - enhanced learning in the Morris water maze - enhanced visual object recognition memory What are the Ca++ dependent enzymes? • There are several called protein kinases - Protein kinase C - Type II Ca++/Calmodulin-dependent protein kinase or CAM-KII - Tyrosine kinase What if we create a knockout mouse for CAMKII? • Silva et al. (1992) - CAMKII abundant in hippocampus - Developed a mouse deficient in CAMKII mRNA 1. examined hippocampal LTP 2. examined spatial learning in Morris water maze - Result: 1. deficient LTP 2. retarded Morris water maze learning Will excess CAMKII produce LTP? • Petitt et al. (1994) - inject the hippocampal slice (CA1) with a virus - virus causes CA1 cells to manufacture LTP Develops During learning • Mitsuno et al. (1994) - Radial arm maze - Experiment 1. Two groups of rats: 1. Experimental group - maze learning 2. Control group – handled Measured LTP in the hippocampus after 7 days of maze training or handling Result: Enhanced population spike in trained rats Mitsuno et al.- cont. • Experiment 2 - determine the amplitude of population spike each day after maze training Result: - Population spike gradually increases over training days in maze-trained, but not in handled group Question: Does the increase in the population spike really reflect memory or simply some performance variable?? Does Learning Affect Neurogenesis in the Hippocampus? • Gould et al. (1999) Morris water maze training in rat enhances survival of new neurons in hippocampal dentate gyrus net increase in number of new neurons Question: Implications for Memory??? What other brain structures contribute to memory? • The Dorsolateral Prefrontal Lobes • Working memory = memory in the active state - the memory that the organism needs and uses for the performance of acts in the short term - often called Short Term Memory The Prefrontal Lobes and Working Memory Fuster et al. (1995) - monkeys - cryoprobe to cool the dorsolateral prefrontal cortex - delayed matching to sample task - Result: deficits at short delay intervals (e.g., 8 seconds) Recall: Lesions of medial temporal lobe structures do not produce delays at such short delay intervals The Dorsolateral Prefrontal Lobes and Working Memory • Fuster et al. - delayed response task - recorded from cells – dorsolateral prefrontal cortex • Result: - a type of neuron that only becomes active during the delay period - activity is specific to the memory task - working memory cells??? The Dorsolateral Prefrontal Cortex and Working Memory • Humans - frontal lobe damage - damage produces deficits in delay tasks - deficits similar to that observed in monkeys • Humans – PET scan during working memory task - Petrides et al. (1993ff) - verbal working memory task Petrides et al. (1993) – cont. 3. Externally ordered condition - experimenter reads numbers from 1-10, omitting one number - subjects asked to monitor the numbers carefully in order to determine which number was omitted • Pet scans performed under all conditions • Results: Increased activity in dorsolateral prefrontal cortex during the self- and externally-ordered conditions Petrides et al. (1993) • Verbal Working Memory Task - three conditions 1. Control condition - Count aloud from 1 to 10 repeatedly for 60 seconds 2. Self-ordered condition - Say aloud the numbers 1-10 in random order without repeating a number - Start a new trial with the number 1 ALZHEIMER’S DISEASE • The most common form of dementia. 3 Pathological Changes in the Brain: – Extensive Neural Degeneration – Neurofibrillary Tangles • threadlike tangles in the neural cytoplasm – Amyloid Plaques • Spherical clumps of scar tissue composed of degenerating neurons interspersed with an abnormal protein called amyloid ALZHEIMER’S DISEASE ALZHEIMER’S DISEASE • Pathological changes are prevalent in the structures of the medial temporal lobe and the basal forebrain. • In addition to retrograde and anterograde amnesia, AD patients show some short-term memory loss and some implicit memory loss. ALZHEIMER’S DISEASE Patients with AD show a reduction in cholinergic (ACh) activity: • Less acetylcholine • Less choline acetyltransferase (synthesis) • Less acetylcholinesterase (breakdown) – Also lower levels of NE & 5-HT ALZHEIMER’S DISEASE TREATMENT • Acetylcholine agonists tried as nootropics (memory-improving drugs), but have failed. • Now developing acetylcholinesterase inhibitors that seem to be working (e.g., Rivastigmine; a.k.a. Exelon) – Shown to improve CNS function and daily living over 6 month period.