Please go watch these 2 lectures after class

Please go watch these 2 lectures after class 2008 HHMI lecture by Eric Kandel and Tom Jessell http://www.hhmi.org/biointeractive/neuroscience/lectures.html This week http://media.hhmi.org/hl/08lect1.html More history about early works on mapping the brain function Next week http://media.hhmi.org/hl/08lect4.html Several modern disciplines study of learning and memory System part of memory Psychology classification of learning and memory Physiology/Anatomy Which part of brain is important for learning and memory Molecular Biology Molecular mechanism of learning and memory 1

Importance of hippocampus in long term memory formation: case of H.M. Most famous case reported by Scoville & Milner (1957) HM: bilateral medial temporal lobe lesion for status epilepticus in 1953 The medial temporal lobe and memory storage HM unable to form new long term memory 2

Part of HM s hippocampus preserved 23.6mm in the left hemisphere and 24.3mm in the right. 3

H.M. showed normal motor learning and long term memory H.M. s specific memory deficit IQ and personality unchanged Normal learning and short term memory Normal long term memory for facts before operation Loss of information acquired just before the operation Unable to transfer new short term memory into new long term memory (explicit memory) Normal procedural (motor) memory 4

What we learn from H.M. s case We have two types of memory: Short term and long term. The hippocampus is not involved in the formation of short term memory and retrieval of long term memories. The hippocampus is not involved in 'procedural memories. The hippocampus is not be involved in personality, IQ and other cognitive functions. The hippocampus is involved in transferring short term explicit memory to long term memory. 5

The anatomical organization of the hippocampus pyramidal cell layer Hippocampus anatomy sub CA=Cornu Ammonis DG=dentate gyrus Sub=subiculum hilus granular cell layer 6

The input and output pathways of the hippocampal formation London Taxi Drivers : Structural MRI & Neuropsychological Analysis Bus drivers were not found such correlation 7

Memory can be classified along 2 dimensions The time course of storage Short term (working) memory Long term memory The nature of the information Short term: verbal information and visuospatial information Long term: explicit (conscious) and implicit (subconscious) Memory Types of memory: short term (working) memory temporary limited capacity needs rehearsal long term memory 'permanent' greater capacity no continual rehearsal needed 8

Current view of explicative memory CPU RAM Hard disk Short term memory Works like RAM memory in computers; provides a working space. A limited capacity for 7±2 independent information. Last only few seconds to minutes Vulnerable to interruption or interference The information held in short term memory may be: recently processed sensory input items recently retrieved from long term memory 9

Short term (working) memory Short term (working memory) : maintains transient representations of information relevant to immediate goals Short term memory is selectively transferred to long term memory 2 types: verbal information and visuospatial information Ways to move information to long term memory 1. Senses and emotions 2. Repetition and Rehearsal 3. Organization Principles 10

Senses and emotions Where were you on the following day? 0 9 3 5 1 5 7 3 7 6 September 01, 2004 September 11, 2001 September 21, 1999 Repetition and Rehearsal Effortful learning usually requires rehearsal or conscious repetition. Ebbinghaus studied rehearsal by using nonsense syllables: TUV YOF GEK XOZ 23 11

Organization Principles Acronyms are another way of chunking information to remember it. Abuse Ab = away, from Long term memory Long term memory store containing the accumulated knowledge base Characteristics Duration: Hours to years Capacity: Huge possibly limitless 12

Forms of long term memory Explicit Implicit Memory can be classified as implicate or explicit on the basis of how information is stored and recalled 13

Explicit versus Implicit Memory Explicit (or declarative) memory recalled by a deliberate, conscious effort. semantic memory (facts) episodic memory (events) Implicit memory (nondeclarative) a memory that is recalled unconsciously. Stored in perceptual, motor and emotional circuits. procedural memory (swimming, biking) associative learning (conditioning) nonassociative learning priming Semantic vs. episodic memory Episodic Memory refers to memories for particular events that have been experienced. Semantic Memory refers to knowledge such as vocabularies, concepts, numbers or facts. 14

Brain imaging The perfrontal cortex maintains a working memory 15

Episodic knowledge depends on interaction between the medial temporal lobe and association cortices Semantic knowledge is stored in distinct association cortices and retrieval depends on the prefrontal cortex 16

Explicit knowledge involves four distinct processes Encoding: process of newly learned information. Consolidation: make new information more stable for long term storage. Synthesis of new proteins is required. Storage: the mechanism and sites to retain memory over time. Retrieval: recall and use of the stored information. The more association, the stronger memory Retrieval of information is most effective when it occurs in the same cues. Long term memory Hippocampal system would mediate the initial steps (encoding and consolidation )of long term storage. It would then slowly transfer information into the neocortical storage system. 17

Implicit memory Implicit memory (nondeclarative) a memory that is recalled unconsciously. Stored in perceptual, motor and emotional circuits. procedural memory (swimming, biking) associative learning (conditioning) nonassociative learning priming Builds up slowly, through repetition over many trials, and is expressed primarily in performance, not in words. Does not depend on conscious processes. 18

Priming The right occipital cortex is required for visual priming HM is NOT impaired in priming test Procedural memory Perceptual learning involves a shift from cognitive to autonomous stages that use different neural pathway Play piano 19

Learning of implicit memory Non associative learning:learns about the properties of a single stimulus Habituation Sensitization Associative learning: learns about the relationship between two stimuli or between a stimulus and a behavior Classical conditioning (Pavlovian conditioning) Operant conditioning (Instrumental conditioning) Nonassociative Learning Habituation : decrease in response to a repeated stimulus not accompanied by changes in other stimuli 如入鮑魚之肆, 久而不聞其臭 Sensitisation: an increase in response to a moderate stimuli as a result of a previous exposure to a strong stimulus 一朝被蛇咬, 十年怕草繩 20

Associative Learning Classical conditioning learning a relationship between two stimuli Operant conditioning learning a relationship between a behavior and the consequences Classical conditioning (CS) (US) (UR) (CR) US UR CS+ US UR CS CR(salivation) 21

Classical Conditioning Unconditioned stimulus (US): unrelated to the response that eventually will be learned. Conditioned stimulus (CS): neutral response During conditioning, the CS and US are paired over many trials Test of learning: Does the CS alone produce a response? CS US paired CR UR TRIALS Pavlov s view of the physiology of learning Pavlov believed that conditioning strengthened connections between the CS center and US center in the brain. 22

Contest vs. cued fear conditioning CS= something neutral (tone, light) US= aversive stimulus (loud noise, shock ) Classical conditioned depend on the degree to which two stimuli are correlated 23

Extinction and spontaneous recovery Training Extinction Re train 10 Tone-Shock Pairings 10 Tone only 1 Tone-Shock Pairings Training Extinction Re train Importance of hippocampus in contextual fear conditioning test Remote training 10 Tone-Shock Pairings Freezing 24

Importance of hippocampus in contextual fear conditioning test Remote Training Recent Training 50 days later 10 light-shock Pairings Importance of hippocampus in contextual fear conditioning test Remote Training Recent Training 50 days later With in 24 hr DH Lesion SHAM Electrolytic Dorsal Hippocampus Lesion 25

Importance of hippocampus in contextual fear conditioning test Remote Training Recent Training 50 days later next day Sham or Hippocampus Lesion 100 C 10 day recovery % freezing 75 50 25 SHAM DH Remote Next day Recent 0 Remote Recent (first six min) Operant Conditioning Voluntary and goal directed Controlled by its consequences Strengthened if rewarded or punished 26

Operant conditioning involves associating specific behavioral with a reinforcing event Associative learning process between a stimulus and a response. The term operant comes from the verb to operate and refers to behavior that operates on the environment to produce a consequence. Not automatic Operant conditioning as a process, has evolved over species history and is based on genetic endowment. Chapter 59. The Aging Brain Increase of human life span and neurodegenerative diseases 27

台灣失智症盛行率 :2013 年新資料 衛生福利部委託台灣失智症協會進行由民國 100 年至 101 年底的全國失智症盛行率調查 全台 65 歲以上長者, 四分之一有認知功能障礙 盛行率 推估人口數 Mild to severe dementia 4.82% 近 13 萬人 Very mild dementia 3.28% 約 8 萬 8 千人 MCI 18.74% 約 50 萬 5 千人 總計 24.18% 約 72 萬 2 千人 Sun Y et al, PLoS One 2014;9:e100303. Prevalence of dementia in Taiwan 2004 vs. 2013 40% 35% 30% 每增加 5 歲, 盛行率增加一倍 30.9% 36.88% 25% 21.92% 20% 15% 2004 2012 13.03% 16.3% 10% 5% 0% 7.19% 8.4% 3.40% 3.46% 4.3% 1.2% 2.2% 65~69 70~74 75~79 80~84 85~89 >90 yrs Sun Y et al, PLoS One 2014;9:e100303. 28

Facts About Alzheimer s Disease (AD) Most common age dependent dementia. Slowly loss of memory, spatial orientation and ability to communicate and carry out daily activities. AD of brain dysfunc on AD is NOT a part of normal aging. Current treatments only have marginal benefit. There is no cure of AD. Diagnosing AD A detailed patient history (Information from family and friends) Physical, neurological and psychological exams Autopsy (plaque and tangle) the definitive diagnosis Neuroimaging (PET, MRI) CSF/plasma biomarkers Optional 29

Pathological changes in the brain of individuals with AD hippocampus The cause of Alzheimer s disease? The #1 risk factor : age 30

The History of Alzheimer s Disease Dr. Alzheimer examined brain of 55 year old woman at 1901. She died 2 yrs later after a rapid downhill course of premature senility/dementia Saw Neurofibrillary tangles and Amyloid plaques Progress after discovery was slow. Took 70 years for scientific community to publicly connect symptoms and define this disease Frau Auguste D Plaques and Tangles Are Pathological Hallmark of AD Amyloid plaques, which are deposits of Amyloid peptide (A ), accumulate outside the nerve cells. Neurofibrillary tangles, which are twisted Tau fibers, build up inside the nerve cells. 31

Genetic Risk Factors Amyloid precursor protein (APP), presenilin 1, 2 Pathogenic mutation can predict AD with 95 100% certainty Almost exclusively in early onset familial AD kindreds, <5% of all AD cases Apolipoprotein E4 Increase the chance for late onset of AD AD Molecules: The Big Three Aβ Tau ApoE Main component of plaques Main component of tangles Main genetic risk factor Molecules involved in disease pathways are widely used to explore target biology and to test potential treatments 32

The Amyloid Precursor Protein (APP) Learning and memory deficits Synaptic deficits Central Role of A in Alzheimer s Disease 1. Progressive deposits in AD patients. 2. APP and presenilin mutations that alter the aggregation or production of A cause early onset AD. 3. ApoE4 that increases A deposition is linked to late onset AD. 4. APP transgenic mice recapitulate many AD features. 5. Synthetic A exhibits toxicity in vitro. The density of A can be imaged by Pittsburgh compound B in PET 33

Tau Protein Microtubule associated protein located in the axons. Neurofibrillary tangle are mostly compose with hyper phosphorylated Tau protein. Very few Tau mutations are associated with AD. The level of tangle and CSF tau phosphorylation reflect the degree of neuronal degeneration. 34

Apolipoprotein E On chromosome 19, three alleles: ε4, ε3, ε2, The presence of ApoE4 allele enhance the chance to get AD ApoE modulate age at onset of dementia, neither necessary nor sufficient for the development of AD Not sensitive or specific to be used alone for the differential diagnosis of AD Use of ApoE as a diagnostic marker in asymptomatic individuals is NOT recommended ApoE3 vs. ApoE4 35

Multiple roles of ApoE 阿茲海默症之藥物治療 輕 中度 : 乙醯膽鹼酶抑制劑 (AchE I) Aricept (Donepezil) 愛憶欣 (1996) Exelon (Rivastigmine) 憶思能 (2000) Reminyl (Galantamine) 利憶靈 (2001) 療效 : 相當, 約三至五成的病人有效 副作用 : 噁心, 嘔吐, 頭暈, 腹瀉 藥物的選擇主要考慮其副作用及使用的方便性 中 重度 : 麩氨酸 NMDA 受體拮抗劑 Memantine (Ebixa 憶必佳,Witgen 威智 滅擾 Manotin ) 36

AD Is a Polyproteinopathy Disease progress in AD patients 37