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• – A long term change in behavior as a function of experiences. • – The capacity to retain and retitrieve ppas t exper p iences. The Neurobiology of Learning and Memory

Mary ET Boyle, Ph.D. Department of Cognitive Science UCSD

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Types of Learning Types of Learning: • Pavlovian Conditioning – A decrease in response following • Type of learning in repeated exposure to which a neutral a non-threatening is paired stilimulus. with a stimulus that elicits a response until the • neutral stimulus – An increase in elicits the reflex reactivity to a response by itself. stimulus following exposure to an intense event.

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Types of Learning: Types of Learning: Pavlovian Conditioning • Learning how to behave to obtain

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Types of Learning: Operant Conditioning Reinforcers • activities that increase the frequency of the behavior

PihPunishers • activities that decrease the frequency of the behavior

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Atkinson-Shiffrin model Baddeley’s rehearsal systems approach • Baddeley argued that go directly from the sensory register to long-term .

November 2001 • American Psychologist

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Working Memory: A Modern Advance Dual task paradigm

 Baddeley  Memorize arrangements of pieces on a chessboard while:  Softly counting from 1 to 10  Phonological  To tap a series of keys in a spatial pattern  Visuospatial  Produce a new random letter every second  Decision-making

Working memory—A system that permits the temporary storage and manipulation of information required for tasks such as comprehension, learning, and reasoning.

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Craik and Lockhart Dual task paradigm • The theory that memories differ in the extent to which they have been processed.  Counting: no effect  Tapping keys: impaired  Producing letters: impaired recall

November 2001 • American Psychologist

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Types of Memories: 1972

• —The memory of temporally related events experienced at a particular time and place. • For example, “What were you doing on your birthday?”

According to Tulving, animals • —The memory like his cat have no episodic of knowledge concerning the use memory so while they may of language and the rules, know many things, they do not remember past experiences the formulas, or algorithms for the wayyyj we do. They just know development of concepts or about them. solutions to problems. • For example, “How do you speak Japanese? Drawing by Ruth Tulving

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• (nondeclarative memory) Skill memory, or the memory o f highly practiced behavior. These memories may not be accessible to conscious awareness.

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• Declarative memory—Factual memory, or the memory of specific events. We are aware of declarative memories.

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The Process: Processes in LTM Hebb’s Cell Assemblies

Cell assembly  Processes used to store info rma tio n in me mo rry Reverberatory activity  Storage  Processes used to maintain Phase sequence information in memory Experience triggers  Retrieval activity  Processes used to get information back out of Activity is essential for LTM memory

Physiological changes

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Is Reverberatory Activity Essential for Memory Storage? • Studies have used ECS (electroconvulsive shock) to break up the consolidation of memory. • CS reminders have brought back • ECS tends to produce retrograde memories apparently lost after supporting the idea that ECS indicating that reverberatory actiiivity i s consolidation has occurred. necessary for memory consolidation. • Therefore, forms of brain intervention (e.g., ECS) affect •There are problems because ECS memory retrilhhieval rather than has aversive properties which consolidation. may inhibit responding.

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The Conditioning (Plasticity) of Neural Circuits

• Thompson and associates – Studied conditioning of the nictitating membrane of the rabbit. – Used a corneal air puff ( UCS) and tone (CS) – Cerebellar interpositus nucleus was found to be site of the conditioned response

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How does the brain associate two events?

Event 1 associate Event 2

Timing is the key!!! Neural Circuits in the Rabbits Nictitating Membrane Response

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two stimuli immediately stimulus separated in time follow one another (trace condition)

Animals require many more Animals learn this trials to learn the association easily. but eventually do it.

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Which structure is LPN: needed? Lateral Pontine Nucleus of the Cerebellum

Hippocampus?

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Formation of trace The LPN is necessary for the memories requires the paired association. hippocampus!!

• If the LPN was damaged – then pp(aired associations (CS-US))w would not be learned. • Remember: paired association means that there is no time bhbetween the presentat ifhCSion of the CS and the US.

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The Cellular Basis of Learning Sensitization in Aplysia & Memory californica

• Kandel’s studies of learning in Aplysia californica (a shell-less marine mollusk) indicated both habituation and sensitization exist in this animal.

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Presynaptic Facilitation in • Normal classical conditioning occurs with a CS of a light touch to the Aplysia mantle or siphon paired with an electric shock to the tail.

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Structural Changes and Storing Experiences

• Experience enhances Ca2+ ion entry into the hippocampus (Lynch, 1986). –Ca2+ ions activate the enzyme calpain which breaks down fodrin, a protein that coats the dendrites. This exposes more glutamate receptors to stimulation from other neurons, making the postsynaptic neuron more sensitive. – This may eventually cause changes in the terminal button and Lynch believes this may be the biological basis of learning and memory.

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The Anatomy of Learning & Memory The Anatomy of Learning and Memory • Squire and others have identified areas of the brain involved in declarative memory. – Medial temporal lobe—Hippocampus • Procedural or nondeclarative and surrounding cortical areas relay memory involves the neocortex information to diencephalic areas (mammillary nuclei, anterior thalamic and neostriatum. nuclei, and the mediodorsal thalamic • Classical conditioning of nucle i); it is p rocessed a nd re layed to depends on the the frontal lobe. cerebellum. – Frontal lobe—Medial temporal lobe structures and the medial thalamus jointly may be essential for the fiflformation of long-term memory; connections between these structures and the frontal lobe may provide a route by which memories can influence behavior.

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Key Brain Structures in Declarative Memory Storage and Retrieval

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The Case of HM Patient H.M. • DtthhiDamage to the hippocampus • Bilateral medial temporal • Bilateral medial temporal lobe lobectomy causes anterograde resection amnesia • PiPatient H HM.M. -surgery to treat severe epilepsy in the 1950’s – Normal intellectual ability – No personality change – CtlthiCannot learn anything new – Language was unimpaired, and reading and writing are still intact • However, HM’s language contains no words/phrases ldihiptilearned since his operation – For example, when asked to define “flower child”, he said it was a young person who grew flowers • STM unimpaired

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The Mirror The Case of HM: In His Tracing Words Task

• “Every day is alone in itself, whatever enjoyment I’ve had, and whatever sorrow IIve’ve had… Right now, I’m wondering. Have I done or said anything amiss? You see, at this moment everyygthing looks clear to me, but what happened just before? That’s what worries me. It’s like waking from a dream; I just don’t remember” • Milner (1970, p37).

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Another famous patient The Importance of the Hippocampus • CliveWearing • Viral encephalitis—destroyed parts of his temporal lobe in his 40s • Lives totally within most recent 1-2 • Damage to hippocampus results minutes in memory deficits. – Remembers what just happened, forgets everything else – Deficits in learning a simple object – Inability to form new memories, discrimination constantly feels like he just woke up – Deficits in delayed nonmatching- • Describes his life as being “like death ” to-sample task • Musician, choral director – Case of R.B.—hippocampal – Wearing still recalls how to play the piano damage produced profound and conduct a choir – Has no recollection of having received a musical education – procedural memory is intact – http://www.youtube.com/watch?v=Vwigmktix2Y& feature=related

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Long-Term Potentiation The Importance of the in the Hippocampus Hippocampus

• In the case of H.M., memories • Long-term acquired before surgery were potentiation—an retained suggesting that the increase in the hippocampus is involved in the amplitude and duration storage of declarative memory of EPSPs in response bibut is not t hihe site o f storage. tthtttilto the test stimulus. • Some researchers have found episodic encoding in the left frontal areas and episodic retrilihihflieval in the right frontal regions.

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Long-Term Potentiation in the Characteristics of LTP Hippocampus • Three pathways involved in LTP – Perforant fiber pathway – Mossy fiber pathway • A brief, sensitizing stimulus is sufficient to – Sc ha ffer co llatera l fiber pat hway prodLTPdttthtduce LTP; demonstrates that hippocampal neurons can change synaptic responsivity following a single event. • LTP-changed synaptic responsivity is confined to a specific neural pathway. • LTP can b e prod uced b y ei th er a si ngl e stimulus or by the convergence of stimuli that individually would not produce LTP. • LTP can last for days or weeks, which suggests that it is not just a temporary chihange in synap tiiittic responsivity.

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LTP and the NMDA Characteristics of LTP Receptor • LTP seemtms to occur rthr throug h modification of the NMDA receptor in • In the mossy fiber pathway, the perforant and Schaffer collateral glutamate binds to both the NMDA pathways. This may be a basis and non-NMDA receptors. LTP for operant and classical conditioning . apparently depends not on Ca 2+ influx into the postsynaptic receptor, but on Ca2+ influx into the presynaptic cell after the LTP- idinduc ing s timul us. • Kandel refers to this as nonassociative—the organism learns about the ppproperties of a single stimulus. Habituation and sensitization are examples of this type of learning.

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Long-Term Depression in the in the Hippocampus Hippocampus

• Long-Term Depression • Neurogenesis—(the formation of new (LTD)—A persistent activity- neurons) helps the brain to be modified in adaptation to changing environmental dependent reduction in conditions. synaptic effectiveness. – Learning that involves the hippocampus – LTD—can be induced by results in new cells surviving at a higher rate. repeated low-frequency The cells become part of neural circuits established by a temporal-based learning stimulation, and LTD in the experience. CA1 region of the hippocampus – Enriched environments have been shown to has been reported to be increase the size of an animal’s brain, their involved in novelty acquisition level of cortical ACh, and their learning in rats and in their reaction to ability. Studies have shown enriched environments increase hippocampal stressfliful situati ons. neurogenesis, even in adult animals.

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The Role of the The Role of the Mediodorsal Thalamus: Mediodorsal Thalamus Korsakoff’sSyndrome s Syndrome

• Mediodorsal thalamus—A brain • Loss of declarative rather than procedural structure associated with memory. profound memory impairment. • Patients are unaware that they don’t – Damage to this area produces remember; make up stories memory impairments (Korsakoff’ s () to fill in the gaps. syndrome). • Patients with medial temporal lobe damage (H.M.) are aware of their memory – People with Korsakoff’s syndrome loss. often have atrophy of cells in the • Emotion is generally intact with medial mediodorsal thalamus caused by a temporal lobe damage but patients with deficiency of Vitamin B . 1 mediodorsal thalamic damage tend to be emotionally flat and apathetic.

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The and Caudate Nucleus- Memory Putamen Memory System • Stimulation of the amygdala results in enhancing the memory of a task • Inhibition of the amygdala • Caudate nucleus and putamen results in decreasing the control the ability to develop emotional effects on pdlprocedural memory. memory.

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Alzheimer’s Disease

• Alzheimer’s Disease (AD)—A type of dementia characterized by progressive neurological degeneration and a profound deterioration of mental functioning. – Early onset—before age 65 – Risk factors include familial clustering of cases, increasing age, and Down syndrome.

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AD: Cellular Pathology The Cellular Basis of Alzheimer’s Disease

• See Scientific American Spotlight “Senile Words” which has suggestions about the factors that lead to AD. • Cellular basis of AD – Neurofibrillary tangles – Senile plaques – AlidAmyloid bibeta protein

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AD: Brain Pathology Preclinical AD

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Moderate and Severe Mild AD AD

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Alzheimer’s Disease: Alzheimer’s Disease: The Degeneration of The Degeneration of Neural Pathways Neural Pathways • Treating with ACh agonists has not resulted in great • Nucleus basalis of Meynert— imppgggrovements suggesting that cholinergic neurons that other neurotransmitters may be originate in this structure of the involved. basal forebrain and synapse in • Glutamate may not be cleared the neocortex and hippocampus from th e syn apti c cl eft and add s degenerate. to the degeneration of neurons • Administration of cholinergic in the affected areas. There is antagonists in animals leads to also evidence that amyloid beta memory dfiideficits. protein may be a causative agent in the disorder.

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Alzheimer’s Disease: TERMS: Genetics Pavlovian Conditioning

• Unconditioned stimulus (UCS)—A stimulus that involuntarily elicits a reflexive response. • There is a link between chromosome 21 • Unconditioned response (UCR)—A and AD. reflexive reaction to an unconditioned stimulus. • Another gene identified is ApoE on • Conditioned stimulus (CS)—An initially chromosome 19. Some people have one neutral stimulus that eventually elicits a or two ApoE4 alleles and have a greater conditioned response after pairing with a risk of having late-onset AD. The UCS. product of ApoE4 is not an effective • Conditioned response (CR)—A learned antioxidant for amyloid beta protein as reaction to a CS. are the products of other allelles. This may indicate a need to develop more effective methods to increase antioxidants in the brains of AD patients.

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Models of Memory Operant Conditioning Storage and Retrieval • Atkinson-Shiffrin model—An experience is sequentially stored in • Reinforcers—events or activities that the sensory register, and the short- ihffhbhiincrease the frequency of the behavior term store, and the long-term that precedes that event or activity. store. • Punishers—events or activities that – Sensory register—the initial storage site where a memory is held for a brief time without decrease the frequency of the . that precedes them. – Short-term store—In the Atkinson-Shiffrin model, a temporary site where information is held before • Skinner box—is an enclosed chamber storage in permanent memory. with a small bar on the inside wall used – Long-term store—The site of permanent memory for studying operant conditioning. storage. • Contingency—The specified relationship – Interference—An inability to recall a specific between a behavior and its reinforcement memory because of other memories. or . – Memory attribute—An aspect of an event that can stimulate memory retrieval.

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The Memory The Memory Consolidation Process: Consolidation Process: Hebb’ s Cell Assemblies Hebb’ s Cell Assemblies • Cell assembly—A circuit of • Experience triggers neurons that become active at reverberatory neural activity. the same time; serves as the site of p erm anen t m em or y. •This activity is essential for storing a memory in a • Reverberatory activity—The continued reactivation of a permanent form. neural circuit following an • The reverberatory activity is experience. fllfollowed db by ph ys iliolog ica l • Phase sequence— changes in the cell assembly interconnected cell assemblies, that produce a relatively all activated at the same time permanent record of the idin order to control compl ex event. processes.

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