Memory. Lynn Yen, class of 2009

Transcription

1 Memory Lynn Yen, class of 2009

2 Objectives 1. Understand the different types of memory. 2. Describe where different types of memory are stored and the CNS structures involved in storage. 3. Describe how damage to the hippocampus and mammillary bodies affects memory. 4. Describe the role of the amygdala in recognition and expression of fear. 5. Describe the pharmacological treatment for Alzheimer s Disease. 6. Describe the Kluver-Bucy syndrome. 7. Describe how the Nuc Accumbens and dopamine are involved in reinforcement of behavior. 8. Describe the source of dopaminergic neurons in the brain. Relevant portions of:

3 Memory, Emotions and the Brain What did I eat this morning Where did I put my keys What is her name What are plants What is a book Know how to walk Know how to bicycle Know how to brush teeth What is memory and where is it stored How did it get there? What conditions damage it? Fear and the role of the amygdala Reward/Motivation and Nucleus Accumbens Christopher Cohan, Ph.D. Dept. of Pathology/Anat Sci University at Buffalo

4 Memory and its Categories Memory - the process of encoding, storing, and retrieving information about our experiences. Types: Sensory memory encodes sensory stimuli (0-2 sec) Short-Term the most recent info (30 sec); Working Memory brief storage of verbal, visual, spatial information Long-Term - relatively permanent Affected by disease processes (dementia) and assessed by memory tests. Semantic memory of facts/general world knowledge Episodic memory of personal events linked to time/place Procedural - how to do something (motor)

5 Memory Categories working memory Sensory memory Short-term memory Long-term memory consolidation Early, simple model of memory helped organize understanding. Limited as a comprehensive model. Working memory has surpassed the concept of short-term memory and provides a better model for how we manipulate information in daily tasks. Memory deficits that accompany dementia impair our ability to manipulate information and consolidation.

6 Working Memory How we store and use information for brief periods in our daily mental tasks. Moment to moment thinking processes use verbal, visual, spatial information in mental tasks. Temporary storage locations in the cortex are used to store and manipulate this information for short periods of time. Linked to reasoning, comprehension, learning and LTM. Cognitive function is assessed clinically by testing working memory.

7 Working Memory Visual/spatial Information storage Working Memory Executive processing Verbal Information repetition/storage Examples: mental arithmetic remember phone # remember location remember objects attention, sequencing, manipulation

8 WHERE is Memory Stored All memory is stored in CORTEX but in different locations and by different mechanisms Working Memory short term storage of verbal, visual, spatial info; executive processing Left and right posterior parietal and prefrontal cortex. Long-Term Memory Semantic- medial temporal lobe Episodic distributed throughout association areas of cortex Procedural - motor association cortex motor words tactile, spatial visual

9 WHERE is Memory Working Memory short term storage of verbal, visual, spatial info; executive processing Left and right posterior parietal and prefrontal cortex. Long-Term Memory Semantic- temporal lobe Episodic distributed throughout association areas of cortex Procedural - motor association cortex motor tactile, spatial words visual

10 How We Know - Lesions Disrupt Memory Working Memory lesions of frontal, parietal cortex and their interconnections in white matter impair temporary storage of verbal, visual, spatial information and its manipulation. Stroke, trauma, degenerative diseases, MS, PML Cortical lesions disrupt long term memory Damage to sensory association areas - agnosia. astereognosis, agraphesthesia, prosopagnosia, words, aphasias, etc Stroke, trauma, cortical degenerative diseases

11 How is LTM Stored Episodic Memory events linked to time/place Hippocampus and (mammillary bodies, thalamus) Procedural Memory for motor learning prefrontal cortex, basal ganglia (association loops), cerebellum all participate

12 Hippocampus and Other Structures an area of rolled cortex (layers!) in the temporal horn of the lateral ventricle.

13 Episodic LTM Requires Hippocampus Through the process of consolidation the hippocampus transfers episodic information to cortex functional areas where it becomes more stable LTM. Sensory memory Short term store Long-term memory consolidation hippocampus Hippocampal damage causes inability to store NEW information, but short term store and long term memory remain intact.

14 How We Know - Lesions Disrupt Storage Hippocampal lesions impair consolidation - The Case of HM medial temporal lobes surgically removed to treat seizures Inability to store new episodic memory (anterograde amnesia) Short-term/WM memory intact Already-stored memories intact Ability to learn new motor tasks intact Hippocampus is also required for spatial learning. Spatial disorientation occurs in dementias. Bilateral lesions can be caused by: Stroke, trauma, Alzheimer s disease

15 Papez circuit, initially proposed for emotion, relates structures involved in memory consolidation. Papez Circuit Hippocampus - Fornix - Mammillary body (hypothalamus) - Anterior nuc thalamus - Cingulate gyrus - Entorhinal cortex - Hippocampus Indicate anatomical links between hippocampus, mammillary bodies and thalamus, but the circuit is not understood.

16 Lesions Disrupt LTM Storage Impaired consolidation of memory and inability to remember new events results from: Hippocampal atrophy; pathology of Alzheimer s Disease Mammillary bodies Wernicke-Korsakoff s Syndrome Chronic alcoholics with thiamine deficiency damage mammillary bodies have impaired memory consolidation. Mammillary bodies

17 Hippocampus is a Unique Structure Life-Long Production of Hippocampal Neurons New neurons are generated in hippocampus throughout life. Proliferation and survival of those neuron, necessary for normal hippocampal function, are affected by physiological conditions: Enhanced by exercise, mental stimulation (Lumosity?) Impaired by depression and stress (hypothalamus-pituitary-adrenal axis- cortisol), age, dementia disorders cause hippocampal atrophy Ultimately affect efficacy of memory consolidation.

18 Memory Mechanisms Physiological Changes + Protein Synthesis Long term memory involves physiological and anatomical changes at synapses that require protein synthesis. Initial changes in synaptic efficacy are made stable by long term structural changes. (NMDA /AMPA glutamate receptors and synaptic plasticity)

19 Memory Mechanisms in the Hippocampus The cellular mechanism for memory is under intense study in the hippocampus. Simple models of memory and learning involve a pre- to postsynaptic neuron circuit where the key feature is activity-dependent change in synaptic efficacy as occurs in Long Term Potentiation. Experiments have shown that the synaptic changes in LTP involve recruitment of AMPA receptors to synapses where NMDA receptors are already located. The increased number of AMPA-R provide the additional depolarization to activate NMDA-R, inducing Ca influx, a cascade of intracellular changes, and increase in synaptic strength. Continued activation of NMDA-R ensure that synaptic changes are maintained. Glutamate plays a major role here, but at the same time it presents a serious liability when the brain is damaged, which causes release of Glu from impaired neurons and large influxes of Ca into cells that lead to cell death.

20 Pharmacological Treatment in Alzheimer s Several deep areas within the cerebral hemispheres send cholinergic terminals to the hippocampus. Application of ACh agonists to muscarinic and nicotinic receptors in the hippocampus facilitate memory formation. Application of ACh antagonists (eg. atropine) to the hippocampus can impair memory formation. Diseases such as Alzheimer s reduce ACh levels in the brain. Acetylcholinesterase inhibitors (tacrine, donepezil) can improve memory in dementia patients, but they produce very limited and short-term effects. produce limited and short-term effects however, early use can delay rate of impairment

21 Memory, Emotion, and Alzheimer s Memory of events and emotions are processed differently: A 2014 study with Alzheimer s patients showed that emotions lasted longer than the memory of the event that caused them. "Our findings should empower caregivers by showing them that their actions toward patients really do matter," Guzmán- Vélez says. "Frequent visits and social interactions, exercise, music, dance, jokes, and serving patients their favorite foods are all simple things that can have a lasting emotional impact on a patient's quality of life and subjective well-being. These positive emotions outlast the patient s memory of the events that caused them, but they continue to promote a positive well-being. Feelings without memory in Alzheimer disease, E Guzmán-Vélez, JS Feinstein, D Tranel, Cognitive and behavioral neurology 27: (2014)

22 Memory and Olfaction Olfactory cortex adjacent to underlying hippocampus. Olfactory sensations can form long lasting and potent memories. Phylogenetic basis in animal world identification based on olfactory cues facilitate memories of friend or foe objects. amygdala

23 Fear-Based Memory - Amygdala Recognition of threatening stimuli and memories formed by them depend upon the Amygdala. large nucleus in temporal lobe at anterior end of hippocampus. It lies inside the uncus. It has a major role in: 1. How we recognize threatening stimuli some innate, others learned 2. How we respond to threatening stimuli fear, ANS activation, anxiety

24 Amygdala Amygdala and hippocampus are part of the limbic system, an area on the border (limbus) between cortex (perceptual processes) and hypothalamus (visceral control), integrating emotion, memory, and autonomic responses. Limbic System includes: cingulate gyrus, parahippocampal gyrus, amygdala, hippocampus, hypothalamus, dorsomedial thalamus, olfactory areas. hypothalamus

25 Expression of emotions (sadness, anger, fear) typically involves a visceral response: crying/tears increased heart rate/blood pressure vasodilation/vasoconstriction pupillary dilation sweating The limbic system attempts to relate the cognitive processes that underlie emotions with the autonomic responses they evoke. One example is how the amygdala activates the autonomic NS.

26 Amygdala 1. Essential for our recognition of threatening, harmful, dangerous stimuli. Sensory stimuli via cortex Amygdala Interprets threat, danger (some fear is innate, some learned) innate fear of snakes 2. Essential for our response to threatening stimuli. visual cliff Experiments showed infants have innate fear of dangerous situations Amygdala hypothalamus Cortex-emotional awareness Autonomic activation Consolidates aversive aspects of negative experiences visceral response Sympathetics heart rate blood pressure sweating b blockers used to treat/break cycle between sympathetic activation and emotional awareness

27 EVIDENCE Amygdala Activity increases with fearful stimuli Stimulation causes feelings of fear/anxiety; autonomic responses (pupils dilate, increased heart rate); aggressive behavior Role in Panic attacks Lesions: patient SM had rare disorder of amydala degeneration in adolescence - decreased emotionality; loss of fear; indifference to fearful stimuli Recurrent, unprovoked episodes of terror.

28 Kluver-Bucy Syndrome One of the first experiments to study the role of the amygdala used surgical removal of the anterior temporal lobe bilaterally in monkeys. The results of the study became known as the Kluver-Bucy syndrome that had the following features: Placid behavior loss of fear and aggressiveness Male animals became hypersexual Psychic blindness Loss of amygdala inability to recognize objects but not blind Oral examination of objects Visual agnosia (what stream)

29 Behavioral Reinforcement Reward and reinforcement of behavior involve Nucleus Accumbens. Important in 1. Motivation of behavior - why we do things 2. Addiction - why we continue to do things (loss of control)

30 Reward/Reinforcement Nucleus accumbens a limbic structure under head of caudate nucleus. It relies heavily on dopamine as a neurotransmitter. NA influences behavior through connections with prefrontal cortex (decision-making, etc). Adaptive behavior attempts to maximize reward and minimize punishment. Positive, adaptive activities release dopamine in NA reinforcing those behaviors. Drugs (cocaine, opiates, alcohol) and activities that increase levels of dopamine in NA act to reinforce and sustain the behavior, leading to addiction. NA also plays a role in regulating mood. Dopamine levels can modulate the presence of depressive symptoms in animals.

31 CNS Sources of Dopamine Pathways that control dopamine, therefore, are important in understanding addiction, mood, action of antipsychotic drugs (D2 receptor blockers). Cell bodies of dopaminergic neurons have only 2 locations: 1. Midbrain - substantia nigra, ventral tegmental area 2. Hypothalamus (inhibits prolactin secretion in ant pituitary) Nuc accumbens Basal ganglia Substantia nigra hypothalamus Ven tegmentum substantia nigra ventral tegmental area

32 Reward Dopaminergic Circuits The 4 dopaminergic projections of the brain: 1. Mesocortical projection - frontal lobe function 2. Mesolimbic projection - to Nuc Accumbens 3. Nigrostriatal projection to Basal Ganglia (movement) 4. Tubero-infundibular projection inhibits prolactin release Addiction, mood Drug side effects Meso = midbrain Save for Psychiatry Antipsychotics that block dopamine receptors will affect these pathways Nuc accumbens 3 Basal ganglia Substantia nigra hypothalamus Ven tegmentum

33 Reward Dopaminergic Circuits Axons from the VTA synapse in cortex and Nuc Accumbens. Terminals release dopamine and affect motivated behavior and mood. Dopamine pharmacology important in understanding drugs of abuse, addiction, psychotic disorders. How these midbrain projections are controlled is a key question in understanding these disorders. Dr Silvestri - Parkinson s meds can induce addictive behaviors.