Chapter 12: Learning & Memory Flashcards
Learning
A relatively permanent change in behavior due to experience
Memory
the means by which past experience is drawn on to guide or direct behavior or thoughts in the present, necessary for learning to take place.
Learning and Memory endow us with the ___ to ___ to an ever-changing environment
Learning and Memory endow us with the flexibility to adapt to an ever-changing environment
Determining the effects of hormones on learning and memory is difficult
……
Learning & Memory occurs in 3 stages:
Acquisition
Consolidation/Storage
Retrieval
Timing of hormone administration is critical to the learning process:
Prior to first exposure to task:
acquisition
At a point between learning & retest:
storage/consolidation
Immediately before retest: retrieval
Hormones may also affect nonmnemonic factors which could indirectly affect learning & memory:
attention, motivation, sensory responsivity, motor capabilities
These performance factors must be ruled out
Hormonal effects on cognition can be examined by:
- Observing effects of naturally occurring hormonal states:
Estrous Cycle.
Seasons.
In response to an environmental event, such as stress. - Manipulating hormonal state of the subject:
Remove hormone producing gland.
Pharmacologically altering hormone synthesis.
Blocking receptors.
Using genetically altered animals that have no receptors for a hormone or no ability to produce particular hormone.
Cognitive Tasks
Use tasks for which the underlying neural circuitry has been partially or fully elucidated .
Advantage: if the hormone does modify performance on the task then the likely site of hormonal action can be identified & examined.
Radial Arm Maze
Spatial task.
Advantages:
Easy to perform
Easy to vary memory load by varying food site or inserting delay between choices.
Can monitor memory retention or strategies for solving task.
Disadvantages:
Many training trials are required to achieve steady performance so hormonal effects must be assessed over days, sometimes weeks, which makes it difficult to isolate the effects of hormones to one stage of learning & memory
Morris Water Maze
Spatial tasks
Makes use of the rodents’ natural tendency to escape to dry land if it is placed in water
Advantages:
Easy to perform
Quickly learned
Disadvantages:
Its an aversively motivated task so that stress of training and testing may activate other hormonal system not under study.
Because it’s easy to learn, hormonally induced improvements in memory may be difficult to detect unless task difficulty is increased (i.e. longer delay between trials, lengthening delay prior to probe trail, vary platform location each day).
Avoidance Tasks
Active Avoidance: animal must act to avoid a noxious stimulus
Passive Avoidance: animal must suppress a behavior that would otherwise be exhibited
Active Avoidance
animal must act to avoid a noxious stimulus
Passive Avoidance
animal must suppress a behavior that would otherwise be exhibited
Fear conditioning
Advantages:
Easy to perform.
Quickly learned and memory retained for many days, therefore used extensively to examine stages of memory when hormones may be acting.
Disadvantages:
Its an aversively motivated task so that stress itself activates other hormonal systems that may confound interpretation
Social Recognition
Makes use of the animals’ natural tendency towards olfactory investigation of novel conspecifics
Procedures:
2 rats allowed to interact and smell one another for several minutes.
After a delay in which they are separated from one another, they are returned for a second meeting.
If recognition occurs, then subject spends less time investigating familiar stems animal.
If no memory present, then subject investigates stimulus more than otherwise, as if it were novel.
Social Recognition:
Pros and Cons
Advantages:
Easy to perform.
Quickly learned and memory retained for many days.
Easy to increase memory demands of task by varying delay between learning and testing.
Disadvantages:
Hormones can affect olfactory processing so it is necessary to be careful that hormones are altering cognitive and not just sensory mechanisms.
Classical eyeblink conditioning
Tone Alone —-> No response
Eyelid shock (US) —> Blink (UR)
Tone + eyelid shock
Tone (CS) —–> Blink (CR)
Neural Basis of Learning & Memory
Many of the tasks & procedures used in studies of hormones and cognition depend upon neural pathways involving the hippocampus, amygdala, and various neocortical regions.
Critical for learning, memory, and emotion.
Contain receptors for several different hormones.
Receive input from other brain regions (i.e. septum) that express hormone receptors.
List the 3 Brain Areas Highly Involved in Learning & Memory
Hippocampus
Amygdala
Neocortex
Stress affects learning and memory
Emotionally charged events are more easily and vividly remembered
Suggests that the hormonal systems activated by stressful experience may directly or indirectly aid learning and long-term memory
Why do we often feel that stress blocks memory?
Yerkes-Dodson law
There is a “Goldilocks” region that’s just the right amount of stress to have the best possible effect.
Represented by a bell curve of performance vs. arousal.
Too much arousal or too little results in less than ideal performance.
Stress Hormones Affect Learning & Memory
The Adrenal Glands play a large part in this.
Adrenal Cortex
Releases Glucocorticoids (like cortisol)
Adrenal Medulla
Releases Epinephrine and Norepinephrine.
Epinephrine
Aka adrenaline.
Generally enhances performance on a variety of learning & memory tasks.
Effects are dose & time dependent.
Inverted U-shaped curve: moderate doses more effective than low or high doses
Greatest enhancement observed shortly after training than before, during or long afterwards
Suggests that epinephrine may be acting on MEMORY STORAGE.
Epinephrine:
Details, Details
Influences memory by making NOXIOUS STIMULI more salient
Evidence:
Animals perform better in avoidance tasks if receive moderate rather than mild shock.
If a mild shock is paired with Epinephrine treatment, then the animal exhibits optimal learning.
How does epinephrine affect learning & memory?
Epinephrine must act in the brain to affect learning & memory, but Epinephrine released from adrenal doesn’t easily cross blood brain barrier.
Epinephrine must affect some processes outside of the brain that subsequently influences learning & memory
Two hypotheses:
Peripheral Receptor Hypothesis
Glucose Hypothesis
Peripheral Receptor Hypothesis
Epinephrine activates peripheral receptors (β-adrenergic receptors) that interact directly with the brain
Peripheral Epinephrine
- –> β-adrenergic receptors on the vagus nerve
- –> vagal afferents project noradrenergic neurons in the nucleus tractus solitarius (NTS)
- –> NE release in the amygdala
- –> affect memory
Evidence:
Memory enhancing effects of Epinephrine can be blocked propranolol (drug that blocks β-adrenergic receptors) in the amygdala.
Blocking any part of this pathway prevents the memory enhancing effects of Epinephrine.
propranolol
drug that BLOCKS β-adrenergic receptors
Memory enhancing effects of Epinephrine can be blocked propranolol in the amygdala
β-adrenergic receptor activation is critical for arousal-induced performance in humans.
Experiment 1:
Control subjects: boy and his mother walk through town, pass several stores, cross the street, enter a hospital, where the boy’s father works and while they are in the hospital they see an X-ray machine
Experimental subjects: boy crosses the street, is hit by a car and taken to the hospital where his father works and brought to the X-ray room
After a delay, experimental subjects recalled the story better but just the final stressful part not the whole story
Experiment 2:
Half the subjects given propanolol, other half given saline.
Those that received the drug and were read the arousing version of the story had poorer recall for the study details that subjects given saline
Glucose Hypothesis
Epinephrine affects memory via its effects on blood glucose, which increases glucose availability to the brain
Evidence:
Glucose enhances memory in rodents & humans.
Just like Epinephrine, the memory enhancing effects of glucose follow an inverted U-shaped curve and are time dependent.
Memory enhancing effects of Epinephrine can be blocked by blocking peripheral Epinephrine receptors, but these have no effect on memory enhancement produced by glucose treatment
How does glucose affect memory?
Elevated blood glucose permits more glucose to enter neurons, which stimulates release of Acetylcholine (ACh) into synapses
Ach from BASAL FOREBRAIN enhances memory (degradation in Alzheimers)
Glucocorticoid: Ideal Range
The ideal range of CORT for optimal learning and memory is an inverted U-shaped curve (i.e., bell curve) again…
Glucocorticoids
In general, acute stress/glucocorticoids enhance learning & memory while chronic stress/glucocorticoids impair learning & memory.
However, the effects of stress/glucocorticoids on learning & memory are more complex than this, and depend on a variety of factors including type of stressor, dose of corticosterone, task, timing of stressor/glucocorticoid administration relative to training/testing, sex, etc…
Acute glucocorticoid administration facilitates memory consolidation
Single injection of natural or synthetic (dexamethasone) glucocorticoids mimic acute stress and enhances performance of inhibitory avoidance learning when administrated immediately after training
Memory enhancing effects involve the basolateral amygdala
Single injection of dexamethasone mimics acute stress and enhances learning & memory.
dexamethasone
synthetic glucocorticoid
Acute stress/corticosterone impair spatial memory retrieval
Rats trained to locate hidden platform in Morris Water Maze
After training, rats received mild stress (footstock) and were tested 2 min, 30 min, or 4 hr later
During test, platform removed
Rats spent less time in target quadrant 30 min after stress when glucocorticoid levels were elevated, suggesting that high Glucocorticoids at time of memory assessment impair performance
Effects of Chronic Stress on Spatial Learning are Task Specific
Chronic stress (21 day restraint, 6hr/day) impairs spatial learning on the RAM, task for which arousal/fear tends to be low
However, under testing conditions when arousal is increased (i.e. filling RAM with water), chronic stress has minimal impairing effects and may even facilitate spatial learning
Effects of Stress on Learning & Memory are Sex Dependent
Acute stress enhances classical eyeblink conditioning in males, but impairs classical conditioning in females
Chronic stress impairs spatial memory in males, but enhances spatial memory in females on the RAM
_____ stress ____ classical eyeblink conditioning in ____, and impairs classical conditioning in _____ .
Acute stress enhances classical eyeblink conditioning in males, but impairs classical conditioning in females
______ stress impairs _____ memory in males, but enhances _____ memory in females on the RAM
Chronic stress impairs spatial memory in males, but enhances spatial memory in females on the RAM
Differential Effects of Stress on Neural Structure in the Hippocampus
Males vs Females
Acute stress increases dendritic spines in hippocampus (CA1) of males, but reduces dendrite spines in females
Chronic stress reduces dendritic length and branching in hippocampus (CA3) of males, but has no effect in females
Females tend to handle chronic stress better than males
Males tend to handle acute stress better than females.
Patients with Cushing’s syndrome
Patients with Cushing’s syndrome have chronic high CORT levels, reduced hippocampal volumes, and impaired memory
Glucocorticoids and Memory in Humans
In healthy adults, high cortisol (given orally 2x/day for 4 days) impairs______ (requires ____)
In healthy adults, high cortisol (given orally 2x/day for 4 days) impairs verbal declarative memory (requires hippocampus)
Glucocorticoids and Memory in Humans
Sex differences in Learning and Memory
….
In regards to sex differences in L&M btwn males and females, females learn _________ avoidance better and males learn _________avoidance better when placed in RAM (random arm maze) task
In regards to sex differences in L&M btwn males and females, females learn active avoidance better.
Males learn passive avoidance better when placed in RAM (random arm maze) task
_____ learn spatial tasks like ____ more quickly and with fewer errors
Males learn spatial tasks like RAM more quickly and with fewer errors
Males and females also use different strategies to solve RAM (similar to humans)
Females tend to use landmark cues and geometry cues
Males tend to use only geometry cues
Sex Differences in Spatial Memory are ORGANIZED by hormones in early development
Male rats and female rats treated with Testosterone less than 10 days of age learned the RAM faster than female rats or neonatally castrated male rats (castrated on day 1).
For Testosterone to masculinize spatial abilities, it must be converted to Estrogen
Treatment of newborn males treated with Aromatase Inhibitor produced males that learn RAM more slowly and use both landmark & geometry cues
Androgens
Few studies report a difference between intact and castrated male rats on tests of maze learning
In hypo-gonadal or normal men, Testosterone treatment does not affect learning & memory
However, Testosterone is not completely without effect:
Testosterone infused into the hippocampus improves performance on passive avoidance task.
In some species of seasonal breeders, learning & memory are enhanced when Testosterone levels are high (spring–summer time)
Testosterone can enhance frontal cortex-mediated learning & memory
Estrogens
On some spatial tasks, high estrogen levels interfere with performance
During PRO-ESTRUS (high E), females rats & mice show slower acquisition on the water maze compared to females in DIESTRUS (low E) show slower acquisition
But…a host of other studies shown that performance on a variety of memory tasks (RAM, passive avoidance, fear conditioning, social recognition) is worse after OVX and improved if E is replaced.
Why the discrepancy?
Effects of estrogens depend on many factors including cognitive process being assessed, difficulty of the task, timing of hormone administration and gonadal state of the individual
Estrogen and the Hippocampus
Estrogen receptors are located in the hippocampus
Estrogen given to OVX rats increases spine density on CA1 neurons
Spine density cyclically changes across estrous cycle with highest spine density during proestrus
Increase in spines represents an increase in synapses
Parallel alterations in spatial memory function
The hippocampus makes its own estrogens and it mediates synaptic plasticity in both males and females!
Estrogen given to OVX rats increases ___ in ___ neurons
Estrogen given to OVX rats increases spine density on CA1 neurons
Spine density cyclically changes across estrous cycle with highest spine density during _______ .
Spine density cyclically changes across estrous cycle with highest spine density during proestrus
The ______ makes its own estrogens and it mediates _______ in both males & females!
The hippocampus makes its own estrogens and it mediates synaptic plasticity in both males and females!
Estrogen and Aging
Rodents:
In mice, estradiol treatment can improve the age-related decline in spatial memory.
In OVX aged rats, estrogen can improve memory performance, but treatment must begin shortly after Estrogen loss
Humans:
Postmenopasual women using hormone replacement therapy (HRT) perform better on recall tasks.
However, randomized controlled trials are equivocal.
Women’s Health Initiative Memory study raised questions about HRT for treatment of cognitive decline.
Timing may be important…administration during critical, but limited, periods of postmenopausal life to maximize positive cognitive effects but minimize unwanted side effects (i.e. increased risk of stroke and blood clots)
There’s a sensitive period that you have to do it in, like within the first 10 years of menopause. Receptors change? Or die?
Posterior pituitary hormones also implicated in cognitive processes
Oxytocin
Vasopressin
Neuroendocrine cell bodies in the Hypothalamus produce oxytocin or vasopressin. Axons from these neurons pass through the pituitary stalk….
…and terminate on capillaries of the Posterior Pituitary.
When an action potential arrives at a terminal, oxytocin or vasopressin is released from the terminal directly into the bloodstream
Vasopressin (AVP) and Brattleboro Rats
Brattleboro rats deficient in AVP are impaired on avoidance tasks
Avoid compartment in which they have been shocked when tested immediately after training but if a delay occurs between learning and testing they enter the compartment in which they were shocked
AVP given immediately after the learning prevents this impairment
Suggests that AVP may act on memory storage
Vasopressin (AVP):
TARGET SITES
Target sites for performance enhancing effects of AVP are the HIPPOCAMPUS and MEDIAL SEPTUM (region of basal forebrain which sends projections to the hippocampus)
These target sites have receptors for AVP
Lesions to these areas prevent effects of AVP
Microinjection of AVP to these regions enhances performance
AVP and Social Recognition
AVP agonists (peripherally or centrally in lateral septum) enhance social recognition memory AVP antagonists administered into lateral septum immediately after an encounter disrupts social recognition memory.
Suggests that endogenous AVP in normal rats contributes to their ability to form a social memory.
Involves the V1aR….
V1aR antagonists block social recognition (pharmacological technique).
Decreasing V1R in lateral septum by antisense oligonucleotides disrupts social recognition.
Viral vector-mediated over-expression of the
V1aR facilitates social recognition by prolonging the memory
V1aR knockout mice show no V1aR binding in the brain and a complete disruption in social recognition that isn’t due to a deficit in olfaction or general learning deficit
Oxytocin
Original studies (using high doses**) suggested that Oxytocin and AVP had opposing effects on memory, with AVP facilitating, and Oxytocin impairing
More recent investigations (using lower, more physiological doses) show that Oxytocin is critical for normal social recognition
Thus, the effects Oxytocin on social recognition follow an inverted U-shapedcurve (bell-shaped curve)
Oxytocin knockout mice exhibit a total deficit in social recognition reversible with central injections of Oxytocin
Medial Amygdala (MeA) is critical for Oxytocin-mediated social recognition
Oxytocin injections into the MeA in the OTKO rescued social recognition and Oxytocin antagonist injected into the MeA in wild type blocked normal social recognition
Way too much oxytocin can inhibit memory. Bell curve of effectivity. There’s a “goldilocks” range
Insulin in brain implicated in memory
Insulin receptors in brain concentrated in CORTEX and HIPPOCAMPUS
Genetic or pharmacological disruption of brain insulin receptor action impairs memory
Cancer drug that kills beta cells in pancreas impairs passive avoidance learning and Morris Water Maze performance
Deficits in verbal and visual memory, attention, numerical reasoning, in adult diabetics
High co-morbitity of type II diabetes (insulin resistance) and Alzheimer’s disease.
Alzheimer’s patients have changes in insulin and receptors. Stabilizing blood sugar helps with memory impairment.
Insulin receptors in brain concentrated in _____ and _____ .
Insulin receptors in brain concentrated in CORTEX and HIPPOCAMPUS
High co-morbitity of ______ (insulin resistance) and _______.
High co-morbitity of type II diabetes (insulin resistance) and Alzheimer’s disease.
Cerebellar circuits are responsible for _____ (where there is no time gap between the conditioned stimulus and the unconditioned stimulus).
Cerebellar circuits are responsible for SIMPLE DELAY CONDITIONING (where there is no time gap between the conditioned stimulus and the unconditioned stimulus).
In functional-imaging studies, ______ (priming based on the visual form of words) is related to reduced activity in _______, presumably because the priming makes the task easier.
In functional-imaging studies, Perceptual Priming (priming based on the visual form of words) is related to reduced activity in Bilateral Occipitotemporal Cortex, presumably because the priming makes the task easier.
____ ____ and _____ regions of the brain appear to be responsible for _______ memory (autobiographical memory that pertains to a person’s particular history, such as remembering where and when you last saw a certain friend).
Right Frontal and Temporal regions appear to be responsible for EPISODIC Memory (autobiographical memory that pertains to a person’s particular history, such as remembering where and when you last saw a certain friend).
Skill learning is impaired in people with damage to the _____.
Damage to other brain regions, especially the ___ and ____, also affects aspects of some skills.
Skill learning is impaired in people with damage to the BASAL GANGLIA
Damage to other brain regions, especially the Motor Cortex and Cerebellum, also affects aspects of some skills.
In _____ conditioning (where the CS ends before the US starts), the _____ is required, as it is for conditioning (where the stimulus that signals reward [CS+] and the stimulus that does not signal reward [CS–] are reversed).
In TRACE conditioning (where the CS ends before the US starts), the HIPPOCAMPUS is required, as it is for DISCRIMINATION REVERSAL conditioning (where the stimulus that signals reward [CS+] and the stimulus that does not signal reward [CS–] are reversed).
_____ memory is generalized memory, such as knowing the meaning of a word without knowing where or when you learned that word.
This type of memory is dependent on intact _____ lobes.
SEMANTIC memory is generalized memory, such as knowing the meaning of a word without knowing where or when you learned that word.
Semantic memory is dependent on intact TEMPORAL lobes.
Conceptual priming (priming based on ______) is associated with reduced activation of the _______.
Conceptual priming (priming based on WORD Meaning) is associated with reduced activation of the LEFT FRONTAL CORTEX.
amygdala
The amygdala is a group of nuclei in the medial anterior part of the temporal lobe.
Considerable evidence suggests that the amygdala is important for both the experience and the recognition of emotions, especially fear.
Fear and the Thalamus
A fear-inducing stimulus reaches the THALAMUS and is relayed to the CORTEX & HIPPOCAMPUS.
All 3 regions project to the AMYGDALA.
FEAR REACTION
A fear-inducing stimulus reaches the thalamus and is relayed to the cortex and hippocampus.
All 3 regions project to the LATERAL NUCLEUS of the AMYGDALA.
The HIPPOCAMPUS is especially important in learning and memory.
A fear-inducing stimulus reaches the thalamus and is relayed to the _____ and ____.
All 3 regions project to the __________ .
A fear-inducing stimulus reaches the thalamus and is relayed to the cortex and hippocampus.
All 3 regions project to the lateral nucleus of the amygdala.
Central Nucleus of the Amygdala
The Central Nucleus of the Amygdala transmits information to various brain stem centers to evoke emotional responses.
Lesions of the central nucleus prevent blood pressure increases and constrain freezing behavior in response to the conditioned fear stimulus.
Pathways through the _______ evoke autonomic responses.
Pathways through the Lateral Hypothalamus evoke autonomic responses.
Elicitation of fear responses involves autonomic signs such as cardiac and respiratory changes.
The lateral hypothalamus is believed to play a role in eliciting these responses.
Pathways through the _____ evoke emotional behavior.
Pathways through the Periaqueductal Gray (central gray) evoke emotional behavior.
The _______ is the main efferent pathway from the ______.
Some of these efferents project to the hypothalamus and mediate _____ responses.
The STRIA TERMINALIS is the main efferent pathway from the AMYGDALA.
Some of these efferents project to the hypothalamus and mediate hormonal responses.
The Structure of the HIPPOCAMPUS
On structural grounds, neuroscientists distinguish 3 major divisions within the hippocampus, labeled CA1, CA2, and CA3.
LTP has been extensively studied in area CA1 of the hippocampus proper.
“CA” refers to “cornu ammonis,” Latin for Ammon’s horn —> the ram’s horn that resembles the shape of the hippocampus.
LTP was originally demonstrated in the dentate gyrus of the hippocampus.
The principal cell layer of the dentate gyrus is made up largely of densely packed granule cells.
The principal cell layer of the ______ is made up largely of densely packed granule cells.
The principal cell layer of the DENTATE GYRUS is made up largely of densely packed granule cells.
The main inputs to the hippocampal formation come from the nearby _______ via the axons of the ______ pathway.
The main inputs to the hippocampal formation come from the nearby Entorhinal cortex via the axons of the Perforant pathway.
The CA1 and CA3 regions also receive inputs from the corresponding regions of the hippocampus in the other hemisphere of the brain via _______ fibers (fibers that cross over the midline through the corpus callosum).
The CA1 and CA3 regions also receive inputs from the corresponding regions of the hippocampus in the other hemisphere of the brain via Commissural fibers (fibers that cross over the midline through the corpus callosum).
Axons from ______ cells in the dentate gyrus (the so-called mossy fibers) extend to the hippocampus, where they synapse in area _____.
Axons from granule cells in the dentate gyrus (the so-called mossy fibers) extend into the hippocampus, where they synapse in area CA3.
Most of the cells in the hippocampus are arranged in a single cell layer populated mostly by ______ cells.
Hippocampal cells extend from the dentate gyrus to CA1.
Most of the cells in the hippocampus are arranged in a single cell layer populated mostly by PYRAMIDAL cells.
Hippocampal cells extend from the dentate gyrus to CA1.
Pyramidal neurons in CA3 send their axons, called ____, to area CA1.
LTP has been studied intensively at these synapses.
Pyramidal neurons in CA3 send their axons, called Schaffer Collaterals, to area CA1.
LTP has been studied intensively at these synapses.
