learning and memory

learning

a relatively permanent change in behavior due to experience

memory

the means by which past experience is drawn on to guide/direct behavior or thoughts in the present

learning and memory

endow us with the flexibility to adapt to an ever-changing environment

1. Learning and memory occurs in stages:

   1. Acquisition of information

   2. Consolidation of storage of information

   3. Retrieval of information

2. Timing of hormonal manipulation is critical 

   1. Acquisition - prior to first exposure to task

   2. Consolidation - at the point between learning and retest 

   3. Retrieval - immediately before re-test 

Hormones may also affect non-mnemonic factors which could indirectly affect learning and memory: attention, motivation, sensory responsivity and motor capabilities

Why is it difficult to determine the effects of hormones on learning and memory?

1. Acquisition

2. Consolidation

3. Retrieval

stages of learning/memory

Hormone administration prior to first exposure to a task

acquisition

Hormone administration between learning and re-test

consolidation

Hormone administration immediately before re-test

retrieval

non-mnemonic factors

performance factors - factors that indirectly affect learning/memory 

Attention, motivation, sensory responsivity and motor capabilities

examples of non-mnemonic factors

Cognitive Tasks - use tasks for which the underlying neural circuitry has been partially or fully elucidated

How can hormonal effects on cognition be examined?

hippocampus and amygdala

Many of the tasks used in studies of hormones and cognition depend on neural circuits involving the BLANK, BLANK and various cortical regions – all areas are critical for learning, memory and emotions; contain receptors for several different hormones or receive input from other brain regions that express hormone receptors

radial arm maze

Spatial task used commonly for learning/memory tasks in behavior endocrinology; the subject is allowed to wander until all food sites have been found; the subject learns to avoid arms that never have food and to avoid revisiting arms that it had previously visited on that day; locate food sites by using spatial cues in the room

advantage of radial arm maze

easy to perform

disadvantages of radial arm maze

many training trials required to achieve steady performance so hormonal effects must be assessed over days and sometimes weeks which makes it difficult to isolate the effects of hormones to one stage of learning and memory

morris water maze

Spatial task used commonly for learning/memory tasks in behavior endocrinology; makes use of the rats natural tendency to escape to dry land if it is placed in the wate

advantage of morris water maze

 easy to perform and quickly learned

disadvantages of morris water maze

its an aversively motivated task so the stress of training and testing may activate other hormonal systems not under study

active avoidance

Animal must act to avoid a noxious stimulus

passive avoidance

Animal must suppress a behavior that would otherwise be exhibited (must learn to stay put)

Fear conditioning

type of learning where a neutral stimulus becomes associated with an aversive event, causing it to trigger a fear response

advantages of fear conditioning

 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 of fear conditioning

it is an aversively motivated task so that stress itself activates other hormonal systems that may confound interpretation

social recognition

Makes use of the animal’s tendency towards olfactory investigation of novel co-specifics

• Two rats are 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 - subject spends less time investigating familiar stimulus animal

  • If no memory present - subject investigates familiar animal a lot as if it were novel

advantages of social recognition

 easy to perform and quickly learned and memory retained for many days

disadvantages of social recognition

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

a learning process where a neutral stimulus (CS), like a tone, is repeatedly paired with an unconditioned stimulus (US), such as eyelid shock, which naturally triggers an eyeblink (UR). Over time, the neutral stimulus alone begins to elicit a conditioned response (CR) of an eyeblink before the eyelid shock occurs, demonstrating associative learning

yerkes-dodson law

Optimal performance occurs at moderate levels of stress or arousal; if stress/arousal is too high or too low, learning is adversely affected

epinephrine

1. enhances performance on a variety of learning and memory tasks; these effects are dependent on dose and time 

   1. Moderate doses are more effective than low/high doses

   2. There is greatest enhancement observed shortly after training than before, during or long afterwards → suggests that epinephrine may be acting on memory storage

EPI and memory

1. Influences memory by making noxious stimulus more salient 

   1. Evidence: animals perform better in avoidance tasks if receive moderate rather than mild shock; if the mild shock is paired with EPI treatment, the animal exhibits optimal training

EPI and BBB

1. EPI does not cross the Blood Brain Barrier - EPI must affect some processes outside of the brain that subsequently influences learning and memory 

peripheral receptor hypothesis

1. EPI activates peripheral receptors that interact directly with the brain 

2. Evidence - memory enhancing effects of EPI can be blocked by peripheral blockade of beta adrenergic receptors or by infusing the receptors directly into the amygdala

glucose hypothesis

1. EPI affects memory via its effects on blood glucose; increasing glucose availability to the brain

2. Evidence - just like EPI, the memory enhancing effects of glucose follow the inverted U shaped curve and are time dependent 

   1. Moderate doses are most effective

3. How does glucose affect memory → elevated blood glucose permits more glucose to enter neurons, this releases the release of ACH into synapses

It follows an inverted U-shaped curve—moderate CORT enhances learning/memory, while very low or very high levels impair it.

What is the relationship between CORT (glucocorticoid) levels and learning/memory?

Enhances learning and memory.

How does acute stress affect learning and memory?

Impairs learning and memory.

How does chronic stress affect learning and memory?

Yes—effects depend on factors such as sex, type of stressor, and type of task

Are there exceptions to stress effects on cognition?

It enhances memory consolidation, mimicking acute stress—improves avoidance learning when given right after training.

What effect does acute glucocorticoid administration have on memory consolidation?

It impairs memory retrieval.

What effect does acute glucocorticoid administration have on memory retrieval?

• Males: Acute stress enhances classical eyeblink conditioning.

• Females: Acute stress impairs classical eyeblink conditioning.

How does acute stress affect learning/memory in males vs females?

• Males: Chronic stress impairs spatial memory.

• Females: Chronic stress enhances spatial memory on the Radial Arm Maze.

How does chronic stress affect spatial memory in males vs females?

• Acute stress: ↑ dendritic spines in male hippocampus; ↓ dendritic spines in females.

• Chronic stress: ↓ dendritic length and branching in male hippocampus.

What brain changes accompany sex-dependent stress effects?

Patients with Cushing’s syndrome (chronically high CORT) show reduced hippocampal volume and impaired memory.

Give a human example showing glucocorticoid effects on memory.

• Females: Use landmark cues.

• Males: Use geometric cues.

What spatial strategies do males vs females use?

• Testosterone treatment before day 10 → masculinizes spatial ability and improves RAM learning.

• Castration at birth → impairs RAM learning.

• Blocking aromatization (aromatase inhibitor) → males learn more slowly and use mixed cues → estrogen conversion required for masculinization.

How do hormones early in development organize sex differences in spatial abilities?

What effects do androgens have on learning/memory in rodents?

• Castration can impair spatial abilities.

• Testosterone replacement can restore/improve performance.

Yes—low testosterone in men (hypogonadism/aging) is linked to poorer cognition and can be improved with testosterone supplementation.

Do androgens affect learning and memory in humans?

Low testosterone may increase Alzheimer's risk; supplementation can improve spatial and verbal memory in Alzheimer’s patients.

How is testosterone related to Alzheimer’s disease risk/performance?

High estradiol during proestrus can enhance spatial memory, and many studies show estradiol improves performance on tasks like passive avoidance, fear conditioning, and social recognition.

What are the general effects of estrogen (estradiol) on spatial learning and memory?

Memory improvements depend on methodological variables such as dose, route of administration, progesterone co-administration, and task demands.

Why do some studies show discrepancies in estrogen’s effects on memory?

Aging causes a sharp decline in estrogen levels and is associated with reduced learning and memory performance.

How does aging affect estrogen levels and cognitive function?

Estradiol can improve age-related spatial memory decline, but only if treatment occurs shortly after estrogen loss.

What is the effect of estrogen replacement in aged female rodents?

Observational studies show better recall performance, but RCTs show mixed results and raise concerns about HRT for cognitive decline.

What are the effects of estrogen replacement therapy (HRT) on cognition in postmenopausal women?

HRT did not protect against dementia; instead, it increased risk of dementia, cognitive decline, stroke, and blood clots. Effects depend on hormone type, dose, route, and especially timing of therapy.

What did the Women’s Health Initiative conclude about using HRT to treat cognitive decline?

HRT started during or soon after menopause may benefit cognition, while later initiation shows no benefit or may worsen outcomes.

Why is timing important when considering HRT for cognition?

AVP enhances social recognition when administered peripherally or centrally; blocking AVP disrupts social recognition.

What effect does AVP have on social recognition?

AVP antagonists in the lateral septum disrupt social memory; AVP agonists enhance it.

What evidence shows that endogenous AVP is necessary for social recognition?

The V1a receptor (V1aR).

Which receptor mediates AVP’s effects on social recognition?

• V1aR antagonists block social recognition

• Reducing V1aR with antisense disrupts recognition

• Overexpressing V1aR prolongs social memory

• V1aR knockout mice show complete loss of social recognition (not due to olfactory or general learning deficits)

What evidence supports V1aR involvement in social recognition?

Early studies suggested OT impaired memory, opposite to AVP.

What did early studies conclude about OT and learning/memory?

OT is essential for normal social recognition.

What do more recent studies show about OT’s role in memory?

Older studies used excessively high doses of OT.

What explains discrepancies between older and newer OT studies?

OT influences social recognition in an inverted U-shaped manner (optimal at moderate levels).

What are the effects of OT on social recognition?

OT knockout mice show complete social recognition deficits that are reversed by central OT injections.

What evidence shows OT is necessary for social recognition?

The medial amygdala (MeA).

What brain region is critical for OT-mediated social recognition?

• OT injections into the MeA of OT-KO mice restore social recognition

• OT antagonists in the MeA block social recognition in wild-type mice

What evidence supports the MeA as the target region for OT’s memory effects?