Hippocampus Major cellular components: dentate gyrus (major source of inputs) Ammon’s horn: fields CA1, CA2, CA3/CA4 (integrative role) subiculum (major

HippocampusMajor cellular components:

• dentate gyrus (major source of inputs)

• Ammon’s horn: fields CA1, CA2, CA3/CA4 (integrative role)

• subiculum (major source of efferents)

Major pathways and connections:

• hippocampus receives highly processed sensory information about internal and external

events:

– perforant pathway: hippocampus is reciprocally connected to the entorhinal cortex;

entorhinal cortex has connections with other corticial areas (visual, auditory information)

– fimbria-fornix: hippcampus is also reciprocally connected to septum, thalamus and

hypothalamus

• several pathways that allow for intrahippocampal connections:

– commissural connections: neuronal connections made between neurons in two hippocampi

– Schaffer collaterals: connections between neurons made on one side of hippocampus

HippocampusHippocampus plays an important role in two main processes:

• learning and memory

– especially tasks that involve processes of spatial cues

– evidence for sex differences in hippocampal structure

– also evidence for sex differences in the performance of spatial tasks; gonadal steroids have

been implicated in organizational and activational effects on performance

– in the adult, changes in hippocampal structure accompany hormone changes during estrus

• “brake” on HPA axis

– hippocampus possesses mineralocorticoid and glucocorticoid receptors

– mineralocorticoid receptors are linked to circadian changes in HPA axis

– glucocorticoid receptors are linked to terminating a stress response

– chronic exposure to glucocorticoids can damage the hippocampus leading to higher levels

of glucocorticoids, more hippocampal damage, and so on; damage to the hippocampus has

been linked to memory deficits

HippocampusPatient H.M.:

• H.M. suffered from intractable epilepsy (epileptic seizures)

– an epileptic seizure means that a large collection of neurons in the brain discharge in

abnormal synchrony--seizures can be focal that spread throughout cortex or generalized,

and may involve loss of consciousness as well as contraction of groups of skeletal muscle

– intractable means that his epileptic seizures were resistant to treatment

• to stop his epileptic seizures, heunderwent bilateral hippocampectomy--bilateral

removal of his hippocampi

• following surgery:

– GOOD NEWS: his epilepsy stopped

– BAD NEWS: while he could remember events early in his life, he could not remember

events just prior to surgery (mild form of “retrograde amnesia”), and he was unable to form

new memories (“anterograde amnesia:)

HippocampusPatient H.M.:

• these events in Patient H.M. highlight the important role that the hippocampus plays

in the processes of learning and memory

– mild form of retrograde amnesia and anterograde amnesia indicates that the hippocampus

plays an important role in learning and in the formation of short-term memory (working

memory)

– however, the ability of H.M. to remember early events in his life indicates that the

hippocampus is not the location where long-term memories are stored

HippocampusWhat processes have been implicated in learning and memory?

• long-term potentiation (LTP)

– an increase in neural activity at particular synapses will “strengthen” those synapses

– this strengthening process involves an in crease in synaptic efficacy which simply means

that a greater synaptic response will be produced in response to a given input

– response is believed to last from hours to days (short-term responses)

oneaction

potential

littleNT released

“weak”synapse

oneaction

potentiallots of

NT released

“strong”synapse

littleneural

activity

lots ofneural

activity

Hippocampus• changes in neuronal morphology

– an increase in neural activity will lead to an increase in neuronal connections

– this strengthening process involves increasing synaptic input and the dendritic complexity

of neurons: 1) more synapses, 2) more dendritic spines, 3) increase in length and branching

of dendrites

– response can last from days to weeks to years (short and long-term responses)

littleneural

activity

lots ofneural

activity

HippocampusLearning and Memory:

• cellular mechanisms are varied but can involve:

– enhanced neurotransmission within synapse--increase in synaptic efficacy; this is thought

to reflect an increase in release of neurotransmitter

– formation of new connections

• these cellular mechanisms of learning and memory have been observed within the

hippocampus

– these changes are thought to reflect learning and formation of short-term memories

especially associated with tasks involving spatial cues

• similar plastic events have also been observed within other brain areas including the

cerebral cortex (e.g., visual cortex) and cerebellum

HippocampusDo gonadal steroids affect neuronal morphology in the hippocampus?

• Answer--yes!

– There is evidence that elevations in estrogen and progesterone can regulate the number of

dendritic spines on neurons in the hippocampus in adult female rats.

Study by Gould et al. (1990):

• Question: Does estrogen and progesterone regulate spine density in neurons within

the hippocampus?

– spine density = number of spines per length of dendrite = number of synapses on spines

dendriticshaft

dendriticspine

Synapses:axosomatic

axodendritic

shaft

spine

axoaxonal

dendrite

Hippocampus• Methods:

– adult female rats: intact, OVX + oil, OVX + estrogen, OVX + estrogen + progesterone

– euthanized animals and stained brain tissue with Golgi technique--silver stain that “fills”

the dendrites, cell bodies and axons of specific neurons

– measured the number of spines per length of apical or basilar dendrites of neurons in CA1,

CA3, and dentate gyrus in female rats

• Results:

– ovariectomy produced a significant decrease in spine density in apical dendrites of neurons

within CA1 region of hippocampus

– administration of estrogen or estrogen plus progesterone produced a significant increase in

spine density in the apical dendrites of CA1 region of hippocampus

– the effect was specific to CA1 region of hippocampus; no change occurred in CA3 region

or in dentate gyrus

– the effect was rapid occurring after only two days of estrogen and 5 hours of progesterone

Hippocampus• Conclusion:

– the levels of estrogen and progesterone can affect the number of spines present within a

select group of neurons within the hippocampus (CA1 region) of adult female rats

• Subsequent studies have shown that such changes in spine density also occur with the

natural fluctuation in hormones that takes place during the estrus cycle.

– high estrogen and progesterone levels = high spine density (late proestrus/early estrus)

– low estrogen and progesterone levels = low spine density

– these changes are occurring in adult female rats every four or five days

HippocampusAre there sex differences in the structure of the hippocampus?

• Answer--yes! There is evidence for a complex interaction between early experience

(rearing), dendritic morphology and sex of individual (rats).

– animals raised in an enriched environment possess neurons that are more complex than

animals raised under normal laboratory conditions; an enriched environment involves the

presence of other animals and various objects to interact with, while normal laboratory

conditions are more plain and animals may be housed alone or in small groups with no

objects to play with

– if you compare males and females housed in the complex environment to rats housed under

normal laboratory conditions, you can see several differences:

– in the apical dendritic tree of CA3 neurons, females housed in the enriched environment

have more dendrites concentrated proximal (close) to the cell body, while males in the

enriched environment had more dendrites concentrated distal (far) from cell body

– in the dentate gyrus, females housed in enriched environments had granule cells with an

increase in dendritic length while males in a similar environment did not show this change

HippocampusAre there sex differences in learning and memory?

• Answer--yes!

• There are numerous examples of differences between males and females in

performance on various tests of learning and memory.

– Males are “better” at passive avoidance learning than females (e.g., males learn more

quickly to not leave a platform because they will get shocked).

– Females are “better” at active avoidance learning than males (e.g., females learn to respond

more quickly to a cue such as a light or tone that signals that they should move to another

part of a chamber to avoid being shocked).

– However, Beatty has argued that such differences may simply reflect sex differences in

activity. That is, females are more active than males and as a consequence they may do

better on active avoidance tasks because of an increased likelihood of making the

association between movement to a given part of a chamber , cue presentation and a

decrease in shock. Females may do more poorly on passive avoidance tasks because of

they can’t sit still.

HippocampusAre there sex differences in learning and memory?

• It is thought that performance on other more complex tasks, such as radial arm maze or

the Morris water maze, may be less influenced by sex differences in activity.

– Maze tasks are considered tests of spatial abilities in rodents because animals solve these

maze tasks by using cues from the surroundings outside of the maze.

– The hippocampus (in rats) is thought to be essential for solving tasks that require the animal

to use its spatial abilities.

• There is evidence that males tend to perform better on spatial tasks than females.

– This sex difference in seen in some species but not all.

– This difference is also somewhat limited--greatest sex differences are observed during

acquisition of the task, and often fewer differences are seen once the task has been learned.

– It has been suggested that males and females used different cues to solve spatial tasks (which

may underlie differences in acquisition), and there is evidence to suggest that exposure to

gonadal steroids during development and in the adult can alter what cues are used to solve a

given task.

HippocampusStudy by Williams et al. (1990)

• Question: Does exposure to androgens or estrogens early in life affect spatial

abilities in adulthood?

• Methods:

– 4 groups: male rats castrated on day 1 (MNC), sham-operated control males (MC), female

rats exposed to estrogen from days 1-10 (FNE), and sham-operated control females treated

with oil (FC)

– at 45 days of age, all groups were gonadectomized (MNC group was already castrated); this

was done to control for any activational effects of on performance

– at 70 days of age, all rats were placed on a food deprivation schedule that kept tham at 85%

of their free-feeding body weight; rats were trained to run down arms of the maze for food

– tested the performance of the rats on locating food pellets when only some of the arms were

baited--12-arm maze, 8 arms were baited with food and 4 arms were not; this relationship

remained constant throughout the experiment


• Methods:

– they determined how well animals performed on this task by analyzing number of errors

made until all food pellets were obtained

– 2 types of errors: 1) remembering not to go into unbaited arms, and 2) remembering what

arms were visited on a given day (1 test per day for 18 days)

• Results:

– males and masculinized females showed faster acquisition of maze task than did females or

feminized males

– however, after acquisition, no sex differences in performance were observed


• Question: Why are males and females different in acquisition of the radial arm

maze? Do these differences reflect the cues that males and females use to solve the

task?

• Methods:

– similar groups as before: 4 groups: male rats castrated on day 1 (MNC), sham-operated

control males (MC), female rats exposed to estrogen from days 1-10 (FNE), and sham-

operated control females treated with oil (FC); all groups were gonadectomized

– trained the animals on the radial arm maze until high performance levels were obtained

– they changed either landmark cues, geometry or both and tested the performance of the

animals on task

– landmark cues: cues located within or around a maze (table, chair, transport cart); they

manipulated these cues by rearranging items or removing them

– geometric cues: shape of room (corners of room); manipulated geometry by enclosing the

maze within a black circular arena


• Results:

– males and androgenized females used primarily geometry to solve the task

– females and feminized males used both geometry and landmarks in performing task

• Conclusions:

– males use fewer cues (geometry) to solve the radial maze than females (geometry and

landmark cues)

– the need to learn fewer cues may explain why males acquire the task more quickly than

females

– enhanced spatial ability in males is promoted by perinatal exposure to gonadal steroids--1)

castration of newborn males decreased rate of acquisition, and 2) administration of estrogen

to newborn females within first 10 days of life increased rate of acquisition

– after acquisition, no sex differences in performance were observed

Hippocampus• Sex differences in maze performance have been associated with sex differences in

brain structure--hippocampus.

• Study by Jacobs et al. (1990) compared the size of the hippocampus in two species of

prarire voles that show sex differences in performance on spatial tasks.

meadowvole

pinevole

Spatial Task Hippocampus

males performbetter than

females

no sexdifference

in performanceon task

11% largerin males than

in females

no sexdifferencein size of

hippocampus

HippocampusPerformance on spatial tasks can also be affected by hormones in the adult.

• In males:

– maximal performance on some spatial tasks are seen in males only after puberty (rise in

testosterone levels)

– increase in spine density in CA1 neurons of male mice observed after puberty

• In females:

– performance on spatial tasks can be altered during estrus cycle

HippocampusStudy by Warren & Juraska (1997)

• Question: Does performance on spatial tasks by females vary with their estrus

cycle?

• Methods:

– several groups of animals were studied, but they focused primarily on females during 2

stages of the estrus cycle in 2 forms of the Morris water maze

– 2 main groups of females: females in late proestrus (elevated estrogen levels) versus

females in late estrus (estrogen levels are low)

– Morris water maze requires that an animal learn to find a platform submerged under water

(water is murky--not a visual task)

– place form of maze--females had to use spatial cues surrounding the maze to find platform

(spatial task)

– cued form of maze--a black ball was suspended above the platform, so females had to learn

to find platform by going toward black ball (cued task)

“Cued Task”“Spatial Task”

HippocampusStudy by Warren & Juraska (1997)

• Methods:

– animals received pretraining trials on either the spatial task or the cued task

– on the day of the experiment, females in late proestrus or late estrus received 8 trials, 1 hour

break, followed by 8 additional trials

– how quickly did they find the platform?

• Results:

– on spatial task, late estrus females found platform more quickly than late proestrus females

– on the cued task, late proestrus females found platform more quickly than late estrus

• Conclusions:

– the increase in estrogen during late proestrus (when there is an increase in dendritic spines)

is associated with decreased performance on the spatial task, but increased performance on

the cued task

HippocampusOverall Summary:

• sex differences can be seen in tasks involving spatial learning and memory

• in males:

– increased performance may be associated with the use of fewer cues to learn the task

(geometry)

– gonadal steroids have an organizing effect on spatial ability

– rise in testosterone at puberty may also act to enhance spatial abilities (at least on some

tasks)--activating effect

• in females:

– decreased performance may be associated with learning more and possibly different cues

associated with a spatial task

– in adults, increased estrogen (and associated changes in spine density in the hippocampus)

appears to inhibit performance on tasks requiring use of spatial cues but may enhance

responsiveness to other cues

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Hippocampus-Chronic Stress-Memory DeficitsThe pituitary has 2 modes of operation:

• diurnal variations in secretion

– daily rhythm of glucocorticoid secretion

– glucocorticoid levels rise when an individual becomes “active” during the day

– in humans, glucocorticoids are elevated in the morning and are decreased at night

– in rats, glucocorticoids are elevated in the evening (or when lights go out); rats are

nocturnal animals being most active at night

• stress-induced secretion

– glucocorticoid levels rise, in part, to increase blood glucose levels available for fight or

flight reactions

Hippocampus-Chronic Stress-Memory DeficitsThere are two different receptors populations that respond to glucocorticoids:

• mineralocorticoid receptor (MR)

– receptor binds with high-affinity to glucocorticoids (receptor responds to small changes in

glucocorticoid levels)

– MRs are thought to modulate diurnal variations in glucocorticoid secretion

– MRs are found in select brain regions--hippocampus, septum and amygdala

• glucocorticoid receptor (GR)

– receptor that binds with low-affinity to glucocorticoids (receptor responds to large changes

in glucocorticoid levels)

– GRs are thought to modulate stress-induced secretion of glucocorticoids

– GRs are found throughout the brain and body

• the increase in glucocorticoids, either during daily rhythm or during stress, would

activate the appropriate receptor, stimulating neurons within the hippocampus that

would act to inhibit activity of the HPA axis

Hippocampus-Chronic Stress-Memory DeficitsAging is associated with several phenomenon:

• memory deficits

• decreased ability to inhibit glucocorticoid secretion:

– elevation in level of basal glucocorticoids

– failure to terminate glucocorticoid secretion following exposure to a stressor

• loss of cells within hippocampus

exposure toglucocorticoidsover a lifetime

damage tohippocampus

decreased abilityto inhibit

glucocorticoidsecretion

memorydeficits

Hippocampus-Chronic Stress-Memory DeficitsExposure to chronic stress can accelerate this aging process:

• repeated exposure of animals to stress can accelerate damage to the hippocampus

and lead to memory loss

• this effect of chronic stress exposure can be reproduced by administering high levels

of glucocorticoids to animals

– you can make a young rat look old

exposure toglucocorticoidsover a lifetime

damage tohippocampus

decreased abilityto inhibit

glucocorticoidsecretion

memorydeficits

CHRONICSTRESS

Hippocampus-Chronic Stress-Memory DeficitsStudy by Arbel et al. (1994)

• Purpose:

– to determine the effects of long-term corticosterone administration on hippocampal morphology

and cognitive performance of middle-aged rats

• Method:

– prescreened rats by testing them on their ability to learn the Morris water maze--learning the

location of a platform submerged under water

– young rats (3 months of age) learn quickly; middle-aged rats (12 months of age) vary--some

learn as quickly as the young rats (‘non-impaired’ rat) and others that show a decrease in

performance (‘impaired” rats)

– a subset of the prescreened rats were killed--the rat’s performance on the Morris water maze was

compared with number of damaged cells within the hippocampus

– a different subset of prescreened rats were tested on the radial arm maze--8-arm maze in which

all of the arms were baited with food; the goal of the task was to obtain all of the food with the

least number of errors; in this task, some of the ‘non-impaired’ rats were given corticosterone


• Results:

– the response of middle-aged rats varied on the Morris water maze--some were ‘non-

impaired’ and showed escape latencies that were as quick as those made by young

rats(escape latency = time to find the platform); other middle-aged rats were ‘impaired’ on

the task taking longer to find the platform

– performance on the Morris water maze task reflected differences in the morphology of

neurons within the hippocampus: 1) young rats and middle-aged ‘non-impaired’ rats had

few cells that were damaged in the hippocampus and showed short latencies(10-50 sec) to

find the platform, 2) middle-aged ‘impaired’ rats had more cells that were damaged in the

hippocampus and they showed longer latencies (81-120 sec) to find the platform

– damaged cells were dark-stained cells having pyknotic nuclei

– administration of corticosterone (9-week period) reduced performance of the ‘non-impaired’

middle-aged rats to that of impaired’ middle-aged rats


• Conclusions:

– decreased performance on the Morris water maze task by ‘impaired’ middle-aged rats was

associated with a greater number of pyknotic of damaged cells in the hippocampus

– administration of corticosterone to ‘non-impaired’ middle-aged rats decreased their

performance on the radial-arm maze

Hippocampus-Chronic Stress-Memory DeficitsHow do glucocorticoids damage the hippocampus?

• complex interaction between transport of glucose into cells, elevated levels of

glutamate at synapse, and elevated levels of calcium within cells

– earlier we noted that glucocorticoids act at intracellular receptors to increase the synthesis

of enzymes that act to increase the process of gluconeogenesis

– evidence that glucocorticoids can also act to increase blood glucose levels by blocking

transport of glucose into some cells of body--a decrease in glucose uptake by cells in the

body allows for more glucose to reach brain, heart and skeletal muscle, however, glucose

uptake can even be reduced in the brain (there is evidence for 25% decreased glucose-

uptake in neurons and glia within the hippocampus)

– decrease in glucose-uptake by neurons and glia is thought to reduce the ability of these

cells to function normally

– of interest, administration of energy substrates, such as glucose, can reduce the damaging

effects of glucocorticoids on hippocampal structure and function

Hippocampus-Chronic Stress-Memory DeficitsHow do glucocorticoids damage the hippocampus?

– in glial cells, the decrease in glucose-uptake following glucocorticoid administration can

inhibit their ability to buffer synapses from excess levels of glutamate

– glutamate is an excitatory neurotransmitter that acts at specific receptors; at the NMDA

receptor, glutamate acts to increase the flow of Ca2+ into cells

– too much glutamate at synapse can lead to too much influx of Ca2+ within neurons

– an inability to regulate intracellular Ca2+ levels can damage cells and ultimately lead to

cell death

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Documents

Hippocampus Major cellular components: dentate gyrus (major source of inputs) Ammon’s horn: fields CA1, CA2, CA3/CA4 (integrative role) subiculum (major