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Neuroscience 410: Neurobiology of Aging and

Neurodegenerative Disorders

Normal Aging: Cellular Correlates of Learning and Memory

Clayton DicksonDepartment of Psychology& Centre for Neuroscience

Learning, Memory and Aging• Learning

– Process by which the environment or interaction with the environment modifies behaviouralexpression

– Process by which knowledge is acquired• Memory

– Process by which environmental modifications upon behavioural expression (i.e., learning) are maintained

– Process by which knowledge is maintainedAging effects on Learning and Memory

– Certain forms of learning and memory may be affected by normal aging

– What are the biological underpinnings of such changes?

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Outline: Normal Aging: Cellular Correlates

of Learning and Memory1. Hippocampal dependent learning and memory in rats

– Tests of spatial memory– Effects of aging

2. Hippocampal structure & function– Effects of aging

3. Hippocampal synaptic plasticity as a model for learning and memory

– Hebbian synapses: Long-Term Potentiation & Depression– Effects of aging

4. Link between hippocampal synaptic plasticity and spatial memory

– Hippocampal place cells, spatial fields and behaviour– Effects of Aging

Rat Models for Hippocampal-Dependent (Spatial) Memory

• In rodents (and primates), spatial memory appears to be an important function of the hippocampus

• Various tests have been developed to assess spatial memory– Circular maze – 8 arm radial maze– Water maze

• Rats with hippocampal damage perform poorly on these tests

• Aged rats?

Barnes circular maze

Morris water maze

8-arm radial maze

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Rat Models for Hippocampal-Dependent (Spatial) Memory

• Barnes circular maze:– Aged rats impaired in:

• Learning escape location • Remembering a learned

location• Learning a new escape

location

• 8-arm radial maze– Aged rats make more errors

and are impaired in remembering locations of arms visited

– No deficits in non-spatial (tactile) version

• Morris water maze:– Aged rats impaired in:

• Learning platform location• No deficits in non-spatial

(cued) version

Hippocampal Anatomy and Physiology: Effects of Aging

Anatomy:– Loss of volume (35%)

• Not due to loss of neurons• Due to loss of connections

between cells– Loss of anatomical

synapses– Loss of synaptic

markers

– Reduction of cholinergic (ACh) inputs

Figure 6.1Dudai, 1989

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Hippocampal Anatomy and Physiology: Effects of Aging

– Ca2+ regulation• ↑ density of high

threshold (L-type) Ca2+

channels• ↑ in Ca2+ currents

– Reduction of influence of ACh

– Functional inter-connectivity

• Mixed evidence of impairments:

Physiology:– Basic intrinsic

neuronal properties unchanged:

• Resting membrane potential, input resistance, time constant, spike threshold, and firing rates

Hippocampal Anatomy and Physiology: Effects of Aging

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• Summary:– DG

• Reduction of input fibres• Decrease in number of synapses• Increase in synaptic strength of remaining synapses• Decrease in relative NMDA component

– CA1• No change in input fibres• Decrease in number of synapses• No change in synaptic strength of remaining synapses• No change in relative NMDA component

Hippocampal Anatomy and Physiology: Effects of Aging

Behavioral Plasticity = Neural PlasticityPremise: The brain is the organ of

behaviour– The operation of the nervous

system is completely responsible for behaviour and mind

Therefore, changes in behaviour must involve changes in the brain– Environmental influences that

modify behaviour or thought must reflect functional (& structural) changes in the nervous system

– Plasticity• What are the anatomical and

physiological mechanisms of these changes?

• How are these processes affected by normal aging?

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How is Neural Plasticity Manifested?

• How can the functioning of the brain be changed?1. Modification of the properties

or responsiveness of neurons• Intrinsic• Fast, short-term alterations• Example: State-changes

(arousal vs. sleepy)2. Modification of the

connections and interactions between neurons• Synaptic• Slower, long-term alterations• Example: Reflex

strengthening with practice

Synaptic Modifications: The Hebbian Synapse

• In 1949, Donald Hebb proposed a theoretical mechanism for the strengthening of synaptic connections :– “When an axon of cell A...

excites[s] cell C and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A's efficiency as one of the cells firing C is increased.”

• “Neurons that fire together, wire together”

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Long-term Potentiation (LTP): Real-life Hebbian Synapses

• An enduring increase in synaptic efficacy resulting from an activity dependent (Hebbian) process– Example of synaptic enhancement:

• Larger amplitude response for a similar input– Requires presynaptic and postsynaptic activity– Properties:

Specific, Cooperative, Associative

• Discovered in 1973 (Bliss and Lomo) in the hippocampus– Since then it has been shown to exist at most (if not all)

glutamatergic synapses in the brain:• Neocortex, Cerebellum, Amygdala, Brainstem, Spinal cord,…

• A model for memory-related synaptic plasticity?

Long-term Potentiation (LTP): Real-life Hebbian Synapses

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LTP Phases: Induction, Expression, and Maintenance

LTP has been shown to last days and even weeks

• Early – Induction Phase– NMDA receptor activation &

Calcium dependence

• Medium – Expression Phase– Changes to receptors and release

machinery– Local protein synthesis

• Late – Maintenance Phase– Genomic involvement– Translation dependent– Anatomical changes?Hargreaves, 1998

LTP Phases: Induction

• LTP induction follows Hebb rule:– Requires coincident presynaptic & postsynaptic activity– NMDA receptor dependent

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LTP Phases: Induction

• NMDA receptor critical– Blockade eliminates Induction of LTP– Double-gated – coincidence detector

• Ligand-dependent (requires binding of glutamate)• Voltage-dependent (requires depolarization to remove Mg2+

block of channel pore)• Activation requires BOTH elements:

– Glutamate binding and postsynaptic depolarization (via AMPA receptor activation and temporal and spatial summation of EPSPs)

– Calcium (Ca2+) entry through NMDA channel critical for the Induction & Expression of synaptic changes

– Large changes in intracellular [Ca2+] induce LTP

LTP Phases: Induction

Figure 3.3Eichenbaum, 2002

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LTP Phases: Induction

• At certain synapses the induction of LTP can occur without the participation of NMDA neurotransmission– Unmasked with NMDA receptor blockers

• This type of LTP also requires Ca2+ and appears to use voltage-dependent high-threshold (L-Type) calcium channels– Blocked by nifodipine

• VDCC LTP

LTP Phases: Expression & Maintenance

• Ca2+ is both an ion and a signaling molecule– Intracellular second messenger

• Large post synaptic increase in Ca2+ triggers an increase in post-synaptic responsiveness via:– ↑ in AMPA receptors (post-synaptically)– ↑ neurotransmitter release (pre-synaptically)– ↑ synaptic contacts

Figure 22.25Bear et al, 2001

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LTP Phases: Expression and Maintenance

• For medium-term expression of LTP, local signaling mechanisms suffice although local protein synthesis may be necessary

• For long-term maintenance of LTP, nuclear involvement is necessary via genomic translation

Figure 3.4Eichenbaum, 2002

Long-term Depression (LTD)• A mechanism for synaptic enhancement like LTP requires an

opposing mechanism to prevent synaptic saturation• LTD can be induced by stimulation patterns violating Hebb’s

principal:1. Presynaptic activity without postsynaptic activity

• Weak, low-frequency repetitive stimulation of presynaptic inputs• Temporally mismatched (uncorrelated) activation of (different) weak

and strong presynaptic inputs2. Postsynaptic activity without presynaptic activity

• Repetitive low frequency depolarization of postsynaptic cell• Temporally mismatched (uncorrelated) activation of weak presynaptic

inputs and depolarization of post synaptic cell

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Long-term Depression (LTD)

Figure 12.10Nicholls et al, 2001

Long-term Depression (LTD)

• Mechanism?– Ca2+-dependent synaptic depression

• Lower concentrations of calcium entry in post-synaptic elicit changes which oppose synaptic enhancement

• Evoked by both NMDA receptor and voltage-dependent Ca2+

channels activation• Likely to include both pre and post-synaptic elements:

– ↓ in post-synaptic AMPA receptors– ↓ in pre-synaptic release of glutamate– ↓ in synaptic contacts

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Effects of Aging on Hippocampal LTP and LTD

“Traditional” LTP:• Induction:

– Stimulus threshold higher• Intact when high intensity

stimulation used– Synaptic alterations in

hippocampus

• Maintenance:– Faster rate of decay

• Disruption of intracellular 2nd messenger systems?

VDCC-dependent LTP:• Induction:

– Stimulus threshold lower• Altered Ca2+ homeostasis

• Maintenance:– Unknown

NMDA-dependent LTP:• Induction:

– Stimulus threshold higher• Maintenance:

– Unknown

Effects of Aging on Hippocampal LTP and LTD

LTD:• Induction:

– Enhanced (lowered threshold)• Altered Ca2+

homeostasis

• Maintenance– Unknown

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Is LTP a Neural Analogue of Learning and Memory?

If so then:1. Learning should elicit an LTP-like change in the brain2. Artificial LTP should interfere with normal learning or

induce false memories (& vice versa)3. Saturation of LTP should prevent learning and

interfere with previous memories 4. Blockade of LTP should prevent learning but should

not interfere with previous memories5. Reversal of LTP should erase previous memories6. Aging effects on LTP should parallel aging effects on

hippocampal-dependent (spatial) learning and memory tasks

Hippocampal Activity and Space• One of the most striking

links for hippocampal function and spatial memory is the existence of “place”cells– Cells which show increased

firing rates when the animal is in a specific location

• Place fields form rapidly but require experience to become stable– NMDAR-dependent!

• Requiring LTP-like process?– Aged rats have unstable place

fields!!!

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Hippocampus, Space, and Aging

• Unstable place fields in elderly rats occur across, but not within sessions in a given environment

Hippocampus, Space, and Aging: Place Field Expansion

• When rats repeatedly travel along a given path, hippocampal place fields expand

• This could reflect an LTP-like association between sequentially activated place cells and might be a network mechanism for stable place field formation:– Place field expansion ALWAYS occurs in the direction opposite to

travel (i.e., backwards)– Place field expansion NMDAR-dependent– Older rats show less place field expansion

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Hippocampus, Space, and Aging: Cognitive Maps?

• If stable place fields in networks of hippocampal neurons reflects a spatial “map” then spatial behaviour should correlate with changes in this “map”

• 4-arm radial maze performance and recordings showed that place field activity corresponded to the rat’s “selected” goal arm

Summary: Hippocampus, Spatial Memory, LTP, & Aging

• Integrated study of hippocampal-dependent rat spatial memory, hippocampal synaptic plasticity (LTP & LTD), and aging allows for an experimental examination of the neurobiology of learning and memory across the life span:

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Acknowledgment

• Major source:Rosenzweig and Barnes, (2003) Impact of aging on

hippocampal function: plasticity network dynamics, and cognition Progress in Neurobiology 69 143-179.