Bear: Neuroscience: Exploring the Brain 3e

Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright © 2007 Lippincott Williams & Wilkins

Bear: Neuroscience: Exploring the Brain 3e

Chapter 25: Molecular Mechanisms of Learning and Memory


Introduction

 Neurobiology of memory  Identifying where and how different types

of information are stored  Hypothesis by Hebb

 Memory results from synaptic alterations   Study of simple invertebrates

 Synaptic alterations underlie memories (procedural)

 Electrical stimulation of brain  Experimentally produce measurable

synaptic alterations - dissect mechanisms


Procedural Learning Declarative and procedural memories Nonassociative Learning

Habituation Learning to ignore a

stimulus that lacks meaning

Sensitization Learning to intensify

response to stimuli

Figure 25.1 Types of nonassociative learning. (a) In habituation, repeated presentation of the same stimulus produces a progressively smaller response. (b) In sensitization, a strong stimulus (arrow) results in an exaggerated response to all subsequent stimuli.


Associative Learning Classical Conditioning

Procedural Learning

Figure 25.2 Classical conditioning. (a) Prior to conditioning, the sound of a bell (the conditional stimulus, CS) elicits no response, in sharp contrast to the response elicited by the sight of a piece of meat (the unconditioned stimulus, US). (b) Conditioning entails pairing the sound of the bell with the sight of the meat. The dog learns that the bell predicts the meat.


Associative Learning (Cont’d)  Classical Conditioning

 Associates a stimulus that evokes response - unconditional stimulus - with second stimulus that does not evoke response - conditional stimulus

 Instrumental Conditioning  Experiment by Edward Thorndike  Complex neural circuits due to motivation

Procedural Learning


Simple Systems: Invertebrate Models of Learning

Experimental advantages in using invertebrate nervous systems  Small nervous systems  Large neurons  Identifiable neurons  Identifiable circuits  Simple genetics


Nonassociative Learning in Aplysia


Figure 25.3 Aplysia californica. One cool sea slug, used for neurobiological studies of learning and memory.

Figure 25.4 The gill-withdrawal reflex in Aplysia. (a) The mantle is held aside to show the gill in its normal position. (b) The gill retracts when water is sprayed on the siphon. That repeated jets of water lessen this reflex is an example of habituation.


Habituation of the Gill-Withdrawal Reflex Nonassociative Learning in Aplysia (Cont’d)


Figure 25.5 The abdominal ganglion of Aplysia. The gill-withdrawal reflex involves neurons within the abdominal ganglion that can be dissected and studied electrophysiologically.

Figure 25.6 A simple wiring diagram for the gill-withdrawal reflex. The sensory neuron that detects stimuli applied to the skin of the siphon synapses directly on the motor neuron that causes the gill to withdraw.


Habituation of the Gill-Withdrawal Reflex Nonassociative Learning in Aplysia (Cont’d)


Figure 25.7 Habituation at the cellular level. Repeated electrical stimulation of a sensory neuron leads to a progressively smaller EPSP in the postsynaptic motor neuron.


Sensitization of the Gill-Withdrawal Reflex Nonassociative Learning in Aplysia (Cont’d)


Figure 25.8 A wiring diagram for sensitization of the gill-withdrawal reflex. A sensitizing stimulus to the head of Aplysia indirectly activates an interneuron, L29, which makes an axoaxonic synapse on the terminal of the sensory neuron.


Sensitization of the Gill-Withdrawal Reflex

Nonassociative Learning in Aplysia (Cont’d)


Figure 25.9 A mechanism for sensitization of the gill-withdrawal reflex. Serotonin (5-HT) released by L29 in response to the head shock leads to G-protein-coupled activation of adenylyl cyclase in the sensory axon terminal. Activation of this enzyme leads to the production of cyclic AMP, which in turn activates protein kinase A. Protein kinase A attaches phosphate groups to a potassium channel, causing it to close and prolong the presynaptic action potential of the sensory neuron.


Sensitization of the Gill-Withdrawal Reflex

Nonassociative Learning in Aplysia (Cont’d)


Figure 25.10 The effect of decreased potassium conductance in the sensory axon terminal. (a) The trace shows membrane voltage changes during an action potential. The rising phase is caused by the opening of voltage-gated sodium channels, and the falling phase is caused by the closing of the sodium channels and the opening of potassium channels. In the axon terminal, voltage-gated calcium channels stay open as long as the membrane voltage exceeds a threshold value, indicated by the red line. (b) The resulting entry of Ca2+ stimulates the release of neurotransmitter. (c) A decrease in K+ conductance after sensitization prolongs the action potential. (d) The voltage-gated calcium channels stay open longer, thereby admitting more Ca2+ into the terminal. This causes more transmitter to be released per action potential.


Associative Learning in Aplysia


Classical conditioning CS-US pairing at cellular and molecular levels

Figure 25.11 Classical conditioning in Aplysia. (a) A gentle water jet to the siphon is the CS. A shock to the tail is the US. The response measured is the withdrawal of the gill. (b) The wiring diagram for classical conditioning. The US activates the same serotonergic cell (L29) that is activated during sensitization. (c) Timing of the CS and US during three different types of training. (d) Plotted here is the magnitude of the gill withdrawal in response to the CS. After pairing (classical conditioning), the animal withdraws the gill in response to the CS, which before training was ineffective in eliciting a response.



Figure 25.12 The molecular basis for classical conditioning in Aplysia. (a) The US alone leads to activation of the motor neuron (via an interneuron, not shown) and to sensitization of the sensory input by the same mechanism illustrated in Figures 24.9 and 24.10. and 24.10. (b) Pairing the CS and the US causes greater activation of adenylyl cyclase than either stimulus does by itself because the CS admits Ca2+ into the presynaptic terminal. The Ca2+ (by interacting with a protein called calmodulin, not shown) increases the response of adenylyl cyclase to G-proteins.

Molecular basis for classical conditioning in Aplysia


 Neural basis of memory learned from invertebrate studies  Learning and memory can result from

modifications of synaptic transmission  Synaptic modifications can be triggered by

conversion of neural activity into intracellular second messengers

 Memories can result from alterations in existing synaptic proteins

Vertebrate Models of Learning


  Synaptic Plasticity in the Cerebellar Cortex  Cerebellum: Important site for motor learning  Anatomy of the Cerebellar Cortex

 Features of Purkinje cells  Dendrites extend only into molecular layer  Cell axons synapse on deep cerebellar

nuclei neurons  GABA as a neurotransmitter



The structure of the cerebellar cortex Vertebrate Models of Learning

Figure 25.13 The structure of the cerebellar cortex. (a) A view of the cortex showing the organization of the granule cell, Purkinje cell, and molecular layers. (b) The major inputs to the Purkinje cells are parallel fibers arising from cerebellar granule cells and climbing fibers arising from the inferior olive. The major input to the granule cells is the mossy fibers, arising from neurons in the pontine nuclei.



Figure 25.14 Cerebellar long-term depression. (a) The experimental arrangement for demonstrating LTD. The magnitude of the Purkinje cell response to stimulation of a "beam" of parallel fibers is monitored. Conditioning involves pairing parallel fiber stimulation with climbing fiber stimulation. (b) A graph of an experiment performed in this way. After the pairing, LTD of the response to parallel fiber stimulation results.

Synaptic Plasticity in the Cerebellar Cortex Long-Term Depression in the Cerebellar Cortex



Figure 25.15 A mechanism of LTD induction in the cerebellum. Climbing fiber activation strongly depolarizes the Purkinje cell dendrite, which leads to the activation of voltage-gated calcium channels. Parallel fiber activation leads to Na+ entry through AMPA receptors, and the generation of diacylglycerol (DAG) via stimulation of the metabotropic receptor. DAG activates protein kinase C (PKC). Extra Ca2+ with PKC internalizes AMPA receptors, decreasing the number of AMPA receptor channels.

Synaptic Plasticity in the Cerebellar Cortex (Cont’d) Long-Term Depression in the Cerebellar Cortex


 Cerebellar LTD & Classical Conditioning in Aplysia  Similarity: Input-specific synaptic modification  Dissimilarity: Site of convergence and nature of

synaptic changes  Mechanisms of cerebellar LTD

 Learning  Rise in Ca2+ and Na+ and the activation of

protein kinase C  Memory

 Internalized AMPA channels and depressed excitatory postsynaptic currents

Vertebrate Models of Learning Synaptic Plasticity in the Cerebellar Cortex (Cont’d)

Long-Term Depression in the Cerebellar Cortex


 LTP and LTD Key to forming declarative memories in the brain

 Bliss and Lomo High frequency electrical stimulation of

excitatory pathway

 Anatomy of Hippocampus Brain slice preparation: Study of LTD and LTP

Synaptic Plasticity in the Hippocampus Vertebrate Models of Learning


Synaptic Plasticity in the Hippocampus (Cont’d) Vertebrate Models of Learning

Figure 25.17 Some microcircuits of the hippocampus. (1) Information flows from the entorhinal cortex via the perforant path to the dentate gyrus. (2) The dentate gyrus granule cells emit axons called mossy fibers that synapse on pyramidal neurons in area CA3. (3) Axons from the CA3 neurons, called Schaffer collaterals, synapse on pyramidal neurons in area CA1.

Anatomy of the Hippocampus



Figure 25.18 Long-term potentiation in CA1. (a) The response of a CA1 neuron is monitored as two inputs are alternately stimulated. LTP is induced in input 1 by giving this input a tetanus. (b) The graph shows a record of the experiment. The tetanus to input 1 (arrow) yields a potentiated response to stimulation of this input. (c) LTP is input-specific, so there is no change in the response to input 2 after a tetanus to input 1.

Properties of LTP in

CA1



Figure 25.19 A rose is a rose, but it is not an onion. Because the sight and smell of the rose occur at the same time, the inputs carrying this information to a neuron may undergo LTP, thus forming an association between the two stimuli.



Mechanisms of LTP in CA1 Glutamate receptors mediate excitatory synaptic transmission NMDARs and AMPARs

Figure 25.20 Routes for the expression of LTP in CA1. Ca2+ entering through the NMDA receptor activates protein kinases. This can cause LTP (1) by changing the effectiveness of existing post-synaptic AMPA receptors or (2) by stimulating the insertion of new AMPA receptors.



Figure 25.21 Hippocampal long-term depression. (a) The response of a CA1 neuron is monitored as two inputs are alternately stimulated. LTD is induced in input 1 by giving this input a 1 Hz tetanus. (b) The graph shows a record of the experiment. The low-frequency tetanus to input 1 (arrow) yields a depressed response to stimulation of this input. (c) LTD is input-specific, so there is no change in the response to input 2 after tetanus to input 1.

Long-Term Depression

in CA1


Figure 25.22 NMDA receptor activation and bidirectional synaptic plasticity. The long-term change in synaptic transmission is graphed as a function of the level of NMDA receptor activation during conditioning stimulation.


BCM theory (Bienenstock, Cooper, Munro)

When the post-synaptic cell is weakly depolar-ized by other inputs: Active synapses undergo LTD instead of LTP Accounts for bidirectional synaptic changes (up or down)



LTP, LTD, and Glutamate Receptor Trafficking Stable synaptic transmission: AMPA receptors are replaced maintaining the same number LTD and LTP disrupt equilibrium Bidirectional regulation of phosphorylation

Figure 25.23 A model for how Ca2+ can trigger both LTP and LTD in the hippocampus. High-frequency stimulation (HFS) yields LTP by causing a large elevation of [Ca2+]. Low-frequency stimulation (LFS) yields LTD by causing a smaller elevation of [Ca2+]. (Source: Adapted from Bear and Malenka, 1994, Fig. 1.)


Figure 25.24 An egg carton model of AMPA receptor trafficking at the synapse. Each egg represents an AMPA receptor, and the carton is PSD-95 which determines the capacity of the synapse for receptors. (a) The initial steady state. Each AMPA receptor that is removed is replaced with a new receptor. (b) LTP. More PSD-95 is added, increasing the synaptic capacity for AMPA receptors. The new receptors (blue) contain the GluR1 subunit. (c) The new steady state. Over time, ongoing turnover of receptors replaces those with GluR1. (d) LTD. Some PSD-95 is destroyed, decreasing the synaptic capacity for AMPA receptors. (e) The new steady state following LTD.


LTP, LTD, and Glutamate Receptor Trafficking (Cont’d)


Figure 25.25 Bidirectional synaptic modifications in human area IT. Slices of human temporal cortex, removed during the course of surgery to gain access to deeper structures, were maintained in vitro. Synaptic responses were monitored following various types of tetanic stimulation. As in rat CA1, stimulation of 1 Hz produced LTD, while 100 Hz stimulation produced LTP. (Source: Adapted from Chen et al., 1996.)


LTP, LTD, and Glutamate Receptor Trafficking (Cont’d)


LTP, LTD, and Memory  Tonegawa, Silva, and colleagues

 Genetic “knockout” mice  Consequences of genetic deletions (e.g.,

CaMK11 subunit)  Advances (temporal and spatial control)

 Limitations of using genetic mutants to study LTP/learning: secondary consequences



The Molecular Basis of Long-Term Memory Phosphorylation as a long term

mechanism: Problematic (transient and turnover rates)

Persistently Active Protein Kinases  Phosphorylation maintained:

Kinases stay “on”  CaMKII and LTP

 Molecular switch hypothesis

Figure 25.26 The regulation of CaMKII (Calcium-Calmodulin-dependent protein kinase II). (a) The hinge-like subunit of CaMKII is normally "off" when the catalytic region is covered by the regulatory region. (b) The hinge opens upon activation of the molecule by Ca2+-bound calmodulin, freeing the catalytic region to add phosphate groups (P) to other proteins. (c) A large elevation of Ca2+ can cause phosphorylation of one subunit by another (autophosphorylation), which enables the catalytic region to stay "on" permanently.


Protein Synthesis Requirement of long-term memory

 Synthesis of new protein Protein Synthesis and Memory Consolidation

 Protein synthesis inhibitors  Deficits in learning and memory

CREB and Memory  CREB: Cyclic AMP response element binding

protein Structural Plasticity and Memory

 Long-term memory associated with formation of new synapses

 Rat in complex environment: Shows increase in number of neuron synapses by about 25%

The Molecular Basis of Long-Term Memory


Gene Expression for Protein Synthesis The Molecular Basis of Long-Term Memory

Figure 25.27 The regulation of gene expression by CREB (Cyclic AMP response element binding protein). Shown here is a piece of DNA containing a gene whose expression is regulated by the inter-action of a CREB protein with a CRE on the DNA. (a) CREB-2 functions as a repressor of gene expression. (b) CREB-1, an activator of gene expression, can displace CREB-2. (c) When CREB-1 is phosphorylated by protein kinase A (and other kinases), transcription can ensue.


Concluding Remarks

Learning and memory   Occur at synapses

Unique features of Ca2+

 Critical for neurotransmitter secretion and muscle contraction, every form of synaptic plasticity

 Charge-carrying ion plus a potent second messenger  Can couple electrical activity with long-term

changes in brain


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Bear: Neuroscience: Exploring the Brain 3e

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