Dendritic Protein Synthesis

In this final section we will begin to address issues related to the E-LTP to L-LTP transition. I include them in this chapter because they involve the generation of persisting signals, specifically the increased synthesis of proteins thus, these mechanisms fit well within the general theme of this chapter. Also, there are data to suggest that regulation of protein synthesis may be a downstream target of some of the specific persisting signals involved in E-LTP, such as persistently activated...

Control Experiments

Open Field Analysis and Elevated Plus Maze Performance Open field analysis is used to measure the level of spontaneous motor activity, exploratory behavior, and habituation of animals to an open area. Animals are placed in an open field chamber (e.g., 40 by 40 by 30 cm box) for 15 minutes in standard room-lighting conditions. Activity in the open field is typically monitored by light beams and photoreceptors on each side of the chamber and analyzed by a computer-operated optical animal...

Conscious Learningsubject To Conscious And Unconscious Recall

Human declarative learning is what we typically think of when we think of learning. This is the conscious acquisition of new facts, or the formation of memories for events that occur in our lives, that are available for subsequent recall at will. The extent to which you remember what you read in this book will depend upon the processes of conscious declarative learning. Of course, the extent to which you remember this book will also depend on a large number of other factors, such as motivation,...

Introduction

In this chapter we will discuss the mechanisms unique to inducing and maintaining the long-lasting, late phase of LTP. This is an exciting, wide-open area of LTP research right now, one of those areas where it is clear that important work is underway but where the surface has just been scratched in terms of our understanding. L-LTP is defined in terms of an enduring, protein synthesis-dependent form of synap-tic potentiation in area CA1, as I will describe in more detail later. However, the...

Alternative Mechanisms For

It seems obvious that if there is an increase in synaptic strength, it must be the result of either an increase in neurotransmitter release or an increase in postsynaptic responsiveness. However, what if it's neither of these Are there alternative models that can explain synaptic potentiation that involve neither mechanism Two alternate possibilities have received some attention. They are the possibilities of diminished re-uptake of glutamate, leading to increased synaptic glutamate levels and...

Studying The Hippocampus

If you are interested in studying the roles of the hippocampus in the behaving animal, how do you even begin to go about it One approach is to remove the hippocampus or inactivate it and assess the cognitive and behavioral consequences of this experimental manipulation. These types of studies were the first to lead to an appreciation of the role of the hippocampus in memory consolidation (reviewed in reference 1). In fact, studies in a human patient, known as patient H.M., were breakthrough...

Summary

In this chapter, we talked about those molecular mechanisms that are uniquely involved in triggering long-lasting and very long-lasting changes in synaptic transmission in the hippocampus. We focused most of our attention on how a signal gets from the synapse to the genome, highlighting the PKA ERK RSK CREB pathway as a principal player in L-LTP. We also touched upon the intriguing problem of how altered gene expression becomes manifest at just the appropriate synapse, looking at Arc mRNA as a...

Ltp Can Include An Increased Ap Firing Component

Another caveat to keep in mind is that the preceding discussion deals only with mechanisms contributing to increases in synaptic strength. The increased EPSP is typically measured in field recording experiments as an increase in the initial slope of the EPSP (or EPSP magnitude), as was discussed in the previous chapter. A second component of LTP is referred to as EPSP-spike (E-S) potentiation. E-S potentia-tion was identified by Bliss and Lomo in the first published report of LTP (11) and is...

Unconscious Learning

In this section, we will explore several simple (i.e., nonassociative) forms of learning. Keep in mind that even those forms of learning that exhibit themselves in a fairly straightforward manner at the behavioral level involve elaborate underlying cellular and molecular machinery. In this section, we will emphasize that several forms of nonassociative learning are exhibited by animals, including habituation, dishabituation, and sensitization (see Figure 6). These forms of learning involve...

Modern Experimental Uses Of Rodent Behavioral Models

Having briefly described several of the basic rodent learning paradigms in common use, we now turn our attention to thinking about their application in cellular and molecular studies. By way of introduction to this topic, I think it is useful to step back and review the basics of experimental design. In the next section we will consider the basics of hypothesis testing. We then will proceed to considering how the fundamentals of experimental design are applied in the modern era in extending...

Angelman Syndrome

The use of traditional (i.e., non-inducible) knockout mouse models to try to study the signal transduction events involved in synaptic plasticity and memory has been widely and legitimately criticized because of the great confound of secondary effects of loss of the gene. In particular, developmental derangements can contribute to any observed phenotype, and there is a real concern that the effect of loss of the gene product is not an indication of the protein having any necessary role in an...

Signaling Mechanisms

Ponse Immunitaire Theileria Annulata

We now turn our attention to discussing the mechanisms by which L-LTP-associated changes in gene expression are achieved. How does the L-LTP-triggering calcium elevation at the synaptic spine get a signal to the nucleus In the following section, I will summarize a variety of studies investigating this question. Leading groups in this area are the laboratories of Dan Storm, Dick Tsien, Eric Kandel, Susumu Tonegawa, Alcino Silva, Tim Bliss, and Jocelyn Caboche the following summary draws...

Info

Pkc Isoforms

However, those PKC inhibitors reported to be isoform-selective do not generally differ greatly in their potency for inhibiting the various isoforms of PKC, limiting their effectiveness for hippocampal slice physiology studies. Obviously, transgenic mouse knockout technologies have been used to good effect to selectively eliminate specific protein kinase isoforms. Thus, at the present time, utilization of knockout technology to evaluate the roles of PKC isoforms in LTP...

Ltp Does Not Equal Memory

The strong hypothesis that LTP equals memory makes a number of predictions. We can frame these in the general form that we have been using throughout the book block, mimic, and measure. Thus, The block experiment agents that block LTP should block memory formation. A corollary of this is that agents that enhance LTP should enhance memory. The mimic experiment inducing LTP in the right place in the brain should cause a behavioral change indistinguishable from learned behavior. A variation of...

Homer Bdnf Nt3 Mkp1 Ssat

FIGURE 5 Transcriptional regulation pathways controlling the expression of synaptic plasticity-associated genes. See text for discussion. occurs with L-LTP, these interesting findings support the idea that late waves of altered gene expression contribute to memory consolidation involving hip-pocampal neurons. Thus, we see that at least two (zif268 and krox 20) and probably several more transcription factor-encoding genes are up-regulated in L-LTP. Overall, these findings that transcription...

Monitoring Baseline Synaptic Transmission

Magnitude of the stimulus one delivers to the presynaptic fibers, differences from preparation to preparation (electrode placement, slice thickness, etc.) cause variability in the magnitude of the synaptic response elicited by a constant stimulus amplitude. One approach commonly to compare one preparation (or animal strain) to the next is to quantitate the EPSP relative to the amplitude of the fiber volley in that same hippocampal slice (see figure 5A). The rationale is that the fiber volley,...

Downs Syndrome

Mental retardation can arise not only from loss or derangement of the function of a gene product but also from aberrant overproduction of a gene product. One example of mental retardation in this category is Down's Syndrome. Down's Syndrome results not from a genetic mutation but from aberrant chromosome duplication, specifically duplication of one copy of chromosome 21. For this reason, Down's Syndrome is also referred to as Trisomy 21. Because of this unique mechanism, Down's Syndrome is not...

Of Mice And Rats

Rats have been the prototype animal for learning studies, although recently great effort has been expended to adapt these procedures to mice. This is because the recent advent of transgenic mouse technologies has generated substantial optimism concerning the development of murine models for human learning disorders and memory dysfunction, as well as optimism for their application to understanding the basic molecular mechanisms of memory itself. Moreover, the potential applicability of...

B

FIGURE 9 Path tracking in the probe test. Representative probe trial of a mouse in the Morris water maze task. (A) The swim path trace shown here provides an excellent example of a selective search. This particular subject was trained with the platform located in the northeast quadrant. During the probe trial, this mouse spent 56 of the time in the correct quadrant and crossed the exact area where the platform had been nine times. Adult male 129S3 SvImJ mice (formerly 129 Sv-+p+Tyr-c+Mgf-slJ J...

Ltp Can Be Divided Into Phases

Contemporary models divide very long-lasting LTP (i.e., LTP lasting in the range of 5 to 6 hours) into at least three phases. LTP comprising all three phases can be induced with repeated trains of high-frequency stimulation in area CA1 (see Figure 7), and the phases are expressed FIGURE 5 Increased action potential firing over the course of TFS. (A) The TFS protocol and TFS-induced LTP in mouse hippocampal slices. (B) Electrode placement configuration for recording EPSP and population spikes...

The Chemistry of Perpetual Memory

Short-, Long-, and Ultralong-Term Forms of Learning II. Use of Invertebrate Preparations to Study Simple Forms of Learning III. Short-Term Facilitation in Aplysia is Mediated by Changes in the Levels of Intracellular Second Messengers Thus, Reaction Category 1 Altered Levels of Second Messengers IV. Intermediate-Term Facilitation in Aplysia Involves Altered Gene Expression and Persistent Protein Kinase Activation A Second Category of Reaction Thus, We Have Reaction Category 2 Generation of...

Eyeblink Conditioning

During classical associative learning, an animal is taught to associate a neutral conditioned stimulus (CS) with an aversive unconditioned stimulus (US). Classical conditioning of the eye-blink response in rabbits uses the association of a neutral stimulus such as tone or light with a nociceptive stimulus, such as an airpuff delivered to the eye or a periorbital shock. Re-presentation of the CS results in an eye-blink conditioned response (CR) in anticipation of the US. Trace eye-blink...

Central Pattern Generators

BOX 1, cont'd Central program for swimming in Tritonia. (A) Swimming movements as described previously. (B) Intracellular recordings from neurons in the Tritonia CNS. The top record represents a cell that drives the animal's downward (ventral) flexion the lower record shows the cell that drives the upward (dorsal) flexion. The numbers between records correspond to the numbers in A and show the types of recordings obtained during the corresponding phases of the swimming movement. From Willows...

Recording From Individual Neurons

Most of the data under discussion in this chapter were generated using extracellular recording techniques, but a number of much more sophisticated electrophysiologic techniques have been used to great effect in studies of LTP. These types of techniques fall into two broad categories generally referred to as sharp electrode recording and patch clamp recording. The basic difference in the two techniques is that sharp electrode recording impales the neuron with the recording electrode, while patch...

Summary A General Chemical Model For Memory

Learning and memory have always intrigued those interested in the functioning of the brain. The mammalian CNS has an amazing capacity to store and recall diverse types of information, and learned responses shape to a great degree an animal's behavior. How are memories formed and stored Contemporary understanding of this issue highlights the importance of changes in synaptic strength (synaptic plasticity) as the means whereby the nervous system forms and stores memory. But by what means are...

The Biochemistry of LTP Induction

LTP Induction Component 1 Mechanisms Upstream of the NMDA Receptor That Directly Regulate NMDA Receptor Function A. The Structure of the NMDA Receptor B. Kinase Regulation of the NMDA Receptor C. Redox Regulation of the NMDA Receptor D. Polyamine Regulation of the NMDA Receptor III. LTP Induction Component 2 Mechanisms Upstream of the NMDA Receptor That Control Membrane Depolarization A. Dendritic Potassium Channels B. Voltage-Dependent Sodium Channels (and Calcium Channels ) IV. LTP...

A

Burst Length of Spikes Data Set FIGURE 9 Experience-dependent changes in place cell firing. A Histogram of the total firing rate at various distances from the place field center during the first and the last visitation to the same place in an environment light curve, visit 1 solid curve, visit 17 bin width 0.41 cm, which corresponds to the resolution of the position tracking camera . Firing rates increase as the animal approaches the place field center. Data and figure from Mehta et al. 11 . B...

Behavioral Assessments In Rodents

Conditioning Fear

One popular behavioral model system with which to study learning and memory is a robust learning paradigm that capitalizes on the capacity of mammals, including rodents, to associate environmental cues with a mild aversive stimulus. This type of learning, generally called fear conditioning, is an example of classical associative conditioning similar to Pavlovian conditioning. Some aspects of the neuronal circuitry underlying this behavior have been worked out and it is clear that the amygdala...

Mechanisms For The Generation Of The Actual Persisting Biochemical Signals

Coincidence Illustration

Thus far, we have been discussing the mechanisms for regulating postsynaptic calcium and its immediate effectors, mechanism that determine if an LTP-inducing level of calcium is reached. Point 6 transitions us into the mechanisms whereby this triggering level of calcium is converted into a persisting signal that maintains LTP. As described in the beginning of the chapter, the details of these mechanisms are dealt with in Chapter 7 for E-LTP and Chapter 8 for...

Mouse Models For Ad

Progress in understanding AD and developing new therapies for AD hinges upon the availability of suitable model systems for investigating the disease in the laboratory. In this vein, the application of transgenic animal technology to the pursuit of investigating AD appears to be a critically important endeavor. There are several considerations that factor into the critical role of genetic engineering in developing suitable laboratory models for AD. First, AD is an exclusively human disorder no...

Diagnosing Ad

Ads That Feature Attribute

At present there is no definitive method for pre-mortem diagnosis of AD. Accepted practice is for AD to be diagnosed postmortem by pathological examination of autopsy tissue. Histopathological analysis of post-mortem tissue uses criteria not appreciably different from those described by Alois Alzheimer himself in 1907 10 . The gross hallmarks are cortical atrophy, enlargement of the ventricles, and shrinkage of the hippocampus and surrounding areas of the medial temporal lobe. Microscopic...

Shortterm Facilitation In Aplysia Is Mediated By Changes In The Levels Of Intracellular Second Messengers

What happens when serotonin is applied to sensory neurons Serotonin binds to receptors in the neuron's cell surface membrane that are coupled to adenylyl cyclase and phospholipase C, which generate cAMP and DAG, respectively. When a sensory neuron sees a single pulse of serotonin, adenylyl cyclase and phos-pholipase C are activated, cAMP and DAG levels increase, and the activities of PKA and PKC are greatly enhanced. As long as serotonin is present, these enzymatic activities remain elevated....

Neurogenesis In The Adult

BOX 2, cont'd C Acquisition of the delay eye-blink conditioned response delay paired and the unpaired condition delay unpaired . D Total numbers of BrdU-labeled cells in the dentate gyrus of these animals following delay conditioning. These animals received BrdU injections 1 week before training and were perfused 24 hours after the last day of training. n 5-6 . E Acquisition of place and cue learning in the Morris water maze. F Total numbers of BrdU-labeled cells in the dentate gyrus of these...

BOX 1contd Central Pattern Generators

Leech Swim Central Pattern Generator

Again, this pattern of behavior is mediated by the highly coordinated firing of an elaborate network of neurons in the animal's nervous system. Much of the circuitry and cellular physiology of this central pattern generator was worked out in the late Peter Getting's laboratory. Why do I bring this up in the context of general theories of the chemistry of memory Because these are classic examples of hard-wired behavioral responses. They are seemingly immutable in the absence of injury to the...

Coupling Of Receptors To Intracellular Messengers

Hydrolyzes the membrane phospholipid phosphatidylinositol 4,5-bis phosphate at the linkage between the glycerol backbone and the phospho-head group, liberating diacylglycerol DAG and inositol 1,4,5-tris phosphate. Both of these compounds serve as second messengers. DAG binds to and activates the downstream effector protein kinase C PKC . IP3 binds to an intracellular receptor in the endoplasmic reticulum that is a calcium channel, leading to calcium mobilization from intracellular stores....

Temporal Integration In Ltp Induction

At one level, it is a statement of the obvious to say that LTP induction depends on temporal integration. After all, the only thing that distinguishes the LTP induction protocols from baseline stimulation is that, during the LTP induction protocol, stimulation is delivered at a higher rate. It obviously is the case that if the only thing that is different is that the synapse is seeing activity at 100 pulses per second rather than once every 20 seconds, then LTP is being triggered by unique...

Types Of Receptors And Potential Sites Of Plasticity

Brain Slice Recording Chamber

And phospholipase A2 PLA2 , which liberates free arachidonic acid that can be converted into a wide variety of active metabolites. We will explore these systems and others in excruciating detail in Chapters 6-8. Finally, it is important to note that the targets of these various signaling pathways are as diverse as the genome itself. In terms of neuronal function, particularly important targets are the presynaptic proteins associated with neurotransmitter release, membrane K channels, Ca2...

Chapter Overview

The chapter will be broken down into three broad sections see Figure 1 . The first section will deal with two well-established targets of the triggering calcium for LTP CaMKII and PKC. In this section, I will focus principally on the known mechanisms for generation of persistently activated forms of these kinases, forms of the molecules that are capable of serving as molecular memory traces in LTP and memory in FIGURE 1 Chapter summary. This chapter deals with three primary issues related to...

Modulation Of Ltp Induction

In one sense, the hippocampal slice is a denervated preparation. In the intact animal, the hippocampus receives numerous input fibers that provide modulatory inputs of the neurotransmitters dopamine DA , norepi-nephrine NE , serotonin 5HT , and acetylcholine ACh . Functionally these inputs are largely lost as a necessity of physically preparing the hippocampal slice for the experiment. However, these lost modulatory inputs can be partially reconstituted by directly applying the...

Rodent Models Of Pain Plasticity

In humans, tissue injury results in persistently increased pain sensation to mildly noxious stimuli hyperalgesia and pain perception to normally non-noxious stimuli allodynia . These two forms of sensitization clearly fit within the definition of learning developed in the first chapter persisting behavioral modification in response to an environmental signal. However, in this case, one mechanism contributing to the altered behavior is persisting production of chemical signals locally at the...

Akap

Regulate likelihood of LTP induction This consideration also serves as an important caveat for interpreting results from NMDA receptor knockout mice. This apparently clean experimental manipulation, wherein the NMDA receptor is entirely lost, likely results in a large number of secondary effects on molecules normally associated with the NMDA receptor postsynaptically. In fact, experiments using various deletion mutants missing the cytoplasmic anchoring domains of the NMDA receptor have allowed...

Depotentiation And

When scientists began to think seriously about the possible involvement of LTP in memory in the animal, a theoretical conundrum arose. If synapses can be potentiated and this potentiation is very long-lasting, over time the synapses will be driven to their maximum synaptic strength. In this condition, there is no longer synaptic plasticity and no further capacity for that synapse to participate in synaptic-plasticity-dependent processes. Worse yet, over the lifetime of an animal, synapses will...

Aedvgsnkgai Iglmvggvv

Sequenz App Secretase

This is the human amino acid sequence. In keeping with our focus on rodent models, I also have included in parentheses the rat sequence, which differs only at the three indicated amino acids. Current work focuses on the 42-amino acid variant as a principal culprit in AD, as we will return to later. Ap42, being a fairly small peptide, can assume a number of different conformations in solution and even in protein crystals. One three-dimensional structure of an Ap peptide that has been determined...

20 0 20 40

These data are from recordings in vitro from mouse hippocampal slices, demonstrating the NMDA receptor-dependence of tetanus-induced LTP. Identical high-frequency synaptic stimulation was delivered in control filled circles and NMDA receptor antagonist APV, open triangles treated slices. Data courtesy of Joel Selcher. work has shown that an NMDA receptor-independent type of LTP can be induced in area CA1, and elsewhere in the hippocampus mossy fibers to be precise ,...

Reconsolidation Of Memories

Radiant Thinking

What if every time you recalled a memory you made that memory subject to erasure A frightening thought, certainly. The idea also seems somewhat at odds with our perception of consistency in our own memories recalling them seems to make them stronger, not weaker. Nevertheless, recent provocative studies have suggested that every time we recall a specific memory, we make it necessary for that memory to be reestablished. The word used to describe this attribute of memory is reconsolidation in...

Neurofibromatosis Coffinlowry Syndrome And The Raserk Cascade

Camp Signal Transduction Hypothesis

Neurofibromatosis is an autosomal-dominant disease that exhibits a variety of clinical features, principally neurofibromas, or benign tumors of neural origin. Other characteristics can include skin discoloration caf au lait spots and skeletal malformation. The gene that causes neurofibromatosis when mutated in humans is the neurofibromatosis type 1 oncogene, NF1. NF1 is distinct from the gene coding for a TABLE 1 Mouse Models of Human Mental Retardation Syndromes FMR2 protein putative...

R

Rac, 165, 165f, 328b RACK1, 152, 153f, 172 raf-1, 330b Rapid Eye Movement REM sleep, 71-72b GAPs and GEFs, 166b, 311, 311f human learning and memory, 308 MEK ERK MAPK cascade, 314 PI3 Kinase pathway, 213-215b RC3, see neurogranin Reactive oxygen species, 154, 204-205, 204f, 338, 350 Recall, 4, 6, 52 conscious recall, 20 expression of memory, 257 memory component, 7 Reconsolidation, 11-12, 84b Reelin, 355 Regulated Intramembrane Preteolysis RIP , 348 Regulatory elements, 241 Renger, John,...

Lever Burgess O Keefe

In this chapter, we explored hip-pocampal function in more detail, drawing specific examples from the literature for each of the four broad categories of cognition in which the hippocampus participates space, time, multimodal associations, and memory consolidation. This outline of the complexities of hip-pocampal function prepares us for the next chapter, where we will begin to dissect the hippocampal synaptic circuit and its cellular physiology. This will allow us to begin to understand how...

Rodent Behavioral Learning and Memory Models

Behavioral Assessments in Rodents III. Modern Experimental Uses of Rodent Behavioral Models A. The Four Basic Types of Experiments B. Using Behavioral Paradigms in Block and Measure Experiments A. Open Field Analysis and Elevated Plus Maze Performance B. Rotating-Rod Performance Coordination and Motor Learning C. Acoustic Startle and Pre-Pulse Inhibition E. Vision Tests Light-Dark Exploration and Visual Cliff

Contextual Fear Conditioning

Classical Fear Conditioning

HERMISSENDA THE GOOD-LOOKING ONE IN THE FAMILY Even a dedicated neurobiologist would be hard-pressed to describe Aplysia as aesthetically attractive, but another popular invertebrate species used in studies of learning and memory is a clear winner in any molluscan beauty contest. With its bright coloration and striking profile, Hermissenda is the closest thing to a poster child available among the invertebrate species commonly studied by neurobiologists. HERMISSENDA THE GOOD-LOOKING ONE IN THE...

Hierarchical Organization of Memory

Long Term Memory Explicit And Implicit

FIGURE 2 Hierarchical organization of memory. Short- and long-term memory is subject to being learned by either conscious or unconscious processes. Similarly, memory can be recalled either consciously or unconsciously. Many forms of simple learning such as motor learning, simple associative conditioning, and non-associative learning can be learned and recalled unconsciously. More complex forms of learning typically involve conscious processes. Short-term working memory is listed as a separate...

The Basics of Psychological Learning and Memory Theory

Categories of Learning and Memory B. Memory Exhibits Long-Term and Short-Term Forms II. Unconscious Learning B. Unconscious Learning and Unconscious Recall C. Unconscious Learning and Subject to Conscious Recall E. Currently Popular Associative Learning Paradigms III. Conscious Learning Subject to Conscious and Unconscious Recall IV. Final Note Will Molecular Studies Change the Way We Think about Learning Behavior References