One of the most remarkable aspects of an animal's behavior is the ability to modify that behavior by learning, an ability that reaches its highest form in human beings. For me, learning and memory have proven to be endlessly fascinating mental processes because they address one of the fundamental features of human activity: our ability to acquire new ideas from experience and to retain these ideas over time in memory. Moreover, unlike other mental processes such as thought, language, and consciousness, learning seemed from the outset to be readily accessible to cellular and molecular analysis. I, therefore, have been curious to know: What changes in the brain when we learn? And, once something is learned, how is that information retained in the brain? I have tried to address these questions through a reductionist approach that would allow me to investigate elementary forms of learning and memory at a cellular molecular level-as specific molecular activities within identified nerve cells.

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The Molecular Biology of Memory Storage: A Dialogue Between Genes and Synapses

Vulnerable periods during the development of the nervous system are sensitive to environmental insults because they are dependent on the temporal and regional emergence of critical developmental processes (i.e., proliferation, migration, differentiation, synaptogenesis, myelination, and apoptosis). Evidence from numerous sources demonstrates that neural development extends from the embryonic period through adolescence. In general, the sequence of events is comparable among species, although the time scales are considerably different. Developmental exposure of animals or humans to numerous agents (e.g., X-ray irradiation, methylazoxymethanol, ethanol, lead, methyl mercury, or chlorpyrifos) demonstrates that interference with one or more of these developmental processes can lead to developmental neurotoxicity. Different behavioral domains (e.g., sensory, motor, and various cognitive functions) are subserved by different brain areas. Although there are important differences between the rodent and human brain, analogous structures can be identified. Moreover, the ontogeny of specific behaviors can be used to draw inferences regarding the maturation of specific brain structures or neural circuits in rodents and primates, including humans. Furthermore, various clinical disorders in humans (e.g., schizophrenia, dyslexia, epilepsy, and autism) may also be the result of interference with normal ontogeny of developmental processes in the nervous system. Of critical concern is the possibility that developmental exposure to neurotoxicants may result in an acceleration of age-related decline in function. This concern is compounded by the fact that developmental neurotoxicity that results in small effects can have a profound societal impact when amortized across the entire population and across the life span of humans.

Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models.

Activation of T cells by antigen-presenting cells (APCs) depends on the complex integration of signals that are delivered by multiple antigen receptors. Most receptor-proximal activation events in T cells were identified using multivalent anti-receptor antibodies, eliminating the need to use the more complex APCs. As the physiological membrane-associated ligands on the APC and the activating antibodies probably trigger the same biochemical pathways, it is unknown why the antibodies, even at saturating concentrations, fail to trigger some of the physiological T-cell responses. Here we study, at the level of the single cell, the responses of T cells to native ligands. We used a digital imaging system and analysed the three-dimensional distribution of receptors and intracellular proteins that cluster at the contacts between T cells and APCs during antigen-specific interactions. Surprisingly, instead of showing uniform oligomerization, these proteins clustered into segregated three-dimensional domains within the cell contacts. The antigen-specific formation of these new, spatially segregated supramolecular activation clusters may generate appropriate physiological responses and may explain the high sensitivity of the T cells to antigen.

Three-dimensional segregation of supramolecular activation clusters in T cells

Neuronal circuits in the brain are shaped by experience during 'critical periods' in early postnatal life. In the primary visual cortex, this activity-dependent development is triggered by the functional maturation of local inhibitory connections and driven by a specific, late-developing subset of interneurons. Ultimately, the structural consolidation of competing sensory inputs is mediated by a proteolytic reorganization of the extracellular matrix that occurs only during the critical period. The reactivation of this process, and subsequent recovery of function in conditions such as amblyopia, can now be studied with realistic circuit models that might generalize across systems.

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Critical period plasticity in local cortical circuits.

Microglia Promote Learning-Dependent Synapse Formation through Brain-Derived Neurotrophic Factor

Perhaps the most striking finding in the biology of memory is that long-term memory involves structural changes. A variety of memory processes ranging in complexity from those produced by elementary forms of nonassociative learning in invertebrates to those produced by higher order associative tasks in mammals are accompanied by alterations in the structure of synaptic connections. This finding raises three interesting conceptual issues. First, how does short-term memory, which involves only covalent modification of pre-existing proteins and an alteration of pre-existing connections, become transformed into a structural change? Second, is the stability of long-term memory achieved because of the stability of synaptic structures? If so, is loss of memory with time reflected in loss of synaptic connections? Finally, how do the structural changes that accompany long-term memory compare with the de novo synapse formation and synaptic pruning that occur during development? In this review we consider the recent evidence for structural changes in learning by focusing on these three issues. We begin by examining

Structural changes accompanying memory storage

The morphological basis of the persistent synaptic plasticity that underlies long-term habituation and sensitization of the gill withdrawal reflex in Aplysia californica was explored by examining the fine structure of sensory neuron presynaptic terminals (the critical site of plasticity for the short-term forms of both types of learning) in control animals and in animals whose behavior had been modified by training. The number, size, and vesicle complement of sensory neuron active zones were larger in animals showing long-term sensitization than in control animals and smaller in animals showing long-term habituation. These changes are likely to represent an anatomical substrate for the memory consolidation of these tasks.

http://science.sciencemag.org/content/sci/220/4592/91.full.pdf

Morphological Basis of Long-Term Habituation and Sensitization in Aplysia

Tissue Plasminogen Activator Contributes to the Late Phase of LTP and to Synaptic Growth in the Hippocampal Mossy Fiber Pathway

The long-term facilitation of synaptic efficacy that is induced by serotonin in dissociated cell cultures of sensory and motor neurons of Aplysia is accompanied by the growth of new synaptic connections. This growth is associated with a down-regulation in the sensory neuron of Aplysia cell adhesion molecules (apCAMs). To examine the mechanisms of this down-regulation, thin-section electron microscopy was combined with immunolabeling by gold-conjugated monoclonal antibodies specific to apCAM. Within 1 hour, serotonin led to a 50% decrease in the density of gold-labeled complexes at the surface membrane of the sensory neuron. This down-regulation was achieved by a heterologous, protein synthesis-dependent activation of the endosomal pathway, which leads to internalization and apparent degradation of apCAM. The internalization is particularly prominent at sites where the processes of the sensory neurons contact one another and may act there to destabilize process-to-process contacts that normally inhibit growth. In turn, the endocytic activation may lead to a redistribution of membrane components to sites where new synapses form.

Serotonin-mediated endocytosis of apCAM: an early step of learning-related synaptic growth in Aplysia.

Consolidation of implicit memory in the invertebrate Aplysia and explicit memory in the mammalian hippocampus are associated with remodeling and growth of preexisting synapses and the formation of new synapses. Here, we compare and contrast structural components of the synaptic plasticity that underlies these two distinct forms of memory. In both cases, the structural changes involve time-dependent processes. Thus, some modifications are transient and may contribute to early formative stages of long-term memory, whereas others are more stable, longer lasting, and likely to confer persistence to memory storage. In addition, we explore the possibility that trans-synaptic signaling mechanisms governing de novo synapse formation during development can be reused in the adult for the purposes of structuralsynapticplasticityandmemorystorage.Finally, wediscusshowthesemechanisms set in motion structural rearrangements that prepare a synapse to strengthen the same memoryand, perhaps, to allow it to take part in other memories as a basis for understanding how theiranatomical representation results in the enhanced expression and storage of memories in the brain.

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Craig H. Bailey

Papers

Structural changes accompanying memory storage

Morphological Basis of Long-Term Habituation and Sensitization in Aplysia

Tissue Plasminogen Activator Contributes to the Late Phase of LTP and to Synaptic Growth in the Hippocampal Mossy Fiber Pathway

Serotonin-mediated endocytosis of apCAM: an early step of learning-related synaptic growth in Aplysia.

Structural Components of Synaptic Plasticity and Memory Consolidation.