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Alzheimer's disease (AD) is characterized by extensive, yet selective, neuron death in the cerebral neocortex leading to dramatic decline in cognitive abilities and memory. A more modest disruption of memory occurs frequently in normal aging, in humans and in animal models. Significant neuron death does not appear to be the cause of such age-related memory deficits, but in AD, hippocampal and long association corticocortical circuits are devastated. Evidence from rodent and nonhuman primate models reveals that these same circuits exhibit subtle age-related changes in neurochemical phenotype, dendritic and spine morphology, and synaptic integrity that correlate with impaired function. Molecular alterations of synapses, such as shifts in expression of excitatory receptors, also contribute to these deficits. These brain regions are also responsive to circulating estrogen levels. Interactions between reproductive senescence and brain aging may affect cortical synaptic transmission, implying that certain synaptic alterations in aging may be reversible. As such, integrity of spines and synapses may reflect age-related memory decline, whereas the loss of select cortical circuits is a crucial substrate for functional decline in AD.

Information processing in neurons is critically dependent on dendritic morphology. The overall extent and orientation of dendrites determines the kinds of input a neuron receives. Fine dendritic appendages called spines act as subcellular compartments devoted to processing synaptic information, and the dendritic branching pattern determines the efficacy with which synaptic information is transmitted to the soma. The development of the dendritic tree is influenced by a number of factors. Studies in Drosophila have identified key components of the genetic program that regulates dendritic morphogenesis. Parallel studies in vertebrates have revealed that extracellular signals and neuronal activity exert a major influence on the growth and branching of dendrites and the formation of dendritic spines. The identification of genes that mediate these processes is providing important insight into the molecular mechanisms of dendritic morphogenesis.

Most synapses are made onto dendrites, and most excitatory connections are made onto dendritic spines. Synaptic plasticity is thus an intrinsically dendritic phenomenon, but the functional significance of the structural, electrical, and molecular properties of dendrites for synaptic plasticity is still very poorly understood. Do dendrites have a computational or cell biological role in the modification of synaptic strength that is more than circumstantial? This chapter aims to summarize experimental data and theoretical considerations that may be relevant to the role of dendrites in synaptic plasticity. The focus is on associative Hebbian synaptic plasticity, including spike-timing-dependent forms, mediated by NMDA receptor activation.

Dendrites have both an electrical and a biochemical character, which are closely linked. This chapter discusses dendritic structures as compartments for chemical signals such as concentration changes of ions or other second messengers, which control enzyme activity and signaling cascades. It focuses on the following question: to what extent can these signals be confined to only part of the dendritic tree or to dendritic spines? Such ‘compartmentalization’ is considered the basis of local modifications of dendritic properties, in particular to achieve input-specific changes in synaptic strength. General factors that affect compartmentalization of chemical signals are first discussed, including diffusion, intracellular binding, and removal mechanisms. Examples are given of measurements of dendritic ion and second messenger signaling, with the main focus on calcium signaling, for which the most detailed information is available from imaging studies. Subsequently, in an attempt to define functional units, an overview of the different spatial scales of dendritic compartmentalization is given, spanning a range of three orders of magnitude. Finally, there are examples of how chemical signals are used for dendritic information processing.

This chapter explores our recent advances in our understanding of how estrogens can modulate spinogenesis within the cortex and its relevance for estrogenic-regulation of cognition. It describes how estrogens, including 17β‎-estradiol and estrogen receptor modulators, rapidly modify dendritic spine density concurrently with influencing cognitive behaviors that require cortical processing. Furthermore, it reviews the evidence that these effects are not limited to female animals but may represent a relevant mechanism in the male brain. This chapter will also explore the emerging role for a novel estrogen receptor, G-protein estrogen receptor (GPER), in mediating the rapid effects of estrogens on dendritic spines. Finally, the chapter also reviews the potential molecular mechanisms that underlie rapid estrogenic signaling, linking this signaling to the modulation of spinogenesis, which may ultimately provide a cellular model by which estrogens can produce long-lasting changes in neural circuitry.

This chapter discusses some of the most exciting recent discoveries concerning the mechanisms of spine synapse plasticity and reviews the most intriguing questions which still loom over these tiny cytoplasmic extrusions. It reveals that the sensory experience affects spine motility. This chapter shows that the formation of dendritic spines may be potentiated around sites of high synaptic activity. It supports the hypothesis that spine morphological changes underlie experience-dependent changes in neuronal circuits.

Dendrites, the neuronal processes that receive synaptic inputs, are found in all nervous systems. The great diversity of dendrites, both within individual species and across phylogeny, reflects their adaptation to particular functional roles. This chapter explores this diversity to consider dendrites from an evolutionary perspective. The evidence that dendrites scale across phylogeny to preserve the number of synapses per neuron is reviewed, as well as the architecture of local microcircuits, including the number of neurons in a single neocortical column. Dendritic spines may have originated to form and regulate connections, and later acquired the function of maximizing information storage in densely packed neuropil. These observations are consistent with the unifying principle that dendrites have adapted to keep circuit-level function the same, even though per-gram metabolic rates vary widely. Finally, the chapter considers an emerging area of investigation in normal function and in disease: molecular and developmental mechanisms regulating dendritic form, the targets upon which selection has acted.

This chapter aims to integrate all current knowledge on dendritic spines, and provide information on the important features of the circuits in which they operate. It discusses the various aspects of the biology of the spines. It then presents a brief summary of each chapter on the book, which explores the different physiological functions of the spine.

This chapter reviews the relationship between estrogens, memory, and dendritic spine plasticity. Estrogens, given systemically or directly into the hippocampus, enhance memory consolidation in object recognition and object placement tasks within minutes of application. Dendritic spine density in the CA1 area of the hippocampus and medial prefrontal cortex increases under the same conditions, suggesting that changes in dendritic spine density are an important component of estrogen’s ability to impact memory processes. Possible receptors and signaling pathways mediating the molecular mechanisms in response to estrogen are discussed. Although the precise mechanisms remain to be elucidated, research to date suggests that modulation of dendritic spines by estradiol is a key component in promotion of memory consolidation.

This chapter narrates the discovery of dendritic spines. It begins with Santiago Ramón y Cajal, a Spanish professor of Pathology and Histology, and his work entitled Estractura delos centros nerviosos de la aves (Structure of the Nervous Centers in Birds) and how he discovered the spines using the Golgi technique. Cajal defined “spine” on the spines of a rose bush, as it resembled one when he first investigated it in Purkinje cells.

Research from the past decade has begun to shed light on the neural mechanisms through which the potent estrogen 17β‎-estradiol (E2) regulates the formation of memories. Consolidation is a rapid process which appears to take advantage of the ability of estrogen receptors to quickly trigger cell signaling alterations that increase gene expression, local protein synthesis, and dendritic spinogenesis. This chapter discusses recent advances in understanding how the rapid effects of E2 on the hippocampus influence memory consolidation in female and male rodents and examines new directions for exploring similar mechanisms in other interconnected brain regions.

Although the potent estrogen, 17β‎-estradiol (E2), has long been known to regulate the hippocampal dendritic spine density and synaptic plasticity, the molecular mechanisms through which it does so are less well understood. This chapter discusses the rapid modulation of hippocampal dendritic spine density and synaptic plasticity in male and female rats, with particular attention to studies in hippocampal slices from male rats. Among the mechanisms described are the roles of specific cell-signaling kinases and estrogen receptors in mediating the effects of E2 and progesterone on hippocampal neurons. In addition, dynamic changes of spine structures over time and sex differences in spine regulation are also considered. Finally, the chapter ends by discussing the importance of local hippocampal synthesis of E2 and androgens to hippocampal spine morphology and plasticity.

Learning belongs to a broad principle of biological design: adapt, match, learn, and forget. Organisms respond to changed demands by re-sculpting at all levels to prepare for what will most likely be next. Physical exercise thickens skin and strengthens muscle; mental practice combined with motor practice refines neural circuits and thereby skills. Circuits at early stages, e.g., V1, re-sculpt to match stable changes in bottom-up statistics. Circuits at later stages can, with extended training and practice, radically rewire. For example, an “object” area can re-wire to recognize and store written symbols and words – as it prunes back circuits that recognize and store objects. Because circuits occupy space in a skull of fixed volume, learning couples inescapably to forgetting. Efficient learning involves all the principles of neural design across all spatial and temporal scales: use chemistry; store only what is needed; store only for as long as needed; store and retrieve information without adding wire. Since learning requires practice, efficient design requires a teaching signal to tell the organism what behaviour to repeat. This is the dopamine reward signal that serves as a final common pathway for many learning systems across the whole brain. A similar circuit operates in insects.

Neuroanatomy and dopamine systems explains how sensory signals ascend the central nervous system via a series of nuclei; axons detecting specific elements converge onto higher-order neurons that respond to particular stimulus features. Assemblies of feature-detection cells in the cerebral cortex detect complex stimuli such as faces. These cell assemblies project to motor nuclei of the dorsal and ventral striatum where they terminate on dendritic spines of efferent medium spiny neurons. Dopaminergic projections from ventral mesencephalic nuclei terminate on the same spines. Individual corticostriatal afferents contact relatively few medium spiny neurons and individual dopaminergic neurons contact a far larger number. Stimuli activate specific subsets of corticostriatal synapses. Synaptic activity that is closely followed by a rewarding stimulus, that produces a burst of action potentials in dopaminergic neurons, is modified so that those specific corticostriatal synapses acquire an increased ability to elicit approach and other responses in the future, i.e., incentive learning.