This brief review summarizes 60 years of conceptual advances that have demonstrated a role for active changes in neuronal connectivity as a controller of behavior and behavioral change. Seminal ...studies in the first phase of the six‐decade span of this review firmly established the cellular basis of behavior – a concept that we take for granted now, but which was an open question at the time. Hebbian plasticity, including long‐term potentiation and long‐term depression, was then discovered as being important for local circuit refinement in the context of memory formation and behavioral change and stabilization in the mammalian central nervous system. Direct demonstration of plasticity of neuronal circuit function in vivo, for example, hippocampal neurons forming place cell firing patterns, extended this concept. However, additional neurophysiologic and computational studies demonstrated that circuit development and stabilization additionally relies on non‐Hebbian, homoeostatic, forms of plasticity, such as synaptic scaling and control of membrane intrinsic properties. Activity‐dependent neurodevelopment was found to be associated with cell‐wide adjustments in post‐synaptic receptor density, and found to occur in conjunction with synaptic pruning. Pioneering cellular neurophysiologic studies demonstrated the critical roles of transmembrane signal transduction, NMDA receptor regulation, regulation of neural membrane biophysical properties, and back‐propagating action potential in critical time‐dependent coincidence detection in behavior‐modifying circuits. Concerning the molecular mechanisms underlying these processes, regulation of gene transcription was found to serve as a bridge between experience and behavioral change, closing the ‘nature versus nurture’ divide. Both active DNA (de)methylation and regulation of chromatin structure have been validated as crucial regulators of gene transcription during learning. The discovery of protein synthesis dependence on the acquisition of behavioral change was an influential discovery in the neurochemistry of behavioral modification. Higher order cognitive functions such as decision making and spatial and language learning were also discovered to hinge on neural plasticity mechanisms. The role of disruption of these processes in intellectual disabilities, memory disorders, and drug addiction has recently been clarified based on modern genetic techniques, including in the human.
The area of neural plasticity and behavior has seen tremendous advances over the last six decades, with many of those advances being specifically in the neurochemistry domain. This review provides an overview of the progress in the area of neuroplasticity and behavior over the life‐span of the Journal of Neurochemistry. To organize the broad literature base, the review collates progress into fifteen broad categories identified as ‘conceptual advances’, as viewed by the author. The fifteen areas are delineated in the figure above.
This article is part of the 60th Anniversary special issue.
The area of neural plasticity and behavior has seen tremendous advances over the last six decades, with many of those advances being specifically in the neurochemistry domain. This review provides an overview of the progress in the area of neuroplasticity and behavior over the life‐span of the Journal of Neurochemistry. To organize the broad literature base, the review collates progress into fifteen broad categories identified as ‘conceptual advances’, as viewed by the author. The fifteen areas are delineated in the figure above.
This article is part of the 60th Anniversary special issue.
Epigenetic Mechanisms in Cognition Day, Jeremy J.; Sweatt, J. David
Neuron (Cambridge, Mass.),
06/2011, Letnik:
70, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Although the critical role for epigenetic mechanisms in development and cell differentiation has long been appreciated, recent evidence reveals that these mechanisms are also employed in postmitotic ...neurons as a means of consolidating and stabilizing cognitive-behavioral memories. In this review, we discuss evidence for an “epigenetic code” in the central nervous system that mediates synaptic plasticity, learning, and memory. We consider how specific epigenetic changes are regulated and may interact with each other during memory formation and how these changes manifest functionally at the cellular and circuit levels. We also describe a central role for mitogen-activated protein kinases in controlling chromatin signaling in plasticity and memory. Finally, we consider how aberrant epigenetic modifications may lead to cognitive disorders that affect learning and memory, and we review the therapeutic potential of epigenetic treatments for the amelioration of these conditions.
Over the past 25 years, the broad field of epigenetics and, over the past decade in particular, the emerging field of neuroepigenetics have begun to have tremendous impact in the areas of learned ...behavior, neurotoxicology, CNS development, cognition, addiction, and psychopathology. However, epigenetics is such a new field that in most of these areas the impact is more in the category of fascinating implications as opposed to established facts. In this brief commentary, I will attempt to address and delineate some of the open questions and areas of opportunity that discoveries in epigenetics are providing to the discipline of neuroscience.
The last decades have witnessed a growing appreciation of the contribution of epigenetic mechanisms to almost all areas of neuroscience. David Sweatt reviews recent advances in this rapidly expanding field of neuroepigenetics and highlights open questions and opportunities for the future.
Experiences during early development profoundly affect development of the central nervous system (CNS) to impart either risk for or resilience to later psychopathology. Work in the developmental ...neuroscience field is providing compelling data that epigenetic marking of the genome may underlie aspects of this process. Experiments in rodents continue to show that experiences during sensitive periods of development influence DNA methylation patterns of several genes. These experience‐induced DNA methylation patterns represent stable epigenetic modifications that alter gene transcription throughout the lifespan and promote specific behavioral outcomes. We discuss the relevance of these findings to humans, and also briefly discuss these findings in the broader contexts of cognition and psychiatric disorder. We conclude by discussing the implications of these observations for future research.
Dynamic changes in 5-methylcytosine (5mC) have been implicated in the regulation of gene expression critical for consolidation of memory. However, little is known about how these changes in 5mC are ...regulated in the adult brain. The enzyme methylcytosine dioxygenase TET1 (TET1) has been shown to promote active DNA demethylation in the nervous system. Therefore, we took a viral-mediated approach to overexpress the protein in the hippocampus and examine its potential involvement in memory formation. We found that Tet1 is a neuronal activity-regulated gene and that its overexpression leads to global changes in modified cytosine levels. Furthermore, expression of TET1 or a catalytically inactive mutant (TET1m) resulted in the upregulation of several neuronal memory-associated genes and impaired contextual fear memory. In summary, we show that neuronal Tet1 regulates DNA methylation levels and that its expression, independent of its catalytic activity, regulates the expression of CNS activity-dependent genes and memory formation.
•Transcription of the Tet1 gene is regulated by neuronal activity•Tet1 expression causes global changes in cytosine methylation and hydroxymethylation•Tet1 positively regulates the expression of memory-related genes•Tet1 overexpression impairs memory formation independent of its catalytic activity
Kaas et al. explore the role of the 5-methylcytosine dioxygenase Tet1 in cognition using a viral-mediated approach to overexpress the enzyme in the hippocampus and demonstrate that Tet1 regulates 5mC hydroxylation, active DNA demethylation, gene transcription, and memory formation.
This mini-review describes recent discoveries demonstrating that experience can drive the production of epigenetic marks in the adult nervous system and that the experience-dependent regulation of ...epigenetic molecular mechanisms in the mature central nervous system participates in the control of gene transcription underlying the formation of long-term memories. In the mammalian experimental systems investigated thus far, epigenetic mechanisms have been linked to associative fear conditioning, extinction of learned fear, and hippocampus-dependent spatial memory formation. Intriguingly, in one experimental system epigenetic marks at the level of chromatin structure (histone acetylation) have been linked to the recovery of memories that had seemed to be “lost” (i.e., not available for recollection). Environmental enrichment has long been known to have positive effects on memory capacity, and recent studies have suggested that these effects are at least partly due to the recruitment of epigenetic mechanisms by environmental enrichment. Finally, an uncoupling of signal transduction pathways from the regulation of epigenetic mechanisms in the nucleus has been implicated in the closure of developmental critical periods. Taken together, these eclectic findings suggest a new perspective on experience-dependent dynamic regulation of epigenetic mechanisms in the adult nervous system and their relevance to biological psychiatry.
This review highlights five areas of recent discovery concerning the role of extracellular-signal regulated kinases (ERKs) in the hippocampus. First, ERKs have recently been directly implicated in ...human learning through studies of a human mental retardation syndrome. Second, new models are being formulated for how ERKs contribute to molecular information processing in dendrites. Third, a role of ERKs in stabilizing structural changes in dendritic spines has been defined. Fourth, a crucial role for ERKs in regulating local dendritic protein synthesis is emerging. Fifth, the importance of ERK interactions with scaffolding and structural proteins at the synapse is increasingly apparent. These topics are discussed within the context of an emerging role for ERKs in a wide variety of forms of synaptic plasticity and memory formation in the behaving animal.
The mitogen‐activated protein kinase (MAP kinase, MAPK) cascade, as the name implies, was originally discovered as a critical regulator of cell division and differentiation. As further details of ...this signaling cascade were worked out, it became clear that the MAPK cascade is in fact a prototype for a family of signaling cascades that share the motif of three serially linked kinases regulating each other by sequential phosphorylation. Thus, a revised nomenclature arose that uses the term MAPK to refer to the entire superfamily of signaling cascades (comprising the erks, the JNKs and the p38 stress activated protein kinases), and specifies the prototype MAPK as the extracellular signal‐regulated kinase (erk). The two erk MAPK isoforms, p44 MAPK and p42 MAPK, are referred to as erk1 and erk2, respectively.The erks are abundantly expressed in neurons in the mature central nervous system, raising the question of why the prototype molecular regulators of cell division and differentiation are present in these non‐dividing, terminally differentiated neurons. This review will describe the beginnings of an answer to this question. Interestingly, the general model has begun to emerge that the erk signaling system has been co‐opted in mature neurons to function in synaptic plasticity and memory. Moreover, recent insights have led to the intriguing prospect that these molecules serve as biochemical signal integrators and molecular coincidence detectors for coordinating responses to extracellular signals in neurons. In this review I will first outline the essential components of this signal transduction cascade, and briefly describe recent results implicating the erks in mammalian synaptic plasticity and learning. I will then proceed to outline recent results implicating the erks as molecular signal integrators and, potentially, coincidence detectors. Finally, I will speculate on what the critical downstream effectors of the erks are in neurons, and how they might provide a readout of the integrated signal.
Hebbian plasticity, including long‐term potentiation and long‐term depression, has long been regarded as important for local circuit refinement in the context of memory formation and stabilization. ...However, circuit development and stabilization additionally relies on non‐Hebbian, homeostatic, forms of plasticity such as synaptic scaling. Synaptic scaling is induced by chronic increases or decreases in neuronal activity. Synaptic scaling is associated with cell‐wide adjustments in postsynaptic receptor density, and can occur in a multiplicative manner resulting in preservation of relative synaptic strengths across the entire neuron's population of synapses. Both active DNA methylation and demethylation have been validated as crucial regulators of gene transcription during learning, and synaptic scaling is known to be transcriptionally dependent. However, it has been unclear whether homeostatic forms of plasticity such as synaptic scaling are regulated via epigenetic mechanisms. This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory‐associated mechanisms that were previously largely considered separately: DNA methylation, homeostatic plasticity, and glutamate receptor trafficking.
This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory‐associated mechanisms that were previously considered separately: glutamate receptor trafficking, DNA methylation, and homeostatic plasticity.
This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory‐associated mechanisms that were previously considered separately: glutamate receptor trafficking, DNA methylation, and homeostatic plasticity.
One of the most exciting discoveries in the learning and memory field in the past two decades is the observation that active regulation of gene expression is necessary for experience to trigger ...lasting functional and behavioral change, in a wide variety of species, including humans. Thus, as opposed to the traditional view of 'nature' (genes) being separate from 'nurture' (environment and experience), it is now clear that experience actively drives alterations in central nervous system (CNS) gene expression in an ongoing fashion, and that the resulting transcriptional changes are necessary for experience to trigger altered long-term behavior. In parallel over the past decade, epigenetic mechanisms, including regulation of chromatin structure and DNA methylation, have been shown to be potent regulators of gene transcription in the CNS. In this review, we describe data supporting the hypothesis that epigenetic molecular mechanisms, especially DNA methylation and demethylation, drive long-term behavioral change through active regulation of gene transcription in the CNS. Specifically, we propose that epigenetic molecular mechanisms underlie the formation and stabilization of context- and cue-triggered fear conditioning based in the hippocampus and amygdala, a conclusion reached in a wide variety of studies using laboratory animals. Given the relevance of cued and contextual fear conditioning to post-traumatic stress, by extension we propose that these mechanisms may contribute to post-traumatic stress disorder (PTSD) in humans. Moreover, we speculate that epigenetically based pharmacotherapy may provide a new avenue of drug treatment for PTSD-related cognitive and behavioral function.
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