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      Synaptic regulation of the hypothalamic–pituitary–adrenal axis and its modulation by glucocorticoids and stress

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          Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis has been implicated in a range of affective and stress-related disorders. The regulatory systems that control HPA activity are subject to modulation by environmental influences, and stressful life events or circumstances can promote subsequent HPA dysregulation. The brain is a major regulator of the HPA axis, and stress-induced plasticity of the neural circuitry involved in HPA regulation might constitute an etiological link between stress and the development of HPA dysregulation. This review focuses on the synaptic regulation of neuroendocrine corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus, which are the cells through which the brain predominantly exerts its influence on the HPA axis. CRH neuronal activity is largely orchestrated by three neurotransmitters: GABA, glutamate, and norepinephrine. We discuss our current understanding of the neural circuitry through which these neurotransmitters regulate CRH cell activity, as well as the plastic changes in this circuitry induced by acute and chronic stress and the resultant changes in HPA function.

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          Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress.

          Variations in maternal care affect the development of individual differences in neuroendocrine responses to stress in rats. As adults, the offspring of mothers that exhibited more licking and grooming of pups during the first 10 days of life showed reduced plasma adrenocorticotropic hormone and corticosterone responses to acute stress, increased hippocampal glucocorticoid receptor messenger RNA expression, enhanced glucocorticoid feedback sensitivity, and decreased levels of hypothalamic corticotropin-releasing hormone messenger RNA. Each measure was significantly correlated with the frequency of maternal licking and grooming (all r's > -0.6). These findings suggest that maternal behavior serves to "program" hypothalamic-pituitary-adrenal responses to stress in the offspring.
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              Role of endogenous cannabinoids in synaptic signaling.

              Research of cannabinoid actions was boosted in the 1990s by remarkable discoveries including identification of endogenous compounds with cannabimimetic activity (endocannabinoids) and the cloning of their molecular targets, the CB1 and CB2 receptors. Although the existence of an endogenous cannabinoid signaling system has been established for a decade, its physiological roles have just begun to unfold. In addition, the behavioral effects of exogenous cannabinoids such as delta-9-tetrahydrocannabinol, the major active compound of hashish and marijuana, await explanation at the cellular and network levels. Recent physiological, pharmacological, and high-resolution anatomical studies provided evidence that the major physiological effect of cannabinoids is the regulation of neurotransmitter release via activation of presynaptic CB1 receptors located on distinct types of axon terminals throughout the brain. Subsequent discoveries shed light on the functional consequences of this localization by demonstrating the involvement of endocannabinoids in retrograde signaling at GABAergic and glutamatergic synapses. In this review, we aim to synthesize recent progress in our understanding of the physiological roles of endocannabinoids in the brain. First, the synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation. The fine-grain anatomical distribution of the neuronal cannabinoid receptor CB1 is described in most brain areas, emphasizing its general presynaptic localization and role in controlling neurotransmitter release. Finally, the possible functions of endocannabinoids as retrograde synaptic signal molecules are discussed in relation to synaptic plasticity and network activity patterns.

                Author and article information

                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Research Foundation
                11 May 2012
                : 6
                1Neuroscience Program, Tulane University, New Orleans, LA, USA
                2Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, USA
                Author notes

                Edited by: Harmen J. Krugers, Universiteit van Amsterdam, Netherlands

                Reviewed by: Yang Dan, University of California Berkeley, USA Corette Wierenga, Utrecht University, Netherlands

                *Correspondence: Jeffrey G. Tasker, Department of Cell and Molecular Biology, Tulane University, 2000 Percival Stern Hall, New Orleans, LA 70118-5221, USA. e-mail: tasker@ 123456tulane.edu
                Copyright © Levy and Tasker.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

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                Figures: 2, Tables: 0, Equations: 0, References: 132, Pages: 13, Words: 0
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