Biomedical subjects

Jeffrey G Tasker

Publications and source records attributed to Jeffrey G Tasker.

12 recordsLinked to original sources

PubMed2006

Minireview: rapid glucocorticoid signaling via membrane-associated receptors.

Glucocorticoids are secreted into the systemic circulation from the adrenal cortex and initiate a broad range of actions throughout the organism that regulate the function of multiple organ systems, including the liver, muscle, the immune system, the pancreas, fat tissue, and the brain. Delayed glucocorticoid effects are mediated by classical steroid mechanisms involving transcriptional regulation. Relatively rapid effects of glucocorticoids also occur that are incompatible with genomic regulation and invoke a noncanonical mode of steroid action. Studies conducted in several labs and on different species suggest that the rapid effects of glucocorticoids are mediated by the activation of one or more membrane-associated receptors. Here, we provide a brief review focused on multiple lines of evidence suggesting that rapid glucocorticoid actions are triggered by, or at least dependent on, membrane-associated G protein-coupled receptors and activation of downstream signaling cascades. We also discuss the possibility that membrane-initiated actions of glucocorticoids may provide an additional mechanism for the regulation of gene transcription.

Animals↗

PubMed2006

Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release.

The hypothalamic paraventricular nucleus (PVN) integrates preautonomic and neuroendocrine control of energy homeostasis, fluid balance, and the stress response. We recently demonstrated that glucocorticoids act via a membrane receptor to rapidly cause endocannabinoid-mediated suppression of synaptic excitation in PVN neurosecretory neurons. Leptin, a major signal of nutritional state, suppresses CB(1) cannabinoid receptor-dependent hyperphagia (increased appetite) in fasting animals by reducing hypothalamic levels of endocannabinoids. Here we show that glucocorticoids stimulate endocannabinoid biosynthesis and release via a Galpha(s)-cAMP-protein kinase A-dependent mechanism and that leptin blocks glucocorticoid-induced endocannabinoid biosynthesis and suppression of excitation in the PVN via a phosphodiesterase-3B-mediated reduction in intracellular cAMP levels. We demonstrate this rapid hormonal interaction in both PVN magnocellular and parvocellular neurosecretory cells. Leptin blockade of the glucocorticoid-induced, endocannabinoid-mediated suppression of excitation was absent in leptin receptor-deficient obese Zucker rats. Our findings reveal a novel hormonal crosstalk that rapidly modulates synaptic excitation via endocannabinoid release in the hypothalamus and that provides a nutritional state-sensitive mechanism to integrate the neuroendocrine regulation of energy homeostasis, fluid balance, and the stress response.

Animals↗

PubMed2006

Rapid glucocorticoid actions in the hypothalamus as a mechanism of homeostatic integration.

The hypothalamic paraventricular nucleus (PVN) is a major integrative site for the control of homeostasis, including energy balance, through coordinated regulation of neuroendocrine and autonomic outputs. However, cross-talk regulation of PVN neuroendocrine and preautonomic systems is poorly understood. The stress response invokes the coordinated control of motor, hormonal, and vegetative systems to establish homeostasis after an environmental perturbation. Elevated stress levels of circulating glucocorticoids give rise to multiple, complex physiological effects. The complexity of the glucocorticoid actions is caused by the wide range of glucocorticoid target tissues and to the broad time scale over which the actions occur. Recent studies have revealed rapid glucocorticoid actions in the hypothalamus that may provide an integrative signal linking stress with the regulation of energy and fluid homeostasis. Glucocorticoids inhibit PVN and supraoptic nucleus neurons by stimulating a rapid synthesis and retrograde release of endocannabinoids, which suppress synaptic excitation through presynaptic CB1 receptor activation. The glucocorticoid-induced endocannabinoid synthesis is mediated apparently by a novel membrane-associated glucocorticoid receptor found in multiple subpopulations of hypothalamic neuroendocrine cells. It may, therefore, represent a mechanism for rapid glucocorticoid control of activity among different neuroendocrine systems to coordinate a global response to stress. In support of this, leptin, a circulating adipose signal that regulates food intake and energy expenditure through central actions, blocks the glucocorticoid-mediated endocannabinoid release in the PVN. This represents a means by which the regulation of stress and feeding may interface in the PVN, thus providing a possible mechanism for the integration of multiple homeostatic functions.

Animals↗

PubMed2006

Intranuclear coupling of hypothalamic magnocellular nuclei by glutamate synaptic circuits.

Magnocellular neurons of the supraoptic nucleus (SON) and paraventricular nucleus (PVN) display bursting activity that is synchronized under certain conditions. They receive excitatory synaptic inputs from intrahypothalamic glutamate circuits, some of which are activated by norepinephrine. Ascending noradrenergic afferents and intrahypothalamic glutamate circuits may be responsible for the generation of synchronous bursting among oxytocin neurons and/or asynchronous bursting among vasopressin neurons located in the bilateral supraoptic and paraventricular nuclei. Here, we tested whether magnocellular neurons of the PVN receive excitatory synaptic input from the contralateral PVN and the region of the retrochiasmatic SON (SONrx) via norepinephrine-sensitive internuclear glutamate circuits. Whole cell patch-clamp recordings were performed in PVN magnocellular neurons in coronal hypothalamic slices from male rats, and the ipsilateral SONrx region and contralateral PVN were stimulated using electrical and chemical stimulation. Electrical and glutamate microdrop stimulation of the ipsilateral SONrx region or contralateral PVN elicited excitatory postsynaptic potentials/currents (EPSP/Cs) in PVN magnocellular neurons mediated by glutamate release, revealing internuclear glutamatergic circuits. Microdrop application of norepinephrine also elicited EPSP/Cs, suggesting that these circuits could be activated by activation of noradrenergic receptors. Repetitive electrical stimulation and drop application of norepinephrine, in some cases, elicited bursts of action potentials. Our data reveal glutamatergic synaptic circuits that interconnect the magnocellular nuclei and that can be activated by norepinephrine. These internuclear glutamatergic circuits may provide the functional architecture to support burst generation and/or burst synchronization in hypothalamic magnocellular neurons under conditions of activation.

Action Potentials↗

PubMed2005

Activity-dependent release and actions of endocannabinoids in the rat hypothalamic supraoptic nucleus.

Exogenous cannabinoids have been shown to significantly alter neuroendocrine output, presaging the emergence of endogenous cannabinoids as important signalling molecules in the neuroendocrine control of homeostatic and reproductive functions, including the stress response, energy metabolism and gonadal regulation. We showed recently that magnocellular and parvocellular neuroendocrine cells of the hypothalamic paraventricular nucleus and supraoptic nucleus (SON) respond to glucocorticoids by releasing endocannabinoids as retrograde messengers to modulate the synaptic release of glutamate. Here we show directly for the first time that both of the main endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), are released in an activity-dependent fashion from the soma/dendrites of SON magnocellular neurones and suppress synaptic glutamate release and postsynaptic spiking. Cannabinoid reuptake blockade increases activity-dependent endocannabinoid levels in the region of the SON, and results in the inhibition of synaptically driven spiking activity in magnocellular neurones. Together, these findings demonstrate an activity-dependent release of AEA and 2-AG that leads to the suppression of glutamate release and that is capable of shaping spiking activity in magnocellular neurones. This activity-dependent regulation of excitatory synaptic input by endocannabinoids may play a role in determining spiking patterns characteristic of magnocellular neurones under stimulated conditions.

Animals↗

PubMed2005

Rapid glucocorticoid-mediated endocannabinoid release and opposing regulation of glutamate and gamma-aminobutyric acid inputs to hypothalamic magnocellular neurons.

Glucocorticoids secreted in response to stress activation of the hypothalamic-pituitary-adrenal axis feed back onto the brain to rapidly suppress neuroendocrine activation, including oxytocin and vasopressin secretion. Here we show using whole-cell patch clamp recordings that glucocorticoids elicit a rapid, opposing action on synaptic glutamate and gamma-aminobutyric acid (GABA) release onto magnocellular neurons of the hypothalamic supraoptic nucleus and paraventricular nucleus, suppressing glutamate release and facilitating GABA release by activating a putative membrane receptor. The glucocorticoid effect on both glutamate and GABA release was blocked by inhibiting postsynaptic G protein activity, suggesting a dependence on postsynaptic G protein signaling and the involvement of a retrograde messenger. Biochemical analysis of hypothalamic slices treated with dexamethasone revealed a glucocorticoid-induced rapid increase in the levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The glucocorticoid suppression of glutamate release was blocked by the type I cannabinoid receptor cannabinoid receptor antagonist, AM251, and was mimicked and occluded by AEA and 2-AG, suggesting it was mediated by retrograde endocannabinoid release. The glucocorticoid facilitation of GABA release was also blocked by AM251 but was not mimicked by AEA, 2-AG, or a synthetic cannabinoid, WIN 55,212-2, nor was it blocked by vanilloid or ionotropic glutamate receptor antagonists, suggesting that it was mediated by a retrograde messenger acting at an AM251-sensitive, noncannabinoid/nonvanilloid receptor at presynaptic GABA terminals. The combined, opposing actions of glucocorticoids mediate a rapid inhibition of the magnocellular neuroendocrine cells, which in turn should mediate rapid feedback inhibition of the secretion of oxytocin and vasopressin by glucocorticoids during stress activation of the hypothalamic-pituitary-adrenal axis.

Animals↗

PubMed2004

Dehydration-induced synaptic plasticity in magnocellular neurons of the hypothalamic supraoptic nucleus.

Norepinephrine plays a critical role in the regulation of hypothalamic neuroendocrine function, in large part through modulation of synaptic glutamate and gamma-aminobutyric acid (GABA) release. Hypothalamic magnocellular neuroendocrine cells undergo dramatic changes in synaptic organization under conditions of increased hormone release, including increased numbers of glutamatergic, GABAergic and noradrenergic synapses. We studied the functional plasticity of magnocellular neurons of the rat supraoptic nucleus induced by chronic dehydration using whole-cell recordings in hypothalamic slices. Dehydrated rats showed increases in glutamate and GABA release onto magnocellular neurons, as evidenced by an increase in the frequency of spontaneous excitatory (29%) and inhibitory (33%) postsynaptic currents. The change in glutamate release was likely due to increased numbers of release sites because paired-pulse facilitation analysis did not reveal a change in the probability of transmitter release. In untreated rats, norepinephrine facilitates glutamate release and attenuates GABA release onto magnocellular neurons. Dehydration resulted in a marked enhancement of norepinephrine's actions, doubling both the norepinephrine-induced increase in glutamate release and decrease in GABA release. The norepinephrine dose-response curve was shifted to the left with dehydration, revealing an increase in norepinephrine sensitivity. Thus, dehydration leads to an increase in glutamate and GABA release onto supraoptic magnocellular neurons as well as a marked enhancement of the facilitatory effect of norepinephrine on glutamate release and inhibitory effect on GABA release. This synaptic plasticity would be expected to increase the excitability of the magnocellular neurons and support the enhanced bursting capacity and facilitated hormone secretion observed in vivo with chronic dehydration.

Animals↗

PubMed2003

Increased tonic activation of presynaptic metabotropic glutamate receptors in the rat supraoptic nucleus following chronic dehydration.

Chronic dehydration induces structural changes in the hypothalamic supraoptic nucleus (SON), including increased glutamate synapses and retraction of astroglial processes. We performed whole-cell recordings in acute hypothalamic slices to determine whether these changes increase tonic activation of presynaptic metabotropic glutamate receptors (mGluRs) by increasing ambient glutamate in the SON. Activation of presynaptic group III mGluRs caused a decrease in the frequency of miniature excitatory postsynaptic currents (mEPSCs) in SON neurones that was significantly attenuated in slices from dehydrated rats (-27.8 %) compared with untreated rats (-41.7 %), suggesting a higher basal occupancy of mGluRs by ambient glutamate during dehydration. Blocking group III mGluRs caused an increase in the frequency of mEPSCs that was significantly higher in slices from dehydrated rats (+42.8 %) than untreated rats (+31.4 %), suggesting greater tonic activation of presynaptic mGluRs by ambient glutamate during dehydration. Increasing ambient glutamate levels by inhibiting astrocyte glutamate uptake resulted in a decrease in mEPSC frequency due to increased activation of presynaptic mGluRs. This was attenuated in slices from dehydrated rats (-35.4 %) compared with slices from untreated rats (-48.8 %), suggesting diminished astrocytic glutamate uptake during dehydration. Immunochemical analyses revealed a robust expression of the GLT-1 transporter protein in the SON, which was diminished in SON punches from dehydrated rats compared with untreated controls. Thus, dehydration leads to increased tonic activation of presynaptic mGluRs on glutamate terminals, consistent with a decrease in glutamate buffering capacity. The resulting reduction in glutamate release probability may compensate for the increase in glutamate release sites that occurs during dehydration.

Animals↗

PubMed2003

Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism.

Glucocorticoid negative feedback in the brain controls stress, feeding, and neural-immune interactions by regulating the hypothalamic-pituitary-adrenal axis, but the mechanisms of inhibition of hypothalamic neurosecretory cells have never been elucidated. Using whole-cell patch-clamp recordings in an acute hypothalamic slice preparation, we demonstrate a rapid suppression of excitatory glutamatergic synaptic inputs to parvocellular neurosecretory neurons of the hypothalamic paraventricular nucleus (PVN) by the glucocorticoids dexamethasone and corticosterone. The effect was maintained with dexamethasone conjugated to bovine serum albumin and was not seen with direct intracellular glucocorticoid perfusion via the patch pipette, suggesting actions at a membrane receptor. The presynaptic inhibition of glutamate release by glucocorticoids was blocked by postsynaptic inhibition of G-protein activity with intracellular GDP-beta-S application, implicating a postsynaptic G-protein-coupled receptor and the release of a retrograde messenger. The glucocorticoid effect was not blocked by the nitric oxide synthesis antagonist N(G)-nitro-L-arginine methyl ester hydrochloride or by hemoglobin but was blocked completely by the CB1 cannabinoid receptor antagonists AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] and AM281 [1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide] and mimicked and occluded by the cannabinoid receptor agonist WIN55,212-2 [(beta)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate], indicating that it was mediated by retrograde endocannabinoid release. Several peptidergic subtypes of parvocellular neuron, identified by single-cell reverse transcripton-PCR analysis, were subject to rapid inhibitory glucocorticoid regulation, including corticotropin-releasing hormone-, thyrotropin-releasing hormone-, vasopressin-, and oxytocin-expressing neurons. Therefore, our findings reveal a mechanism of rapid glucocorticoid feedback inhibition of hypothalamic hormone secretion via endocannabinoid release in the PVN and provide a link between the actions of glucocorticoids and cannabinoids in the hypothalamus that regulate stress and energy homeostasis.

Animals↗

PubMed2002

Functional synaptic plasticity in hypothalamic magnocellular neurons.

The hypothalamic-neurohypophysial system undergoes dramatic morphological plasticity in response to physiological activation during parturition/lactation and dehydration, including somatic swelling, decreased glial coverage and increased synaptic innervation of the magnocellular neuroendocrine cells. Recent in-vitro electrophysiological studies in hypothalamic slices have demonstrated that coordinate changes in the synaptic physiology of the magnocellular neurons also occur under these conditions. Thus, the synaptic release of glutamate and GABA onto magnocellular neurons is increased during lactation and with chronic dehydration, and changes in postsynaptic glutamate and GABAA receptor expression lead to alterations of the functional properties of the glutamate and GABAA receptor channels. The presynaptic noradrenergic facilitation of glutamate release and inhibition of GABA release is also markedly enhanced following chronic dehydration. Additionally, both parturition and chronic dehydration are accompanied by an increase in the tonic activation of presynaptic metabotropic glutamate receptors due to the higher ambient glutamate concentration caused by decreased glial coverage and the resultant reduction in glutamate reuptake. Together, these electrophysiological studies reveal profound functional plasticity in the synaptic physiology of magnocellular neurons at parturition and following dehydration. The plastic changes support an increase in the excitability of magnocellular neuroendocrine cells by increasing glutamate inputs, decreasing GABA inputs, enhancing excitatory noradrenergic modulation, and reducing synaptic glutamatergic noise.

Animals↗

PubMed2002

Local circuit regulation of paraventricular nucleus stress integration: glutamate-GABA connections.

Limbic neurocircuits play a central role in regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Limbic influences on adrenocortical hormone secretion are mediated by transynaptic activation or inhibition of hypophysiotrophic neurons in the medial parvocellular paraventricular nucleus (PVN). Projections from the ventral subiculum, prefrontal cortex, medial amygdala, lateral septum, paraventricular thalamus and suprachiasmatic nucleus (SN) terminate in the immediate surround of the PVN, an area heavily populated by GABAergic interneurons. As such, these regions are positioned to modulate paraventricular output via excitation or inhibition of interneuronal projections into the PVN. In addition, the same limbic and diencephalic regions have projections to local PVN-projecting hypothalamic and basal telencephalic nuclei, including the dorsomedial and medial preoptic nuclei and the bed nucleus of the stria terminalis. These regions are involved in both inhibitory and excitatory regulation of the stress axis, indicating that they contain heterogeneous neuronal populations whose relative impact on the PVN is determined by the nature of afferent stimuli. Thus, limbic modulation of the pituitary-adrenocortical system appears to be a multisynaptic process integrated at the level of local PVN-projecting neurocircuits. Local circuits are likely the primary integrators of anticipatory stress responses, and may indeed be the focus of HPA dysfunction seen with aging or affective disease.

Animals↗

PubMed2002

Role of the paraventricular nucleus microenvironment in stress integration.

The hypothalamic paraventricular nucleus is the primary controller of hypothalamo-pituitary-adrenocortical glucocorticoid release. In performing this function, the paraventricular nucleus summates a variety of information from both external and internal sources into a net secretory signal to the adrenal cortex. In this review, we will provide an overview of neuronal circuit mechanisms governing activation and inhibition of hypophysiotrophic neurons, highlight recent developments in our understanding of nonsynaptic mechanisms regulating paraventricular cellular activity, including dendritic neuropeptide release, direct steroid feedback, cytokine cascades and gaseous neurotransmission, and illustrate the capacity for hypophysiotrophic, neurohypophysial and preautonomic paraventricular effector pathways to work together in control of glucocorticoid release. The current state of knowledge reveals the paraventricular nucleus to be a dynamic entity, capable of integrating diverse classes of signals into control of adrenocortical activation.

Animals↗