Jeffrey G Tasker
Tulane University Of Louisiana
Project start date: 2003-06-01
Project end date: 2013-12-31
Sponsored Links Excellgen http://Excellgen.com
Acute Corticosteriod Actions In The Hypothalamus
Jeffrey G Tasker, Professor
Tulane University Of Louisiana 6823 St Charles Ave New Orleans, La 70118
Grant 5R01MH066958-04 from National Institute Of Mental Health IRG: ZRG1
Abstract: Stress is associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis and increased levels of circulating adrenal corticosteroids. Glucocorticoids feed back onto the hypothalamus to inhibit not only corticotropin releasing hormone (CRH) secretion and HPA activation, but also many other hypothalamic neuroendocrine systems. The negative feedback regulation by glucocorticoids occurs in two stages an acute inhibition of the release of CRH, and a slower down-regulation of CRH and vasopressin synthesis in neurons of the hypothalamic paraventricular nucleus (PVN). To date, it is not known where in the brain glucocorticoids exert their negative feedback regulation of hypothalamic neurosecretion, and what the cellular mechanisms of this feedback are. These questions have profound significance for the treatment of widespread affective disorders, including stress, depression, and eating disorders, that impact large numbers of people. The overall purpose of this proposal is to determine whether acute negative glucocorticoid regulation of PVN neuroendocrine systems occurs directly at the hormone-secreting neurons in the PVN, and to characterize the cellular mechanisms of this regulation. We have preliminary evidence for rapid inhibitory glucocorticoid effects in the PVN mediated by membrane receptor activation and the release of a retrograde endocannabinoid messenger that suppresses excitatory and facilitates inhibitory inputs to PVN neurons. Based on these findings, we propose to conduct whole-cell patch-clamp recordings in acute rat hypothalamic slices to test the following specific hypotheses 1. glucocorticoids inhibit PVN neurons directly by stimulating an endocannabinoid-mediated suppression of glutamate release and facilitation of GABA release; 2. glucocorticoids elicit retrograde endocannabinoid release from PVN neurons by activation of a postsynaptic G protein-coupled receptor and lipid messenger signaling cascade; 3. the endocannabinoid-mediated changes in glutamate and GABA release in the PVN are mediated by presynaptic, G protein- and protein kinase-dependent signaling mechanisms. These studies will reveal for the first time the site and physiological mechanisms of fast glucocorticoid actions in the hypothalamus. Fast glucocorticoid feedback in the hypothalamus plays a critical role in the organism s holistic response to stress, and understanding the mechanisms of glucocorticoid actions in the hypothalamus will provide important cellular targets for the treatment of HPA-related pathologies. Furthermore, the glucocorticoid-endocannabinoid link opens interesting possibilities for interactions between hypothalamic function and the cannabinoids.
Keywords: corticosteroid, glucocorticoid, hormone regulation /control mechanism, hypothalamus, neuron, paraventricular nucleus, G protein coupled receptor kinase, action potential, biological signal transduction, calcium, gamma aminobutyrate, glutamate, neuroendocrine system, neurotransmitter transport, protein kinase C, electrostimulus, polymerase chain reaction, voltage /patch clamp
Project start date: 2003-06-01
Project end date: 2009-04-30
5R01MH066958-04 (2006): $564776
5R01MH066958-03 (2005): $297000
5R01MH066958-02 (2004): $297000
5R01MH066958-06 (2010): $375932
Grants awarded to Jeffrey G Tasker
LOCAL SYNAPTIC INTERACTIONS AMONG HYPOTHALAMIC NEURONS
Jeffrey G Tasker, Professor
Tulane University Of Louisiana 6823 St Charles Ave New Orleans, La 70118
Grant 5R29NS031187-02 from National Institute Of Neurological Disorders And Stroke IRG: NLS
Abstract: Under conditions of increased hormone secretion (e.g., during reproductive functions), neurosecretory neurons in the hypothalamic paraventricular nucleus (PVN) develop characteristic patterns of electrical activity and neurohormone release. These patterns of activation are determined by the intrinsic electrical properties as well as by the synaptic organization of the hormone-secreting cells. Local synaptic circuits are crucial for the generation of patterned electrical activity, yet very little is known about the local synaptic regulation of neurosecretory neurons. The long-term objectives of this study are to characterize physiologically and anatomically the local synaptic organization of PVN magnocellular and parvocellular neurons, and to determine how local synaptic inputs regulate the electrical activity and hormonal/synaptic output of PVN neurons. The specific aims of this proposal are 1) to characterize pharmacologically and map topographically local synaptic inputs to PVN neurons from cells outside the PVN, 2) to determine whether PVN magnocellular and parvocellular neurons are synaptically coupled and the transmitters or hormones which mediate these interactions, and 3) to identify anatomically cell populations of the PVN which receive local synaptic inputs. During the course of these experiments, we will determine the effects of local synaptic inputs on the electrical activity of identified PVN cells. Experiments will be performed in rat hypothalamic slices using intracellular, whole-cell patch-clamp and extracellular recordings of PVN cells. Cells will be identified provisionally as magnocellular or parvocellular by their intracellular electrical characteristics. Glutamate microapplication will be used to stimulate selectively local neurons for topographic mapping of intra- and extra-PVN regions containing cells which provide inhibitory and/or excitatory synaptic inputs to recorded PVN neurons. Conclusive demonstration of synaptic coupling between PVN cells and local interneurons (PVN and non-PVN) will be accomplished with paired recordings and cross-correlation of action potentials and synaptic activity. Specific antagonists will be applied to determine the transmitters and transmitter receptors which mediate these local synaptic interactions. The effect of activation of local synaptic inputs on the patterned activity of PVN cells (e.g., phasic firing of vasopressin cells) will be analyzed. All intracellular/patch-clamp-recorded cells will be intracellularly labeled and immunohistochemically identified with antibodies directed against general neurophysin (to distinguish between magnocellular and parvocellular neurons), oxytocin, vasopressin or corticotropin-releasing hormone. These combined electrophysiological- anatomical studies will elucidate the local synaptic organization of the hypothalamic PVN, and will provide physiological data on the regulation of PVN cell output by local synaptic inputs.
Keywords: neural transmission, neuroanatomy, paraventricular nucleus, synapse, action potential, calcium flux, corticotropin releasing factor, glutamate, neuropharmacology, neurophysin, neurotransmitter, neurotransmitter receptor, neurotransmitter transport, oxytocin, vasopressin, dye, immunocytochemistry, laboratory rat, patch clamp
Project start date: 1994-06-01
Project end date: 1999-05-31
5R29NS031187-02 (1995): $129972
1R29NS031187-01A1 (1994): $116280
5R29NS031187-05 (1998): $103313
5R29NS031187-04 (1997): $99456
GLUTAMATE MODULATION OF HYPOTHALAMIC NEURONS
Jeffrey G Tasker, Professor
Cell And Molecular Biologytulane University Of Louisiana
6823 St Charles Ave
new Orleans, La 70118
Grant 5R01NS034926-04 from National Institute Of Neurological Disorders And Stroke IRG: NLS
Abstract: The long-term goal of this study is to determine the role of glutamate modulation in the generation of patterned output by identified PVN neurons. Experiments will be performed in acute hypothalamic slices using a combination of electrophysiological, anatomical, and in situ hybridization methods. We will use whole-cell patch-camp recordings to monitor changes in resting, voltage-gated and synaptic currents in response to mGluR activation, and pharmacological/ionic manipulations will be performed to isolate the receptor subtypes, ionic currents and second messenger mechanisms involved. Recorded cells will be marked with an intracellular dye, and they will be identified using antisera specific for different hypothalamic neuropeptides and non-radioactive riboprobes to label specific mRNA. The specific bypotheses to be test are 1) mGluR activation enhances PVN cell excitability by reducing postsynaptic leak and voltage-gated k+ currents; 2) specific mGluR subtypes and 2nd messengers are responsible for the different mGluR actions at pre- and postsynaptic sites; 3) mGluRs play a role in the synaptic regulation of PVN neurons; 4) magnocellular and parvocellular neurons, and presynaptic neurons innervating them, express similar mGluR subtypes. The patterned electrical behaviors of hypothalamic neurons are likely to be under neuromodulatory control, but neuromodulation in the hypothalamus remains largely unexplored. These studies will provide basic information on the glutamate modulation of identified subpopulations of hypothalmic neurons. Assigning modulatory actions to glutamate to pre- and postsynaptic sites of specific hypothalamic subpopulations will enhance our understanding of the synaptic mechanisms that shape the electrical activity of neurons that control endocrine and autonomic function, and may provide the basis for future clinical pharmaceutical applications
Keywords: glutamate receptor, hypothalamus, neural transmission, neuron, paraventricular nucleus cell type, neurotransmitter, second messenger, synapse, voltage gated channel electrophysiology, immunocytochemistry, in situ hybridization, voltage /patch clamp
Project start date: 1997-04-01
Project end date: 2003-01-31
5R01NS034926-04 (2000): $177854
5R01NS034926-03 (1999): $168492
5R01NS034926-02 (1998): $158092
1R01NS034926-01A1 (1997): $219817
Acute Corticosteriod Actions In The Hypothalamus
Jeffrey G Tasker, Professor
Tulane University Of Louisiana 6823 St Charles Ave New Orleans, La 70118
Grant 1R01MH066958-01A1 from National Institute Of Mental Health IRG: ZRG1
Abstract: Stress is associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis and increased levels of circulating adrenal corticosteroids. Glucocorticoids feed back onto the hypothalamus to inhibit not only corticotropin releasing hormone (CRH) secretion and HPA activation, but also many other hypothalamic neuroendocrine systems. The negative feedback regulation by glucocorticoids occurs in two stages an acute inhibition of the release of CRH, and a slower down-regulation of CRH and vasopressin synthesis in neurons of the hypothalamic paraventricular nucleus (PVN). To date, it is not known where in the brain glucocorticoids exert their negative feedback regulation of hypothalamic neurosecretion, and what the cellular mechanisms of this feedback are. These questions have profound significance for the treatment of widespread affective disorders, including stress, depression, and eating disorders, that impact large numbers of people. The overall purpose of this proposal is to determine whether acute negative glucocorticoid regulation of PVN neuroendocrine systems occurs directly at the hormone-secreting neurons in the PVN, and to characterize the cellular mechanisms of this regulation. We have preliminary evidence for rapid inhibitory glucocorticoid effects in the PVN mediated by membrane receptor activation and the release of a retrograde endocannabinoid messenger that suppresses excitatory and facilitates inhibitory inputs to PVN neurons. Based on these findings, we propose to conduct whole-cell patch-clamp recordings in acute rat hypothalamic slices to test the following specific hypotheses 1. glucocorticoids inhibit PVN neurons directly by stimulating an endocannabinoid-mediated suppression of glutamate release and facilitation of GABA release; 2. glucocorticoids elicit retrograde endocannabinoid release from PVN neurons by activation of a postsynaptic G protein-coupled receptor and lipid messenger signaling cascade; 3. the endocannabinoid-mediated changes in glutamate and GABA release in the PVN are mediated by presynaptic, G protein- and protein kinase-dependent signaling mechanisms. These studies will reveal for the first time the site and physiological mechanisms of fast glucocorticoid actions in the hypothalamus. Fast glucocorticoid feedback in the hypothalamus plays a critical role in the organism s holistic response to stress, and understanding the mechanisms of glucocorticoid actions in the hypothalamus will provide important cellular targets for the treatment of HPA-related pathologies. Furthermore, the glucocorticoid-endocannabinoid link opens interesting possibilities for interactions between hypothalamic function and the cannabinoids.
Keywords: corticosteroid, glucocorticoid, hormone regulation /control mechanism, hypothalamus, neuron, paraventricular nucleus, G protein coupled receptor kinase, action potential, biological signal transduction, calcium, gamma aminobutyrate, glutamate, neuroendocrine system, neurotransmitter transport, protein kinase C, electrostimulus, polymerase chain reaction, voltage /patch clamp
Project start date: 2003-06-01
Project end date: 2007-05-31
1R01MH066958-01A1 (2003): $297000
GLUCOCORTICOID-ENDOCANNABINOID INTERACTIONS IN THE AMYGDALA
Jeffrey G Tasker, Professor
Tulane University Of Louisiana, 6823 St Charles Ave, New Orleans, La 70118
Grant 1R21MH090453-01 from National Institute Of Mental Health
Abstract: Post-traumatic stress disorder (PTSD) is triggered by a traumatic life event and is characterized by the recurrent retrieval of the traumatic memory in the form of context-induced flashbacks and recurrent nightmares. The amygdala is a critical brain structure involved in both the formation and the extinction of emotional memories. Glucocorticoids, steroid hormones secreted as part of the general stress response, and endocannabinoids, lipid molecules that bind to CB1 receptors in the brain, have been shown to be important for the consolidation and extinction of fear conditioning. Both glucocorticoids and endocannabinoids enhance fear memory formation and extinction via actions within the basolateral amygdaloid complex (BLA). Patients suffering from PTSD typically show low circulating levels of corticosteroids, particularly at the nadir of the diurnal cortisol secretory rhythm, and corticosteroid treatment causes improvement in subjective measures of PTSD symptoms. A recent study showed that the glucocorticoid facilitation of conditioned fear extinction is dependent on CB1 receptor activation in the BLA, linking the actions of glucocorticoids and endocannabinoids in the BLA in conditioned fear extinction. The current study is designed to determine the cellular mechanisms that link glucocorticoid and endocannabinoid effects on fear conditioning in the BLA. We will test the hypothesis that glucocorticoids trigger endocannabinoid synthesis and retrograde release at GABA synapses in the BLA, leading to the suppression of synaptic inhibitory input to BLA neurons. The specific aims of the proposal are 1) to test biochemically for a rapid glucocorticoid-induced increase in endocannabinoid synthesis in the BLA and CeA using a liquid chromatography-mass spectrometry approach; and 2) to determine electrophysiologically whether glucocorticoids induce a rapid suppression of GABA synaptic inputs to BLA neurons via activation of a membrane receptor and the retrograde release of endocannabinoids using whole-cell patch clamp recordings in acute in vitro slices of amygdala. Pharmacological and genetic manipulations of glucocorticoid, mineralocorticoid and cannabinoid receptors and intracellular signaling pathways will be employed to characterize the novel molecular interactions between glucocorticoids and endocannabinoids in the BLA. The importance of endocannabinoids and glucocorticoids in the BLA in the consolidation and extinction of fear conditioning, and the relevance of fear conditioning to memory processing in PTSD, suggests that the outcome of this study will provide important insight into, and possible targets for, pharmacological treatment of stress-related disorders such as PTSD. The proposed research on glucocorticoid-endocannabinoid interactions in the amygdala will provide critical insight into the basic biological mechanisms responsible for emotional memory formation and retention/extinction. The better understanding of emotional memory mechanisms gained from these studies will enhance our ability and improve the tools available to address increasingly prevalent and devastating mental illnesses brought on by stress and trauma, including posttraumatic stress disorder, anxiety disorders and phobias. The link between corticosteroids and endogenous cannabinoids is relevant not only to the basic biology of emotional memory formation, but also to the interaction between illicit drug use and anxiety disorders, as increased drug abuse in certain emotionally disturbed populations may be the result of compensation for a deficit in endogenous psychoactive chemicals involved in the generation of positive emotions
Keywords: 4-Aminobutanoic Acid; 4-Aminobutyric Acid; 5, 8, 11, 14-Eicosatetraenamide, N-(2-hydroxyethyl)-, (all-Z)-; 5, 8, 11, 14-eicosatetraenamide, N-(2-hydroxyethyl)-; 5, 8, 11, 14-eicosatetraenoylethanolamide; Acute; Address; Adrenal Cortex Hormones; Aeroseb-HC; Aldosterone Receptor; Aminalon; Aminalone; Amygdala; Amygdaloid Body; Amygdaloid Nucleus; Amygdaloid structure; Anxiety Disorders; Binding; Binding (Molecular Function); Biological; Biology; Brain; Butanoic acid, 4-amino-; CB1 Receptor; Cannabinoids, Endogenous; Cell Nucleus; Cells; Cetacort; Chemicals; Chemotherapy-Hormones/Steroids; Common Rat Strains; Compensation; Complex; Cort-Dome; Cortef; Cortenema; Corticoids; Corticosteroids; Cortisol; Cortispray; Cortril; Cues; Dermacort; Drug abuse; Drug usage; Drugs, Illicit; Eldecort; Emotional; Encephalon; Encephalons; Endocannabinoids; Endocrine Gland Secretion; Event; Extinction; Extinction (Psychology); Fear; Financial compensation; Fright; GABA; Generations; Genetic; Glucocorticoid Receptor; Glucocorticoids; Hormones; Hydrocortisone; Hydrocortone; Hypothalamic structure; Hypothalamus; Hytone; Illicit Drugs; In Vitro; Knock-out; Knockout; Knockout Mice; LC/MS; Life; Link; Lipids; MCR; MLR; Mammals, Mice; Mammals, Rats; Mammals, Rodents; Measures; Mediating; Membrane; Memory; Mental disorders; Mental health disorders; Mice; Mice, Knock-out; Mice, Knockout; Mineralocorticoid Receptor; Mineralocorticoids; Modeling; Molecular Interaction; Murine; Mus; N arachidonoyl 2 hydroxyethylamide; N-(2-hydroxyethyl)arachidonamide; NR3C2; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; Neurons; Neuroses, Post-Traumatic; Neuroses, Posttraumatic; Nightmare; Nuclear Receptor Subfamily 3 Group C Member 2; Nucleus; Null Mouse; Nutracort; Outcome Study; PTSD; Patients; Pharmacological Treatment; Phobias; Phobic Disorders; Phobic Neuroses; Phobic anxiety disorder; Population; Post-Traumatic Stress Disorders; Pregn-4-ene-3, 20-dione, 11, 17, 21-trihydroxy-, (11beta)-; Proctocort; Psychiatric Disease; Psychiatric Disorder; Rat; Rattus; Receptor Activation; Receptor Protein; Receptor, Cannabinoid, CB1; Recurrence; Recurrent; Research; Retrieval; Rodent; Rodentia; Rodentias; Role; Signal Pathway; Slice; Stress; Stress Disorders, Post-Traumatic; Stress Disorders, Posttraumatic; Structure; Study, Outcome; Symptoms; Synapses; Synaptic; Testing; Therapeutic Corticosteroid; Therapeutic Glucocorticoid; Therapeutic Hormone; Therapeutic Hydrocortisone; Therapeutic Steroid Hormone; Trauma; Unspecified Mental Disorder; abuse of drugs; abuses drugs; amygdaloid nuclear complex; anandamide; anandamide (20.4, n-6); arachidonoyl ethanolamide; arachidonoylethanolamide; arachidonylethanolamide; behavioral extinction; biological adaptation to stress; cannabinoid receptor; conditioned fear; design; designing; drug use; experience; fear conditioning; gamma-Aminobutyric Acid; genetic manipulation; hypothalamic; improved; insight; liquid chromatography mass spectrometry; membrane structure; memory process; mental illness; neuronal; novel; patch clamp; positive emotion; positive emotional state; prevent; preventing; psychological disorder; public health relevance; reaction; crisis; receptor; response; social role; steroid hormone; stress related disorder; stress response; stress; reaction; tool; traumatic neurosis
Relevance: The proposed research on glucocorticoid-endocannabinoid interactions in the amygdala will provide critical insight into the basic biological mechanisms responsible for emotional memory formation and retention/extinction. The better understanding of emotional memory mechanisms gained from these studies will enhance our ability and improve the tools available to address increasingly prevalent and devastating mental illnesses brought on by stress and trauma, including posttraumatic stress disorder, anxiety disorders and phobias. The link between corticosteroids and endogenous cannabinoids is relevant not only to the basic biology of emotional memory formation, but also to the interaction between illicit drug use and anxiety disorders, as increased drug abuse in certain emotionally disturbed populations may be the result of compensation for a deficit in endogenous psychoactive chemicals involved in the generation of positive emotions
Project start date: 2010-05-14
Project end date: 2012-02-28
Budget start date: 14-MAY-2010
Budget end date: 28-FEB-2011
PFA/PA: PA-09-164
1R21MH090453-01 (2010): $223500
Sponsored Links Excellgen http://Excellgen.com
Synaptic Plasticity Of Hypothalamic Neurons
Jeffrey G Tasker, Professor
Tulane University Of Louisiana 6823 St Charles Ave New Orleans, La 70118
Grant 5R01NS042081-05 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: Magnocellular neuroendocrine cells in the hypothalamus are responsible for the synthesis and release of vasopressin and oxytocin, neurohormones involved in fluid balance, blood pressure regulation, parturition and lactation. Much of the synaptic regulation of these neurons is under the control of the neurotransmitters glutamate, GABA and norepinephrine. Anatomical studies have shown that the magnocellular neurosecretory systems undergo dramatic neuronal-glial and synaptic reorganization under conditions of dehydration, representing a unique model of physiologically linked structural plasticity in the adult brain. This includes extensive retraction of glial processes from around the magnocellular neurons and the formation of new glutamatergic, GABAergic and noradrenergic synapses. We postulate that these structural changes lead to an increase in the glutamate, GABA and noradrenergic synaptic inputs to the magnocellular neurons as well as to a decrease in their transporter-mediated clearance, resulting in an increase in the ambient extracellular levels of these neurotransmitters. We will test this first hypothesis by comparing in untreated and dehydrated rats the levels of glutamatergic and GABAergic synaptic inputs to magnocellular neurons of the supraoptic nucleus, as well as the modulation of these inputs by activation of presynaptic metabotropic receptors by ambient neurotransmitter levels. We posit that changes in the expression of glutamate may be responsible for the induction of the structural plasticity caused by dehydration, as these receptors have been implicated in the formation and stabilization of synaptic contacts associated with structural plasticity in developing and adult brain. We will test this hypothesis by assessing dehydration-induced changes in the expression of specific glutamate receptor subunits, and by altering subunit expression in normal animals through viral delivery of specific receptor subunit genes in vivo. These studies are designed to accomplish two goals 1) to determine whether the neuronal-glial structural changes induced by dehydration lead to changes in the synaptic innervation and in the excitability of magnocellular neurons, and 2) to determine whether changes in glutamate receptor expression are causal in the induction of the structural changes associated with dehydration. The successful completion of these studies will reveal the physiological significance of anatomical changes observed under conditions of dehydration, and will provide insight into the molecular mechanisms responsible for these changes.
Keywords: glutamate receptor, hypothalamus, neural plasticity, neuron, synapse, body water dehydration, gamma aminobutyrate, glia, glutamate, neurotransmitter, oxytocin, supraoptic nucleus, vasopressin, electron microscopy, electrophysiology, immunocytochemistry, in situ hybridization, laboratory rat, polymerase chain reaction, western blotting
Project start date: 2003-03-01
Project end date: 2009-02-28
5R01NS042081-05 (2007): $300971
5R01NS042081-04 (2006): $298711
5R01NS042081-03 (2005): $305900
5R01NS042081-02 (2004): $317419
1R01NS042081-01A2 (2003): $329650
CELLULAR PLASTICITY AND HPA AXIS DYSFUNCTION
Jeffrey G Tasker, Professor
Tulane University Of Louisiana, 6823 St Charles Ave, New Orleans, La 70118
Grant 5R01MH069879-06 from National Institute Of Mental Health
Abstract: Chronic stress and depression lead to a sustained increase in the activation of the hypothalamic-pituitary adrenal (HPA) axis and tonically elevated levels of circulating HPA hormones, including glucocorticoids. Sequelae of chronic stress in experimental models and in humans include hypersensitivity of the HPA axis to stressful stimuli, and reduced sensitivity of the HPA axis to negative feedback regulation by circulating glucocorticoids. Likely causes of the chronic stress-induced hypersensitivity of the HPA axis and sustained hypersecretion of HPA hormones is an increased excitatory synaptic drive to and a reduced sensitivity to glucocorticoids of the cells that trigger HPA axis activation, the corticotropin releasing hormone (CRH) neurons of the paraventricular nucleus (PVN). Synaptic activation of the CRH neurons appears to involve an interaction between glutamatergic, GABAergic and noradrenergic systems, suggesting that structural changes in these systems may be responsible for the altered responsiveness of the HPA axis during chronic stress and depression. Rapid feedback inhibitory actions of glucocorticoids appear to be mediated, in part, by activation of endocannabinoid release within the PVN and a resulting retrograde suppression of glutamate release onto the PVN CRH neurons. Through a collaborative network of investigators studying the HPA axis, we have acquired preliminary anatomical and molecular data to suggest that the synaptic innervation of PVN CRH neurons is structurally altered by exposure to chronic stress. This proposal is the cellular physiology component of an IRPG application designed to address the overarching hypothesis that chronic stress leads to long-term molecular, anatomical and functional changes in the synaptic circuitry and glucocorticoid feedback that regulate PVN CRH neurons and the hypothalamic response to stress. We will use whole-cell patch-clamp recordings and genomic analyses to determine whether exposure to chronic stress causes an increase in the excitability of PVN CRH neurons 1) by altering glutamatergic, GABAergic and/or noradrenergic synaptic inputs, and/or 2) by reducing glucocorticoid inhibitory feedback regulation. These studies will provide important insight into the functional changes that occur in the brain during chronic stress, and will offer potential targets for the clinical treatment of certain stress-related affective disorders, such as severe depression
Keywords: 1, 2-Benzenediol, 4-(2-amino-1-hydroxyethyl)-, (R)-; 4-Aminobutanoic Acid; 4-Aminobutyric Acid; ACTH; ACTH (1-39); ACTH-Releasing Factor; ADRGND; Address; Adrenal Cortex Hormones; Adrenal Glands; Adrenal Hormone; Adrenal hormone preparation; Adrenals; Adrenocorticotropic Hormone; Adrenocorticotropin; Affective Disorders; Allergy; Aminalon; Aminalone; Brain; Butanoic acid, 4-amino-; CRF-41; CRH; Cannabinoids; Cannabinoids, Endogenous; Cell Communication and Signaling; Cell Function; Cell Process; Cell Signaling; Cell physiology; Cells; Cellular Function; Cellular Physiology; Cellular Process; Charge; Chronic; Chronic stress; Clinical; Clinical Treatment; Companions; Corticoids; Corticoliberin; Corticosteroids; Corticotropin; Corticotropin (1-39); Corticotropin-Releasing Factor; Corticotropin-Releasing Factor-41; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone-41; Data; Dysfunction; Encephalon; Encephalons; Endocannabinoids; Experimental Models; Experimental Models, Other; Exposure to; Feedback; Functional disorder; Future; G-Proteins; GABA; GTP-Binding Proteins; GTP-Regulatory Proteins; Gene Expression; Gene Transcription; Genetic Transcription; Genomics; Glucocorticoid Receptor; Glucocorticoids; Glutamates; Guanine Nucleotide Coupling Protein; Guanine Nucleotide Regulatory Proteins; HPA; Human; Human, General; Hypersensitivity; Hypophysis; Hypophysis Cerebri; Hypothalamic structure; Hypothalamus; Injection of therapeutic agent; Injections; Intervention; Intervention Strategies; Intracellular Communication and Signaling; Investigators; L-Glutamate; Lead; Levarterenol; Levonorepinephrine; Man (Taxonomy); Man, Modern; Measures; Mediating; Models, Experimental; Modification; Molecular; Monitor; Mood Disorders; Nerve Cells; Nerve Unit; Nervous System, Brain; Nervous System, Pituitary; Neural Cell; Neurocyte; Neurons; Noradrenaline; Norepinephrine; Paraventricular Hypothalamic Nucleus; Paraventricular Nucleus; Pathway interactions; Pb element; Physiologic; Physiological; Physiopathology; Pituitary; Pituitary Gland; Plastics; RNA Expression; RT-PCR; RTPCR; Regulation; Research Personnel; Researchers; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Signal Transduction Systems; Signaling; Slice; Stimulus; Stress; Structure; Structure of paraventricular nucleus; Subcellular Process; Synapses; Synaptic; Synaptic plasticity; System; System, LOINC Axis 4; Testing; Therapeutic Corticosteroid; Therapeutic Glucocorticoid; Transcription; Transcription, Genetic; Whole Organism; Whole-Cell Recordings; base; biocytin; biological adaptation to stress; biological signal transduction; biotinyl L lysine; cannabinoid receptor; corticotropin releasing hormone; depression; design; designing; electrical property; experiment; experimental research; experimental study; gamma-Aminobutyric Acid; heavy metal Pb; heavy metal lead; hypothalamic; hypothalamic-pituitary-adrenal (HPA) axis; hypothalamic-pituitary-adrenal axis; hypothalmus-pituitary-adrenal axis; innervation; insight; interventional strategy; nerve supply; neural circuit; neural circuitry; neuronal; neurotransmitter release; noradrenergic; novel; paraventricular nucleus; parvocellular; patch clamp; pathophysiology; pathway; postsynaptic; presynaptic; reaction; crisis; receptor function; receptor sensitivity; research study; resistant; response; reverse transcriptase PCR; stress response; stress; reaction; stressor; suprarenal gland; trial regimen; trial treatment
Project start date: 2004-07-01
Project end date: 2010-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2010
5R01MH069879-06 (2009): $185547
5R01MH069879-04 (2007): $311695
5R01MH069879-03 (2006): $376408
5R01MH069879-02 (2005): $326919
1R01MH069879-01 (2004): $365641
Sponsored Links Excellgen http://Excellgen.com
Acute Corticosteriod Actions In The Hypothalamus
Jeffrey G Tasker, Professor
Cell And Molecular Biologytulane University Of Louisiana
Grant 2R01MH066958-05A1 from National Institute Of Mental Health IRG: ZRG1
Abstract: Blood glucocorticoid levels rise in response to stress activation of the hypothalamic- pituitary-adrenal (HPA) axis. They feed back onto the brain, where they exert both rapid and delayed inhibitory effects on HPA axis activation, corresponding generally to non-genomic and genomic actions, respectively. Dysfunctional glucocorticoid negative feedback is associated with a wide variety of disorders, including stress disorders and metabolic syndrome. The general goal of this project is to determine the site and mechanisms of rapid glucocorticoid feedback actions. Our working hypothesis is that rapid glucocorticoid actions in the hypothalamus are important for the integration of neuroendocrine signaling during stress. During the first period of funding of this grant, we identified a novel rapid glucocorticoid action in hypothalamic paraventricular nucleus (PVN) neurons that involves the activation of a putative membrane G protein-coupled glucocorti in PVN parvocellular neurons and both retrograde endocannabinoid and NO release in magnocellular neurons. Endocannabinoids are also released and suppress excitatory inputs in response to depolarization of PVN neurons. Thus, glucocorticoids elicit multiple retrograde signals in PVN neurons, suggesting a divergence in membrane glucocorticoid receptor signaling pathways, and both glucocorticoids and electrical activity elicit endocannabinoid synthesis, suggesting a convergence in the signaling mechanisms activated by these stimuli. In this proposal, we will build on our previous findings with experiments that address the following aims Aim 1 is to study the intracellular signaling mechanisms engaged by membrane glucocorticoid receptor actions and depolarization that lead to endocannabinoid and NO synthesis; Aim 2 is to investigate the role of glia in restricting the extracellular actions of endocannabinoids to glutamate synapses; Aim 3 is to determine the role of glucocorticoid-indus-related disorders, including depression, hypertension and obesity. Corticosteroids represent a critical endocrine signal activated during the stress response, and they play various roles throughout the body that increase the chance for survival during stress. Corticosteroids have different mechanisms of action, both rapid and delayed, which are mediated ostensibly by different membrane and intracellular receptors. A clear understanding of the differences in the mechanisms and properties of these receptors will allow the development of pharmacological therapies for stress-related disorders, such as anxiety, depression and feeding disorders, with distinct pharmacodynamics and reduced side effects. 1
Project start date: 2003-06-01
Project end date: 2013-12-31
HYPOTHALAMIC SYNCHRONIZATION BY LOCAL GLUTAMATE CIRCUITS
Jeffrey G Tasker, Professor
Tulane University Of Louisiana 6823 St Charles Ave New Orleans, La 70118
Grant 5R01NS039099-04 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: adapted from applicant s ) Hypothalamic neuroendocrine cells develop patterned electrical activity under certain physiological conditions, which leads to a pulsatility of hormone secretion into the blood. Glutamatergic and noradrenergic synaptic mechanisms appear to play an important interactive role in the generation of bursting electrical behavior in these cells. Preliminary evidence suggests that magnocellular neuroendocrine cells of the paraventricular (PVN) and supraoptic nuclei (SON) receive excitatory synaptic inputs from norepinephrine-sensitive glutamate interneurons located within the respective nuclei. This suggests that local glutamate neurons may relay excitatory signals from noradrenergic afferents to the magnocellular neuroendocrine cells, which provides a potential mechanism for the initiation and synchronization of bursting activity in these cells. This proposal will test the hypothesis that synchronous burst generation among hypothalamic neuroendocrine cells is the result of noradrenergic activation of local glutamatergic synaptic inputs. The specific aims are to determine whether 1) norepinephrine excites magnocellular neuroendocrine cells of the SON by activating intranuclear glutamate circuits; 2) magnocellular neurons of the SON and paraventricular nucleus (PVN) are synaptically coupled via internuclear glutamate circuits. Whole-cell patch-clamp recordings from magnocellular neuroendocrine cells will be performed in acute hypothalamic slices. Intra-and internuclear circuits will be activated using electrical and focal chemical stimulation techniques. Population responses will be studied with multiunit recordings and calcium imaging to detect synchronized synaptic inputs to magnocellular neurons from local glutamate circuits. Magnocellular neurons will be identified as oxytocin and vasopressin cells with intracellular dye injection and post-hoc immunohistochemical labeling. Determining the mechanisms responsible for the generation of specific bursting patterns among different neuroendocrine neuronal populations is one of the main objectives of the physiological study of neuroendocrine systems. Pulsatility, a hallmark of neuroendocrine systems, is caused by patterned electrical activity in the hormone-secreting cells. The development of therapeutic strategies for treating disrupted or abnormal hormonal cycles requires an understanding of the mechanisms responsible for the generation of patterned activity in these cells. This proposal should make a substantial contribution to understanding the mechanisms of burst generation in hypothalamic neuroendocrine cells.
Keywords: bioperiodicity, glutamate, glutamate receptor, neuroendocrine system, norepinephrine, paraventricular nucleus, supraoptic nucleus, laboratory rat, voltage /patch clamp
Project start date: 2000-04-01
Project end date: 2005-03-31
5R01NS039099-04 (2003): $259875
5R01NS039099-02 (2001): $259875
1R01NS039099-01A1 (2000): $311088
Synaptic Plasticity Of Hypothalamic Neurons
Jeffrey G Tasker, Professor
Tulane University Of Louisiana 6823 St Charles Ave New Orleans, La 70118
Grant 3R01NS042081-05S1 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Project start date: 2003-03-01
Project end date: 2008-02-28
3R01NS042081-05S1 (2007): $63150
LOCAL SYNAPTIC INTERACTIONS AMONG HYPOTHALAMIC NEURONS
Jeffrey G Tasker, Professor
Tulane University Of Louisiana 6823 St Charles Ave New Orleans, La 70118
Grant 5R29NS031187-03 from National Institute Of Neurological Disorders And Stroke IRG: NLS
Project start date: 1994-06-01
Project end date: 1999-05-31
5R29NS031187-03 (1996): $92775
3R29NS031187-01A1S1 (1994): $34738