Activity of neurons in the bed nucleus of the stria terminalis (BNST) plays a central role in the normal adaptive response to stress. However, chronic release of stress hormones into the BNST also plays a critical role in several central and peripheral pathologies, including anxiety disorders, posttraumatic stress disorder (PTSD), stress-induced drug abuse, cardiovascular disease, as well as gastrointestinal disorders. To date the cellular mechanisms underlying the switch from a normal adaptive response to a psychopathological state remain unknown. The long-term objectives of this proposal are to delineate the cellular mechanisms contributing to the pathological switch in BNST function, with the hope of identifying novel targets for clinical intervention. The selective serotonin (5-HT) reuptake inhibitors (SSRIs) are the first line drugs of choice in treating many stress-related disorders suggesting that abnormal 5-HT function in key areas, such as the BNST may play an important role in the development of these disorders. We have shown that 5-HT inhibits the majority of BNST neurons in vitro, and evokes an anxiolytic response in vivo. Moreover, acute release of the stress hormone corticotrophin releasing factor (CRF) facilitates the inhibitory response of BNST neurons to 5-HT, suggesting that an interaction between these two systems contributes to the normal adaptive response to stress. Our data suggest that repeated restraint stress (RRS) results in a long lasting enhancement of anxiety-like behavior that is associated with a significant reduction in the mRNA expression of inhibitory 5-HT1A receptor subunits, and an increase in excitatory 5-HT2C/7 receptor subunits in BNST neurons. These data suggest that RRS switches the 5-HT response of BNST neurons from inhibition to excitation. In addition, RRS selectively attenuates the expression of mRNA for the Kv4.2 subunit of the inhibitory transient outward potassium current (IA). Significantly, pilot data suggests that the response to RRS can be blocked by prior administration of a CRF1 receptor antagonist, or a histone-deacetylase inhibitor, which alters gene transcription. Our hypothesis is that in RRS, repeated CRF1 receptor activation initiates a cascade of events that disrupts transcriptional regulation of gene expression resulting in an increase in the excitability of BNST neurons, and particularly CRF-containing neurons, and shifting their response to 5-HT in favor of excitation. We propose that similar shifts in BNST excitability may contribute to the etiology of anxiety disorders and PTSD. Here, we will use patch clamp electrophysiology, molecular biology, and behavioral studies in rats and in a novel transgenic mouse in which a green fluorescent protein (GFP) is expressed in CRF-neurons to test our hypotheses.
Two specific aims are proposed.
Specific Aim #1 will characterize the effects of repeated restraint stress on gene expression and physiological properties of neurons in the anterolateral BNST of the rat.
Specific Aim #2 will characterize the effects of repeated restraint stress on gene expression and physiological properties of CRF-containing neurons of the mouse anterolateral BNST.

Public Health Relevance

Trauma or chronic stress is a major precipitating factor in the development and expression of many anxiety disorders, including post-traumatic stress disorder. Similarly, disruption of normal BNST function is thought to contribute to the development of many anxiety disorders. This proposal will use electrophysiological, molecular biological, and behavioral techniques to examine the effect of repeated restraint stress on the physiological properties and genetic profile of BNST neurons with the goal of identifying novel points for clinical intervention in anxiety disorders and PTSD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Nadler, Laurie S
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Emory University
Schools of Medicine
United States
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Dabrowska, Joanna; Martinon, Daisy; Moaddab, Mahsa et al. (2016) Targeting corticotropin-releasing factor (CRF) projections from the oval nucleus of the BNST using cell-type specific neuronal tracing studies in mouse and rat brain. J Neuroendocrinol :
Daniel, Sarah E; Rainnie, Donald G (2016) Stress Modulation of Opposing Circuits in the Bed Nucleus of the Stria Terminalis. Neuropsychopharmacology 41:103-25
Rainnie, Donald G; Hazra, Rimi; Dabrowska, Joanna et al. (2014) Distribution and functional expression of Kv4 family * subunits and associated KChIP * subunits in the bed nucleus of the stria terminalis. J Comp Neurol 522:609-25
Dabrowska, Joanna; Hazra, Rimi; Guo, Ji-Dong et al. (2013) Striatal-enriched protein tyrosine phosphatase-STEPs toward understanding chronic stress-induced activation of corticotrophin releasing factor neurons in the rat bed nucleus of the stria terminalis. Biol Psychiatry 74:817-26
Dabrowska, Joanna; Hazra, Rimi; Guo, Ji-Dong et al. (2013) Central CRF neurons are not created equal: phenotypic differences in CRF-containing neurons of the rat paraventricular hypothalamus and the bed nucleus of the stria terminalis. Front Neurosci 7:156
Hazra, R; Guo, J D; Dabrowska, J et al. (2012) Differential distribution of serotonin receptor subtypes in BNST(ALG) neurons: modulation by unpredictable shock stress. Neuroscience 225:9-21
Gafford, Georgette M; Guo, Ji-Dong; Flandreau, Elizabeth I et al. (2012) Cell-type specific deletion of GABA(A)α1 in corticotropin-releasing factor-containing neurons enhances anxiety and disrupts fear extinction. Proc Natl Acad Sci U S A 109:16330-5
Guo, Ji-Dong; Hazra, Rimi; Dabrowska, Joanna et al. (2012) Presynaptic muscarinic M(2) receptors modulate glutamatergic transmission in the bed nucleus of the stria terminalis. Neuropharmacology 62:1671-83
Dabrowska, Joanna; Hazra, Rimi; Ahern, Todd H et al. (2011) Neuroanatomical evidence for reciprocal regulation of the corticotrophin-releasing factor and oxytocin systems in the hypothalamus and the bed nucleus of the stria terminalis of the rat: Implications for balancing stress and affect. Psychoneuroendocrinology 36:1312-26
Hazra, Rimi; Guo, Ji-Dong; Ryan, Steven J et al. (2011) A transcriptomic analysis of type I-III neurons in the bed nucleus of the stria terminalis. Mol Cell Neurosci 46:699-709

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