Loss of Gabrd in CRH neurons blunts the corticosterone response to stress and diminishes stress-related behaviors

• Published in: Psychoneuroendocrinology 2014-03, Vol.41, p.75-88
• Main Authors: Lee, Vallent, Sarkar, Jhimly, Maguire, Jamie
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Animals; Anxiety; Anxiety - chemically induced; Anxiety - genetics; Behavior, Animal - drug effects; Behavior, Animal - physiology; Behavioral psychophysiology; Biological and medical sciences; Brain - metabolism; Brain - physiology; Corticosterone; Corticosterone - blood; Corticosterone - pharmacology; Corticotropin-Releasing Hormone - metabolism; CRH neurons; Depression; Depression - chemically induced; Depression - genetics; Endocrinology & Metabolism; Fundamental and applied biological sciences. Psychology; GABA; GABAergic Neurons - metabolism; GABAergic Neurons - physiology; Hormones and behavior; HPA axis; Hypothalamus; Male; Medical sciences; Membrane Potentials - genetics; Membrane Potentials - physiology; Mice; Mice, Knockout; Miscellaneous; Mood disorders; Neural Inhibition - genetics; Neural Inhibition - physiology; Paraventricular Hypothalamic Nucleus - metabolism; Paraventricular Hypothalamic Nucleus - physiology; Paraventricular nucleus; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Psychopathology. Psychiatry; Receptors, GABA-A - deficiency; Receptors, GABA-A - genetics; Receptors, GABA-A - physiology; Restraint, Physical - psychology; Stress; Stress, Psychological - blood; Stress, Psychological - genetics; Stress, Psychological - physiopathology; Tonic inhibition
• ISSN: 0306-4530; 1873-3360
• DOI: 10.1016/j.psyneuen.2013.12.011

Summary The hypothalamic–pituitary–adrenal (HPA) axis is under tight regulation by strong GABAergic inhibition onto corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus. CRH neurons receive two forms of GABAergic inhibition, phasic and tonic, but the specific roles of these two types of signaling have not yet been studied in this cell type. Our lab recently demonstrated a role for the GABAA R δ subunit in the tonic GABAergic regulation of CRH neurons. Using a floxed Gabrd mouse model established in our laboratory, we generated mice in which the GABAA R δ subunit is selectively removed from CRH neurons ( Gabrd / Crh mice), resulting in a loss of tonic GABAergic inhibition in these neurons. Interestingly, the loss of this tonic GABAergic constraint did not significantly alter basal levels of corticosterone (CORT). However, the loss of the GABAA R δ subunit in CRH neurons blunted the CORT response to stress, likely due to the loss of the disinhibitory effect of GABA following acute stress. This blunting of HPA axis reactivity was associated with a decrease in depression-like and anxiety-like behaviors. Exogenous CORT was sufficient to increase anxiety-like and depression-like behaviors in Gabrd / Crh mice. Together, these results show the importance of the GABAA R δ subunit in the regulation of CRH neurons, and thus the HPA axis, and demonstrate that dysregulation of CRH neurons alters stress-related behaviors.