Chronic stress can result in long-term or permanent changes in the emotional, physiological, and behavioral responses that lead to increased risk for physical and psychiatric disorders. Stress responses are controlled importantly by the paraventricular nucleus (PVN) of the hypothalamus, which contains functionally distinct neuronal populations involved in the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis and autonomic nervous system. Stimulation of corticotrophin-releasing hormone (CRH)-expressing parvocellular neurons increases pituitary adrenocorticotropic hormone (ACTH) release and subsequent corticosterone (CORT) secretion under both basal and stressed conditions. Although increased activity of both preautonomic neurons and neuroendocrine neurons are beneficial for short-term survival during acute stress, persistent excitation of these neurons during chronic stress can result in serious metabolic, immune and psychological dysfunction. However, the underlying mechanisms causing hyperactivity of PVN neurons in chronic stress remain unclear. The chronic unpredictable mild stress (CUMS) rat model provides a good analogy to the precipitation of depression by chronic and low-grade stressors in humans. In this project, we will use the CUMS rat model to test the central hypothesis that chronic stress diminishes GABAergic inhibition and contributes to enhanced stress responses through upregulation of NKCC1 and the depolarizing shift of EGABA in the PVN in chronic stress. We have recently developed a novel method to identify rat CRH-expressing neurons by tagging the CRH- expressing neurons with GFP driven by CRH promoter in vivo. We propose to pursue the following four specific aims: (1) determine changes in the cation-chloride cotransporter expression levels in chronic stress;(2) determine the role of NKCC1 in the depolarizing shift of EGABA and increased excitability of the PVN CRH-expressing neurons in chronic stress;(3) determine the contribution of increased glutamatergic inputs to the NKCC1 upregulation in the PVN in chronic stress;and (4) determine the role of NKCC1 upregulation in the PVN in exaggerated stress response in chronic stress. The importance of the depolarizing shift of GABA reversal potential and upregulation of NKCC1 in the PVN in chronic stress has not been recognized previously. Our project is expected to generate novel information that will significantly advance our understanding of the molecular mechanisms involved in the chronic stress. This new information could provide an important rationale for the treatment of exaggerated stress response during chronic stress conditions. Also, these findings may lead to the development of novel therapies to prevent and treat psychiatric diseases such as depression.

Public Health Relevance

In this project, we will delineate the cellular and molecular mechanisms involved in the diminished GABA inhibition in the hypothalamus in chronic stress. The novel information obtained from this project could lead to development of new treatments for exaggerated stress response and related psychiatric diseases such as depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH096086-01A1
Application #
8506777
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Desmond, Nancy L
Project Start
2013-02-04
Project End
2017-11-30
Budget Start
2013-02-04
Budget End
2013-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$369,577
Indirect Cost
$128,658
Name
University of Texas MD Anderson Cancer Center
Department
Anesthesiology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Li, De-Pei; Zhou, Jing-Jing; Zhang, Jixiang et al. (2017) CaMKII Regulates Synaptic NMDA Receptor Activity of Hypothalamic Presympathetic Neurons and Sympathetic Outflow in Hypertension. J Neurosci 37:10690-10699
Qiao, Xin; Zhou, Jing-Jing; Li, De-Pei et al. (2017) Src Kinases Regulate Glutamatergic Input to Hypothalamic Presympathetic Neurons and Sympathetic Outflow in Hypertension. Hypertension 69:154-162
Gao, Yonggang; Zhou, Jing-Jing; Zhu, Yun et al. (2017) Chronic Unpredictable Mild Stress Induces Loss of GABA Inhibition in Corticotrophin-Releasing Hormone-Expressing Neurons through NKCC1 Upregulation. Neuroendocrinology 104:194-208
Zhou, Jing-Jing; Gao, Yonggang; Kosten, Therese A et al. (2017) Acute stress diminishes M-current contributing to elevated activity of hypothalamic-pituitary-adrenal axis. Neuropharmacology 114:67-76
Gao, Yonggang; Zhou, Jing-Jing; Zhu, Yun et al. (2017) Neuroadaptations of presynaptic and postsynaptic GABAB receptor function in the paraventricular nucleus in response to chronic unpredictable stress. Br J Pharmacol 174:2929-2940
Li, De-Pei; Zhou, Jing-Jing; Pan, Hui-Lin (2015) Endogenous casein kinase-1 modulates NMDA receptor activity of hypothalamic presympathetic neurons and sympathetic outflow in hypertension. J Physiol 593:4439-52
Zhou, Jing-Jing; Yuan, Fang; Zhang, Yi et al. (2015) Upregulation of orexin receptor in paraventricular nucleus promotes sympathetic outflow in obese Zucker rats. Neuropharmacology 99:481-90
Li, De-Pei; Chen, Shao-Rui (2014) Nitric oxide stimulates glutamatergic synaptic inputs to baroreceptor neurons through potentiation of Cav2.2-mediated Ca(2+) currents. Neurosci Lett 567:57-62
Li, De-Pei; Zhu, Li-Hong; Pachuau, Judith et al. (2014) mGluR5 Upregulation increases excitability of hypothalamic presympathetic neurons through NMDA receptor trafficking in spontaneously hypertensive rats. J Neurosci 34:4309-17