It is widely appreciated that dysregulation of brain systems controlling stress hormone function may underlie the development of major depression, and other stress-related disease states. The medial prefrontal cortex (mPFC) and hippocampal formation (HF) are known to negatively regulate the hypothalamo-pituitary-adrenal (HPA) axis, and their dysfunction is implicated in the mood and neuroendocrine disturbances in depression and in animal studies of chronic stress. Over the years, progress in developing interventions that target neuroendocrine systems has been lacking, due to the inability to unravel the complex neurocircuitry and mechanisms underlying the withdrawal of mPFC and HF restraining influences following chronic stress. Our recent identification of a discrete GABAergic cell group in the anterior subdivision of the bed nucleus of the stria terminalis (aBST), serves as a disynaptic relay between limbic cortical and the paraventricular hypothalamic nucleus (PVH), and is capable of integrating these stress-inhibitory influences over HPA output during acute emotional stress, allows us to directly examine the role of this novel pathway in controlling depression-related neuroendocrine changes. We hypothesize that chronic stress-induced neuroplasticity (i.e., dendritic/axonal retraction, synapse/terminal loss) in mPFC leads to a disruption in their normal restraining influences on the HPA axis, via decreasing their innervation of key disynaptic inhibitory relays (e.g., involving aBST) to PVH.
Aim 1 will assess the involvement of this new circuit implicated in HPA axis modifications following chronic variable stress exposure, and immunotoxin ablation of key GABAergic relays in these circuits will test the involvement of this pathway in chronic stress-induced endocrine alterations.
Aim 2 will utilize high- resolution microscopy, digital reconstructions, and stereology for the assessment of structural plasticity (dendritic, spine density, axon terminal alterations) in mPFC/HF neurons, specific to the circuitry implicated in HPA axis modifications, following chronic variable stress.
Aim 3 will test whether blockade of GC receptors in mPFC/HF prevents circuit-specific neuroplasticity, and, in turn prevent HPA axis hyperactivity, following chronic variable stress. These studies are expected to (a) define a basis for inhibitory circuit disruptions implicated in the withdrawal of HPA restraining influences following chronic variable stress, and (b) to assess the relationship between limbic cortical neuroplasticity and the endocrine abnormalities associated with chronic stress. It is hoped that identification of novel neuroanatomical targets and underlying cellular processes in this proposal will inform the search for more effective treatments for stress-related psychiatric and systemic disorders.

Public Health Relevance

While it is widely hypothesized that dysregulation of brain systems controlling stress hormone function may be important for understanding the pathophysiology of major depression and other stress-related disease states, their underlying mechanisms have remained elusive. This proposal will (1) utilize animal studies to significantly enhance our understanding of the organization of brain circuitry regulating the stress response, and (2), will help to identify novel anatomical targets and cellular processes underlying the development of depression- related endocrine changes. In doing so, it is hoped that this information will help in the development of more effective treatments of stress-related psychiatric and systemic illnesses.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Desmond, Nancy L
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University of Iowa
Schools of Arts and Sciences
Iowa City
United States
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Radley, Jason J; Johnson, Shane B (2018) Anteroventral bed nuclei of the stria terminalis neurocircuitry: Towards an integration of HPA axis modulation with coping behaviors - Curt Richter Award Paper 2017. Psychoneuroendocrinology 89:239-249
Farley, Sean J; Albazboz, Heba; De Corte, Benjamin J et al. (2018) Amygdala central nucleus modulation of cerebellar learning with a visual conditioned stimulus. Neurobiol Learn Mem 150:84-92
Farley, Sean J; Radley, Jason J; Freeman, John H (2016) Amygdala Modulation of Cerebellar Learning. J Neurosci 36:2190-201
Johnson, Shane B; Emmons, Eric B; Anderson, Rachel M et al. (2016) A Basal Forebrain Site Coordinates the Modulation of Endocrine and Behavioral Stress Responses via Divergent Neural Pathways. J Neurosci 36:8687-99
Anderson, Rachel M; Glanz, Ryan M; Johnson, Shane B et al. (2016) Prolonged corticosterone exposure induces dendritic spine remodeling and attrition in the rat medial prefrontal cortex. J Comp Neurol 524:3729-3746
De Jesús-Cortés, Héctor; Lu, Yuan; Anderson, Rachel M et al. (2016) Loss of estrogen-related receptor alpha disrupts ventral-striatal synaptic function in female mice. Neuroscience 329:66-73
Radley, Jason; Morilak, David; Viau, Victor et al. (2015) Chronic stress and brain plasticity: Mechanisms underlying adaptive and maladaptive changes and implications for stress-related CNS disorders. Neurosci Biobehav Rev 58:79-91
Radley, Jason J; Anderson, Rachel M; Cosme, Caitlin V et al. (2015) The Contingency of Cocaine Administration Accounts for Structural and Functional Medial Prefrontal Deficits and Increased Adrenocortical Activation. J Neurosci 35:11897-910
Radley, Jason J; Sawchenko, Paul E (2015) Evidence for involvement of a limbic paraventricular hypothalamic inhibitory network in hypothalamic-pituitary-adrenal axis adaptations to repeated stress. J Comp Neurol 523:2769-87
Cui, Huxing; Lu, Yuan; Khan, Michael Z et al. (2015) Behavioral disturbances in estrogen-related receptor alpha-null mice. Cell Rep 11:344-50

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