Stress induces an integrated hormonal, autonomic, and behavioral response by activating Corticotropin Releasing Factor (CRF) neurons in the paraventricular nucleus of the hypothalamus (PVN). While CRF is released to the pituitary to initiate Hypothalamic-Pituitary-Adrenal (HPA) axis activity, we have discovered a new mechanism in which CRF acts in the PVN. A previously uncharacterized population of neurons in the PVN express CRFR1, the primary receptor for CRF, allowing them to respond to locally released peptide. Circuit level analysis suggests that PVN CRFR1 neurons synapse back on CRF neurons to provide local feedback to the HPA axis, and synapse on magnocellular and pre-autonomic neurons to coordinate neuroendocrine and autonomic responses. Our preliminary data indicate that in nave animals, this local microcircuit functions to inhibit HPA axis activity, consistent with electrophysiological evidence that CRFR1 neurons make inhibitory synapses on neighboring neurons. However, in the context of chronic stress, intra-PVN signaling is required to maintain HPA axis activity, indicating that CRFR1 neurons potentiate CRF neuron activity. This proposal is focused on resolving this paradox by establishing the architecture of a CRF-CRFR1 microcircuit in the PVN, determining the importance of CRFR1 neurons in shaping HPA axis responses and autonomic tone in the context of acute stress responses, and exploring how the microcircuit changes after chronic stress to invert its influence on the HPA axis. In order to address our hypotheses, we use genetically guided expression of optogenetic, chemogenetic, and viral tracing tools to define the anatomical and functional importance of this new population of neurons. Successful completion of the experiments described in this proposal will define a new facet of HPA axis regulation and coordination of PVN output that is essential for the maintenance of appropriate stress responses. This information will fill a gap in our understanding of how neural circuits impinge on the PVN to orchestrate the stress response. Moreover, failure of this mechanism potentially explains how the HPA axis becomes hyperactive in a subset of diseases such as depression, and hypoactive in other diseases like Post- Traumatic Stress Disorder (PTSD), after exposure to intense or chronic stress.
Many mental, metabolic, and cardiovascular diseases are caused by the failure to regulate circulating hormone levels. This grant explores new mechanisms by which the brain maintains normal hormone release after being confronted by extreme or chronic stress. The discovery of this new mechanism opens new avenues to treat diseases ranging from depression and PTSD to obesity and cardiovascular disease.
|Jiang, Zhiying; Rajamanickam, Shivakumar; Justice, Nicholas J (2018) Local Corticotropin-Releasing Factor Signaling in the Hypothalamic Paraventricular Nucleus. J Neurosci 38:1874-1890|
|Justice, Nicholas J (2018) The relationship between stress and Alzheimer's disease. Neurobiol Stress 8:127-133|
|Hunt Jr, Albert J; Dasgupta, Rajan; Rajamanickam, Shivakumar et al. (2018) Paraventricular hypothalamic and amygdalar CRF neurons synapse in the external globus pallidus. Brain Struct Funct 223:2685-2698|