Currently, centrally acting oxytocin receptor (OTR) agonists are generating considerable interest for their potential to be developed as novel therapeutics for a range of neuropsychiatric disorders including autism, schizophrenia, post-traumatic stress disorder, obsessive compulsive disorder, and more generalized mood and anxiety disorders. Indeed, an extensive literature implicates centrally acting oxytocin in pair bonding and social interactions, and further highlights well noted potential for oxytocin to produce antidepressive and anxiolytic effects. Because oxytocin in the periphery is a very poor penetrator of the blood brain barrier, it is likely that this wide array of powerful central effect depends on oxytocin released by magnocellular neurosecretory neurons located in the supraoptic and paraventricular nuclei of the hypothalamus; the only central nuclei to produce oxytocin in abundance. Oxytocinergic neurons in these areas are unlike many excitable cells in the CNS in that they have two distinctly different ways to release peptide: paracrine and synaptic (which depend on dendritic and axonal structures, respectively). To date, very little is known about the distinctly different mechanisms though which paracrine or synaptic release of oxytocin in the brain ultimately modulates central circuits underlying mood affect and social behavior. In a broad sense, this project seeks to address that gap by developing techniques to independently evaluate neurophysiological mechanisms engaged by these distinct types of endogenous oxytocinergic signaling. More specifically, current Aims will motivate sustained paracrine release of oxytocin in the PVN using a systemic osmotic stressor that has recently been demonstrated to blunt the physiological response to psychogenic stress, and to produce a clear anxiolytic behavioral phenotype in tests for social and generalized anxiety. Based on extensive preliminary data, Aim 1 will test the hypothesis that paracrine release of oxytocin in the hypothalamus contributes to an anxiolytic phenotype in large part by directly inhibiting parvocellular neurosecretory neurons that express corticotropin releasing factor (Aim 1).
Aim 2 will then reveal a previously unexpected and likely disynaptic mechanism through which paracrine release of oxytocin can disinhibit parvocellular preautonomic neurons in the PVN. Finally, Aim 3 will examine the effect of autocrine receptor activation of both dendritic and presynaptic OTRs on PVN magnocellular neurons. This work is expected to reveal a powerful positive feedback loop that supports both sustained paracrine and enhanced synaptic oxytocin release. Overall, Aim 1 has high potential significance because it will indicate a clear mechanism through which centrally acting oxytocin can effectively modulate key aspects of the stress response that have long been implicated in the etiology of mood and anxiety disorders. Further, Aims 2-3 enhance the overall significance of the project by revealing several new functional aspects of the central paracrine oxytocin signal that are likely to help guide and infor rational development of new therapeutics that seek to transiently activate central OTRs.
Oxytocin is a neuropeptide that acts within the brain to powerfully modulate mood, anxiety, and social interaction. The physiology of endogenous oxytocinergic signaling in the brain is complicated by an unusually restricted set of neurons that synthesize the peptide, and an unusually diverse set of mechanisms through which it may be released. This project will reveal how paracrine release of endogenous oxytocin in the brain may ultimately modulate limbic circuits underlying mood, affect, and social behavior, and it will also reveal novel aspects of the paracrine signal that will help guide and inform development of novel therapeutics for neuropsychiatric disorders that seek to target central oxytocin receptors.
| Krause, Eric G; Pati, Dipanwita; Frazier, Charles J (2017) Chronic salt-loading reduces basal excitatory input to CRH neurons in the paraventricular nucleus and accelerates recovery from restraint stress in male mice. Physiol Behav 176:189-194 |
| Harden, Scott W; Frazier, Charles J (2016) Oxytocin depolarizes fast-spiking hilar interneurons and induces GABA release onto mossy cells of the rat dentate gyrus. Hippocampus 26:1124-39 |
| Smith, Justin A; Pati, Dipanwita; Wang, Lei et al. (2015) Hydration and beyond: neuropeptides as mediators of hydromineral balance, anxiety and stress-responsiveness. Front Syst Neurosci 9:46 |
