James A. Carr - US grants

DESCRIPTION (Adapted from applicant's abstract): The goal of the proposed research is to elucidate the mechanisms subserving opiate receptor control of pro-opiomelanocortin (POMC) peptide release from the pituitary intermediate lobe (IL). Administration of opiate agonists, such as morphine, results in profound alterations in the activity of brain and pituitary POMC systems but the mechanisms underlying these effects are not well understood. Recent experiments with the super-active opiate agonist (D-Met2, Pro5)-enkephalinamide (DMPEA) suggest that opiate receptors in the pituitary neural lobe (NL) may mediate the stimulatory effects of DMPEA on POMC peptide release from the IL in vitro. Experiments outlined in the current proposal will utilize a rodent model to investigate the potential role of NL opiate receptors in controlling IL POMC peptide secretion in vitro. The central hypothesis to be tested is that activation of opiate receptors in the NL promotes the release of a chemical modulator that, in turn, stimulates the secretory activity of IL POMC cells. Two major questions will be addressed. First, which opiate receptor subtype (mu, delta, or kappa) mediates the stimulatory effect of DMPEA on IL POMC peptide release in vitro? Second, does DMPEA stimulate IL cells indirectly by acting upon opiate receptors in the adjacent NL to promote the secretion of a POMC peptide-releasing factor (PPRF)? Selective u, o, and k receptor antagonists will be used to determine the relative contribution of these receptor subtypes to DMPEA stimulation of POMC peptide release using an established, fixed-volume in-vitro incubation procedure. Selective receptor agonists and antagonists will be used to determine the relative contribution of known NL neurochemicals to PPRF activity in conditioned incubation medium from DMPEA-treated NLs. If the PPRF proves to be an unidentified chemical substance, preliminary biochemical characterization will be performed to determine if the putative PPRF is a protein or peptide and to determine its approximate molecular weight. Results from the proposed work will lead to a better understanding of the receptor subtypes mediating opiate agonist effects on POMC cells. Findings generated from this work will establish a basis for future investigations on the interactions between opiate agonists and endogenous neurochemical systems, specifically those in the NL, that modulate the activity of pituitary POMC cells.

General Abstract

Detecting and responding to threats such as predators is critical for survival, but also interrupts feeding behaviors required to maintain energy. The brain mechanisms underlying foraging and predator avoidance trade-offs are poorly understood. This work will therefore investigate how and where within the brain threat inhibits food consumption in frogs that have a highly-developed and easily accessible neural circuitry that controls feeding. Specifically, experiments will determine how a chemical produced in the brain when animals encounter a predator disrupts the processing of sensory cues that stimulate feeding and thereby inhibits the behavior when it is not adaptive. The studies fall within US national interests in that they will help maintain our role as a leader in science and technology by advancing knowledge of how nervous systems integrate information and generate behavior, fundamental goals of neuroscience research, as well as in their potential to produce unexpected insight into anxiety-related eating disorders. The work will also impact science education through the training of students from underrepresented groups who will be recruited through existing programs at Texas Tech University, the creation of new neurophysiology laboratory exercises to complement those already developed through NSF-funded programs, and the generation of new case studies for the NSF's National Center for Case Study Teaching in Science. For outreach, the team will create a museum exhibit on sensory detection of prey and the ecology of fear at the Texas Tech Museum and provide supplies and materials related to amphibian biology, behavior and conservation to local elementary schools.

Technical Abstract

The goal of this work is to understand neuroendocrine modulation of food intake in light of the ecological and evolutionary forces that guide optimal foraging. Specifically, the work will identify the neural mechanism(s) underlying modulation of multisensory prey capture by the stress neuropeptide corticotropin-releasing factor (CRF). In the clawed frog, Xenopus laevis, CRF rapidly inhibits prey capture through modulation within the optic tectum, an important brain area for multisensory processing of both prey and predator cues in this and other vertebrates. The PI will now determine if tectal CRF R1 receptors inhibit multisensory guided prey capture. In the first aim, pharmacological and imaging approaches will be used to test if tectal CRF R1 receptors interfere with the processing of lateral line and/or visual cues related to prey capture. In the second aim, the role of sensory afferents and inhibitory GABA+ interneurons in mediating CRF inhibition of multisensory guided prey capture will be investigated. Together, these experiments will identify the mechanisms through which an important satiety peptide interferes with a multisensory pathway required for food acquisition. The findings will broadly impact our understanding of the neuronal basis for aversive behavior and its modulation in vertebrates and possibly shed light on the evolutionary origins of disorders in which fear processing pathways are disrupted. Work associated with this proposal will also be directly incorporated into undergraduate educational experiences, in the classroom and the laboratory, and will guide the development of exhibits in the local community.