Maria A. Sosa - US grants

DESCRIPTION: New Recruitment to Expand Neuroscience Research at the UPR School of Medicine: The purpose of this application is to request funds to support the hiring of two new faculty at the Department of Anatomy &Neurobiology (A &N) of the University of Puerto Rico's (UPR) School of Medicine (SoM) to develop research projects within the context of a SoM Neuroscience Research &Training Core (NRTC). Neuroscience research at UPR is advancing through the work of a community of multidisciplinary researchers. Links between basic science and clinical research are being fostered through collaborations between various departments, including A &N, Biology, Chemistry, Pharmacology, Physiology, Psychology, Psychiatry, Neurology and Neurosurgery. The A &N of the SoM is particularly well positioned to serve as focal point from which these efforts can be centered into a plan to strengthen Neuroscience research in PR, serving as a bridge between basic and clinical sciences. Efforts towards achieving these goals had to recently be put on hold due to unexpected budgetary constraints. While the institution has the necessary space and basic support resources needed to sustain development of new faculty independent research programs and careers, it lacks the needed seed funding for the initial establishment of their projects and laboratories. The Scientific Goals of the proposed program are to: (1) Augment and expand the SoM's community of multidisciplinary researchers focusing in one of the following areas: (a) synaptic/neural circuit physiology;(b) neural development/regeneration/ plasticity;(c) behavioral/cognitive neuroscience;(d) neural mechanisms underlying neurological diseases and stroke;(2) Contribute to achieving a critical mass of researchers that can strengthen the So M capacity to train new generations of Neuroscientists from underrepresented minorities. The Specific Aims of the proposed program are to: (1) Provide salary for the first two years following appointment of two faculty at the Assistant Professor level. The institution is committed to continue providing salary and release time for at least two additional years;(2) Provide start-up funds for purchasing of equipment and supplies needed to operate the new labs;(3) Provide salary for technical assistance for each new faculty to help them establish their independent research programs in Neuroscience.

DESCRIPTION (provided by applicant): Neuropeptide modulation of biogenic amine function and aggression in a crustacean. The long-term goal of this project is to understand the mechanisms that control aggressive behavior in an invertebrate model and how the underlying neural circuits are modulated in response to signals from the organism's internal and external environment. The specific goal is to understand how the effects serotonin (5-HT) and octopamine (OA) have on aggressive behavior of dominant and submissive freshwater prawns are modulated by neuroactive peptides. Adult male prawns develop through three morphotypes, corresponding with the animal's status in a dominance hierarchy. The typical behaviors of each morphotype vary quite markedly in aggression, territoriality and attitude towards females. While other crustacean models such as the crab, crayfish and lobster, have been used extensively to study interactive behaviors, the prawn offers the advantage of marked differences in characteristic behaviors of each morphotype and the fact that the position each animal assumes in the hierarchy of dominance is first determined by its morphotype rather than by its body size. There is ample evidence linking biogenic amines to behaviors associated with the establishment of social hierarchies in both vertebrates and invertebrates, but the specific mechanisms by which these amines act remain largely unknown. Serotonin and OA have been shown to play an important role in modulating aggression and fighting behavior in crustaceans, including the prawn, but the evidence suggests that they are not the sole determinant elements. Aggression and fighting behavior can vary depending on circumstances such as availability of food, shelter and partners for reproduction, level of exposure to contaminants, light/dark cycles, health status, etc. The primary mechanisms that produce aggressive behavior are likely to be susceptible to diverse sources of modulation that allow the organism to adjust its responses to the prevailing circumstances. We are interested in studying the role played by neuroactive peptides in modulating the actions of biogenic amines and how this modulation results in changes in aggressive behaviors in the prawn. The specific scientific aims of the proposed research are to: (1) Characterize the role played by proctolin, FMRFamide, SIFamide and newly identified prawn neuropeptides in modulating natural aggressive behaviors of the prawn male morphotypes and aggressive behaviors induced by injection of 5-HT and OA; (2) Characterize the central nervous system (CNS) distribution of these neuropeptides in the prawn morphotypes and determine how it relates with those of 5-HT and OA; and (3) Quantify the relative amounts of these neuropeptides in the circulating hemolymph of the prawn morphotypes. To achieve these aims, we will use techniques of behavioral observation and quantitation before and after injections of agents of interest, CNS dissection, immunohistochemistry, confocal microscopy, hemolymph sampling and quantitative mass spectrometry.

DESCRIPTION (provided by applicant): G protein-coupled receptors (GPCRs) are one of the largest families of transmembrane receptors and a major target of current therapeutic drugs. At the signaling level, it has become clear that ligands acting on the same receptor can activate multiple and sometime opposing signaling cascades; a process defined as functional selectivity or biased agonism. One of the main effectors of functional selectivity are beta-arrestins, multifunction proteins recruited to activated receptors. However, how receptor activation translates into beta-arrestin signaling is not clearly defined. Our preliminary work combining state-of-the-art live cell imaging with molecular and biochemical techniques identifies ligand-specific dwell times, the time receptors are clustered into individual endocytic pits before endocytosis, as a mechanism by which receptors can control beta-arrestin mediated signaling. Our hypothesis suggests that ligands induce specific phosphorylations at the receptor level, eliciting specific endocytic dwell times during which beta-arrestins remain recruited and engaged in signaling. We propose to define a mechanism by which the Cannabinoid 1 Receptor (CB1R), one of the most abundant receptors in the CNS and target of cannabis, controls beta-arrestin signaling during endocytic dwell times. Our aims are: 1) Characterize ligand-specific dwell times of the CB1R to test our hypothesis that ligands can elicit specific dwell times that ar independent of their endocytic efficacy. 2) Define the mechanisms underlying ligand-specific dwell times of the CB1R. We will test the hypothesis that dwell times are controlled by ligand-specific phosphorylation profiles (bar-codes) of the receptor. Alternative mechanisms will be also investigated. 3) Determine if beta-arrestin signaling is the physiological target of ligand specific dwell times in heterologous systems and native tissue. Finally, we will test different manipulations to control arrestin signaling by altering CB1R dwell times.