Daniel Bitran - US grants

The study of the neurobiological mechanisms of anxiety has been facilitated by the discovery of specific antianxiety compounds and animal models of anxiety-related behavior that are sensitive to the effects of these drugs. In the last 5 years, a large body of evidence has demonstrated that 3alpha-hydroxy pregnane steroids potentiate the inhibitory actions of gamma-aminobutyric acid (GABA) at the GABA/benzodiazepine (BDZ) receptor complex (GABAA), a substrate thought to be a major neural mediator of stress responses and anxiolytic BDZ effects. One of the most potent GABAergic pregnane steroid metabolites, 3alpha-hydroxy5alpha-pregnan-20-one (allopregnanolone), is formed in the ovaries, adrenal glands, and brain by the bioconversion of progesterone. To date, few studies have addressed the role of neuroactive steroid metabolites on behavior. An area of inquiry that has been neglected is the putative effect that fluctuating levels of ovarian steroids have on the GABAA receptor. The goals of this research project are to delineate whether functional indices of the GABAA receptor are affected by the changing hormonal milieu that characterizes altered reproductive states. We will study female rats In different phases of the estrous cycle, ovariectomized rats with and without ovarian hormone replacement treatment, and aged females in reproductive senescence. Spontaneous and drug-induced changes in ambulation in an automated activity chamber, and behavior in 2 animal models of anxiety, the elevated plusmaze and the defensive burying paradigm will be evaluated. Thus, the anxiolytic and sedative effects of diazepam (DZ), a prototypical BDZ, and pregnanolone, a structurally-related isomer of allopregnanolone will be determined. Following the behavioral assays, neurochemical correlates of function of the GABAA receptor will be evaluated in the following: chloride ion (Cl-) enhancement of 3H-flunitrazepam binding (3H-FLU), pregnanolone enhancement of 3H-FLU binding, GABA-stimulated Cl- influx, DZ facilitation of GABA-mediated Cl-influx, and pregnanolone facilitation of GABA-stimulated Cl-influx. Cortex, hippocampus, and cerebellum, regions thought to be involved in mediating anxiolytic and sedative effects of BDZ and pragnanolone, will be chosen for neurochemical assay. Our findings indicate that neuroendocrine conversions of progesterone result in psychoactive pregnane metabolites that influence GABAergic neurotransmission. It is therefore hypothesized that ovarian status, which characterizes different reproductive states, gives rise to fluctuations in brain levels of progesterone and reduced metabolites that alter function of the GABAA receptor. Furthermore, we anticipate that behavioral manifestations of these hormonal and neurochemical changes in animal models of anxiety will be observed. Data generated by the proposed experiments may provide insight into potential neuroendocrine mechanisms of catamenial epilepsy and psychiatric conditions of premenstrual syndrome and postpartum depression.

This project restructures two core courses in a Biological Psychology Concentration offered to biology and psychology undergraduate majors. A large number of courses in the concentration have a significant laboratory component. However, as a result of insufficient instrumentation, Introduction to Neuroscience and Neurochemistry and Behavior courses had been offered in a lecture format. The Introduction to Neuroscience is a gateway course into the concentration. Students completing this course can make a more informed decision concerning their choice to continue study in this area and be better prepared for future courses. Similarly, concepts in neurochemistry and psychopharmacology taught in the Neurochemistry and Behavior course are most effectively conveyed by active student participation. It is for these reasons that systemic reform for these courses is sought. This project reforms the structure of these courses by providing experiments that will serve as the centerpiece of the student's learning experience. Thus, important concepts in neuroscience are first discovered in the laboratory. Discussion of experimental results that follow leads to unveiling of general principles. Only then is the student asked to integrate reading assignments from the textbook and primary literature on the topic with the specific experience gained in the laboratory. Students can gain proficiency in a number of important techniques currently used in neuroscience, and more importantly, they are actively involved in the process of learning, thereby reducing the difficulty in comprehension of technical jargon that characterizes scientific information transmitted either verbally or in writing.

Non-technical Summary Principal Investigator: Bitran, D. Proposal Number:IBN9724139 Neurochemical Analysis of Motivated Behavior The long-term goal of this project is to explore how chemical systems in the brain control motivated behavior. Among motivated behaviors, ingestive behaviors such as feeding and drinking have formed the focus of such studies. To develop general principles to explain the control of motivated behaviors, the results from studies on a variety of behaviors (e.g., reproductive behavior, aggression) are needed. To date, little is known about the neurochemistry of the motivational components of female reproductive behavior. The PIs have pursued studies showing a link between the mesolimbic dopamine system and the control of the incentive (e.g., reward) properties of female reproductive behavior, using female hamsters as our experimental model. The studies in this proposal are designed to further pursue this link between neural dopamine pathways and female reprodcutive behavior in three specific ways. First, the PIs intend to continue microdialysis studies demonstrating proximal relationships between female reproductive function and extracellular dopamine levels in the nucleus accumbens. The PIs have demonstrated that experienced female hamsters show higher, and more sustained extracellular dopamine levels during interactions with males compared with inexperienced females. As sensitization of responsiveness is one property of dopamine neurons repeatedly activated with drugs, the PIs will explicitly test whether this augmentation of nucleus accumbens dopamine levels in experienced female hamsters reflects a sensitized response of these neurons to stimuli received during mating encounters. This would be the first such demonstration of sensitization of dopamine neurons resulting from the expression of a naturalistic behavior. Our second goal is to provide a broader neurolo gical perspective on the relationship between dopamine and female mating behavior. To date, the nucleus accumbens and dorsal striatum are the only brain regions in which in vivo measurements of dopamine during mating encounters have been taken. The PIs intend to extend this analysis to other behaviorally-relevant dopaminergic terminal fields, such as the frontal cortex, medial preoptic area, and amygdala. In the context of these experiments the PIs will determine the degree to which dopamine in each of these areas is related to the expression of female mating behavior or some other factor associated with social encounters. A key issue in the interpretation of these behavioral findings centers around the degree to which individual dopaminergic neurons project to multiple targets. That is, do similarities or differences in dopaminergic activity in each terminal field derive from the activity of the same or different dopamine neurons. This is an unresolved issue for any species, and the PIs propose to determine quantitatively the degree to which individual dopamine neurons innervate multiple terminal fields. Together these studies will provide a framework for defining how functional dopaminergic pathways regulate different components of female reproductive behavior, providing a basis for developing generalizations of the role of dopantine in motivated behavior.

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).

The goal of this project is to increase substantially the number of Holy Cross undergraduates who enter the teaching profession in STEM disciplines, including students from underrepresented groups. The project consists of five elements: (1) aggressive marketing of the Holy Cross Teacher Education Program (TEP) and the Noyce Scholarship Program to first- and second-year students; (2) new opportunities for first- and second-year STEM majors to serve as paid tutors and mentors for local inner-city public and private school students learning concepts in mathematics and science; (3) restructuring of the practicum requirement in the Holy Cross TEP to remove scheduling barriers that uniquely affect STEM majors interested in teaching; (4) enhanced support and instruction specific to teaching science and mathematics for STEM majors enrolled in our TEP; and (5) implementation of induction and mentoring activities to support new STEM teachers once they begin their post-graduate teaching responsibilities. A total of 20 students are to be funded with scholarships through their junior and senior years and 70 student internships.