Kim Huhman, Ph.D. - US grants

The suprachiasmatic nucleus (SCN) in the anterior hypothalamus contains the major circadian pacemaker in mammals. The purpose of this proposal is to examine how the SCN communicates rhythmic information to its target tissues. The rhythmic neuroendocrine systems that will be investigated are the hypothalamic-pituitary-gonadal and hypothalamic-pituitary- adrenocortical axes. Efferent projections from the SCN to the hypothalamic sites that control these axes have been identified. These projections are known to contain a number of different neurochemicals and the different efferents, as characterized by their neurochemical content, appear to project to selective and specific target areas. Initially, this proposal will test the hypotheses that vasoactive intestinal peptide (VIP) and vasopressin (AVP) are inhibitory signals used by the SCN to time the proestrous surge of LH and the circadian rhythm of glucocorticoid release, respectively. These rhythms are robust and easily measurable and, because the temporal pattern of release of LH and glucocorticoids are so different, examination of both systems should provide more generalizable conclusions about SCN efferent mechanisms. Subsequently, this proposal will test the hypothesis that the inhibitory effects of VIP and AVP are mediated by gamma-aminobutyric acid (GABA). Finally, immunohistochemical studies will determine if VIP and AVP are colocalized with GABA within SCN efferents to the following hypothalamic sites: the medial preoptic nucleus, the paraventricular nucleus, the subparaventricular zone, or the dorsomedial nucleus. This study should contribute to our understanding of the basic mechanisms by which the SCN controls circadian rhythmicity. A better understanding of the principles of SCN efferent functioning may lead to more effective treatments for human disorders in circadian timing.

Social conflict is a major source of stress, and perhaps disease, in a variety of species, including humans. The outcome (i.e., whether an individual is a "winner" or a "loser") of even a relatively brief exposure to social conflict can produce profound and long-lasting changes in subsequent behavior and physiology. For example, when a Syrian hamster is defeated during a brief encounter in the home cage of a larger, aggressive opponent, the defeated hamster will subsequently fail to display normal territorial aggression in its own home cage even when the intruder is a docile, younger animal. This dramatic, yet easily obtainable, change in social behavior has been called conditioned defeat, and we propose that it represents an ethologically relevant and valuable addition to current animal models wherein behavioral responses related to stress, fear and anxiety are studied. The long term goal of this project is to define the neural events that trigger the profound changes in behavior that occur during conditioned defeat. There are currently no published data on the neural elements that regulate conditioned defeat. We propose that the basolateral amygdala, central nucleus of the amygdala and the bed nucleus of the stria terminalis (BNST) are critical for the acquisition and expression of conditioned defeat. This hypothesis was developed from several converging lines of evidence from studies on the neurobiology of defensive/submissive behaviors and of fear, as well as from strong preliminary data generated in our laboratory. The proposed studies will not only provide the first information on the anatomical sites mediating conditioned defeat, but they will also provide initial information on the neurochemical signals involved.

Project Summary Neuropsychiatric illnesses represent a wide range of complex emotional and behavioral disorders, but many of these are associated with maladaptive social responses. Unfortunately, we do not have a clear enough understanding of the neural mechanisms underlying these disorders or the fundamental symptoms they share. While it has become clear that there is a substantial overlap in the neural circuitry (i.e., the Social Behavior Neural Network) controlling different social and emotional behaviors, the technology to study how behavior emerges from such a complex interacting neural network has been lacking. Variation in social behavior, both across species and within individuals of given species, arises at least in part from genetic and epigenetic differences within the Social Behavior Neural Network, and we are now in a position to understand the molecular mechanisms mediating this variation. These genetic differences are expressed as variations in critical molecular elements of neural circuits such as neurotransmitters, receptors, transporters, growth factors, etc. A significant current limitation to progress in this area is that there are no well-established genome- engineering technologies for some of the best animal species for studying social behavior and organization. Among these organisms are Syrian hamsters (Mesocricetus auratus), which have proven to be an exceptionally useful rodent model for the study of social behavior and for which there is a wealth of data, much of which has been generated by the PIs, on the neurobiological and hormonal mechanisms controlling social recognition, social avoidance, aggression, and social communication. The goal of this project is to overcome this limitation by developing and implementing state of the art genome engineering technologies in the Syrian hamster model to enable molecular interrogation of how genes act within neural circuits to regulate complex social behavior. To achieve this goal, we will use genome engineering to generate transgenic and gene- targeted mutant hamsters that will be used to investigate the function of genes that have been implicated in social behavior. The generation of these transgenic and gene-targeted hamsters will be facilitated by our recently generated Syrian hamster transcriptome data, which will be used to specifically target and manipulate a variety of neurobehaviorally-relevant hamster genes. Initially, as a proof of principle, we will focus on the arginine-vasopressin V1a receptor because of the significance of this receptor in regulating a wide range of distinct social behaviors and our long-demonstrated expertise with studying this system. The successful development of transgenic and gene-targeting approaches for Syrian hamsters will provide transformative tools to the research community for exploring the neurogenetic bases of social behaviors.

PROJECT SUMMARY The rewarding properties of social interactions are critical to the expression of adaptive social behavior and to the development and maintenance of social relationships. Little is known, however, about the factors that determine the reward value of social interactions or about the basic neural mechanisms that underlie social reward, particularly in females. We do know that the mesolimbic dopamine system (MDS) is central to the neural circuitry controlling the rewarding properties of many other stimuli such as drugs of abuse. A primary component of the MDS is dopamine (DA)-containing neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens (NAc) as well as to other sites such as the medial prefrontal cortex. Critical inputs to the MDS include oxytocin (OT)-containing projections from the hypothalamus. We and others have demonstrated that, in male rodents, activation of OT receptors in the caudal VTA and in the NAc is essential for the rewarding properties of social interaction. Remarkably, despite the considerable evidence for sex differences in OT regulation of social behaviors, the role of OT in regulating social reward in females has not been investigated. This project will provide substantial new information on the factors that determine the reward value of social interactions and on the neural mechanisms that mediate social reward by testing this series of integrated hypotheses in male and female Syrian hamsters. Based on published and preliminary data from our lab and others, we have hypothesized that: 1) there is an inverted U relationship between the ?dose? of social interactions and social reward, 2) this dose-response relationship is initiated at lower doses in females than in males, and 3) this sex difference is mediated by differential OT-induced DA release in the MDS. This project has substantial potential for translation to clinically-related problems by providing: 1) new information on how social stimuli can transition from being rewarding to being less rewarding or even aversive, 2) potential mechanisms for understanding well-known sex differences in the incidence of neuropsychiatric and neurodevelopmental disorders for which dysfunctional social relationships are an important symptom, and 3) the potential for development of gender- specific treatments for these disorders.