Joshua A. Gordon - US grants

DESCRIPTION (provided by applicant): To prepare the candidate for an independent career in neuroscience research, training and research plans are proposed. The training plan combines formal mentorship, didactics, seminars and meetings to facilitate the acquisition of: (1) laboratory skills related to the breeding, maintenance, and behavioral and neurophysiological characterization of genetically modified mice; (2) a fund of knowledge and ability to think creatively regarding genetic models of psychiatric disease how to exploit them; (3) exposure to issues in the responsible conduct of research; and (4) experience in effective laboratory management. The research plan entails the evaluation of serotonin 1A receptor (5-HT1AR) mutant mice, which have increased anxiety related behaviors. Understanding the effects of 5-HT1AR deletion that lead to this phenotype has the potential to help further define the neurobiology of anxiety disorders, and may help identify new targets for anxiolytic therapies. 5-HT1AR expression is required in the forebrain during development to establish normal anxiety-like behaviors, suggesting that the 5-HT1AR acts early in life to set up neuronal circuits underlying these behaviors. The goal of this project is to identify and characterize neurophysiological consequences of the disruption of 5-HT1A receptor expression that correlate with the anxiety-related phenotype. The following hypotheses will be tested: (1) the lack of 5-HT1AR expression during development results in functional dysregulation of the hippocampus, resulting in the phenotype; and (2) this dysregulation is relevant to innate anxiety-like behaviors in intact mice. Awake, behaving neural recordings will be obtained from the hippocampus, with these Aims: (1) evaluating hippocampal activity in 5-HT1AR knockout mice; (2) evaluating hippocampal activity in animals with a forebrain rescue of 5-HT1AR-deficiency expressed only during development or only in adulthood; (3) investigating the relationship between hippocampal activity and innate anxiety through behavioral and pharmacological manipulations; and (4) comparing neurophysiology behavior relationships across dorsal and ventral hippocampal regions, which may have differential involvement in the mediation of innate anxiety. Completing these plans will suggest new areas of investigation related to anxiety disorders, and provide the candidate with the knowledge and experience necessary to develop and characterize other genetic models of psychiatric illness.

DESCRIPTION (provided by applicant): The current proposal is aimed at understanding the neurobiological mechanisms underlying anxiety disorders. Furthering the understanding of anxiety disorders remains a key public health goal, as these disorders represent a large burden to society in morbidity and related costs. Data from human and animal studies implicate the serotonin system, and specifically one particular serotonin receptor, the 1A receptor (5-HT1AR), in the generation and/or regulation of anxiety. Agents which activate the 5-HT1AR, such as serotonin reuptake inhibitors or 5-HT1AR agonists, are anxiolytic both in humans and in animals. Accordingly, genetic deletion of the 5-HT1AR during development results in a robust adult phenotype of increased anxiety-like behavior. Understanding the precise mechanisms by which 5-HT1AR deficiency results in increased anxiety-related behavior promises to add to our understanding of the neurobiology of anxiety. We have recently found evidence of an anxiety-related increase in hippocampal activity, in the form of increased theta oscillations, in 5-HT1AR knockout mice. These data are in agreement with recent findings demonstrating that lesions of the ventral hippocampus increase anxiety. The proposed experiments will test the resulting hypothesis that the increased hippocampal activity accounts for the phenotype of increased anxiety in 5-HT1AR- deficient mice. In particular, we will combine molecular genetic and in vivo neural recordings in behaving mice to address three key questions. First, we will use tissue- specific expression of the 5-HT1AR to ask whether hippocampal receptors are sufficient to reverse the behavioral and physiological phenotypes seen in the knockouts. Second, we will record simultaneously from the ventral hippocampus and downstream structures in wild-type and knockout mice during anxiety-related tasks, to determine if and how these structures coordinate their activity. Third, we will test whether specifically increasing theta oscillations is necessary and sufficient to cause increased anxiety- related behavior. Addressing these three issues will clarify the mechanisms by which 5- HT1AR deficiency causes increased anxiety. Furthermore, they may identify specific patterns of activity in specific neural areas which generate anxiety, providing novel functional targets for therapeutic intervention. Public Health Relevance This proposal is inherently translational in nature, aimed at elucidating the neurobiological substrates of psychiatric disease. It is aimed at identifying specific patterns of brain activity which relate to anxiety. Establishing such relationships would set the stage for a novel approach to anxiolytic therapies, aimed at disrupting these specific patterns.

6. Project Abstract This proposal aims to develop and implement a residency training research track with the explicit goal of recruiting MD, PhD and medical graduates with a track record in conducting research. The program will provide early exposure to clinical research to stimulate interest in translational research among our basic science trainees. The program provides 7 months of exposure to translational research in both inpatient and outpatient clinical research settings, and 16 months of protected time for a mentored research project. These months will be augmented by intensive mentoring, overseen by the Pis, functioning as meta-mentors, as well as preceptorship focused on ethics, statistics, research design and principles of translational research. All this will be attained while meeting ACGME requirements so that graduates will be board eligible. We anticipate that such a track, which we conceptualize as a 4 year program, will permit research track residents to jump start their research career while still residents, rendering them better prepared for research fellowships and the K award process, ultimately leading to careers as independent investigators. Because this is a 4 year program leading to board eligibility, we offer our trainees a no-risk path towards enhanced likelihood of success as independent investigators. This approach is intended to remedy the current state of affairs wherein MD, PhDs often are faced with re-starting their research after a hiatus created by the need for clinical training. We anticipate educating physician-scientists to enhance the pipeline of translational investigators, a key goal of the NIMH.

DESCRIPTION (provided by applicant): Patients with schizophrenia typically suffer from severe and disabling cognitive function, including disturbances in executive function and working memory. To clarify the neurobiology underlying these disturbances, we have studied cognitive function in mouse lines engineered to model a microdeletion on chromosome 22, an etiologically relevant mutation unequivocally associated with susceptibility to schizophrenia. Patients with schizophrenia, as well as subjects with these mutations, have pronounced disturbances in cognitive tasks that depend on the hippocampus and prefrontal cortex. Mice carrying the microdeletion perform poorly in tests of spatial working memory. We have recently shown that deficits in functional connectivity between the hippocampus and prefrontal cortex contribute to this spatial working memory dysfunction in these mice. Building on these findings, we propose to (1) examine the molecular basis of these effects by studying working memory and hippocampal-prefrontal connectivity in mice carrying mutations of single genes within the microdeletion region; (2) study the role of the ventral hippocampus in the behavioral and physiological phenotypes in the mutants, and (3) study the role of the thalamus in these phenotypes. The proposed experiments serve both basic and translational goals. Understanding of the neurobiological mechanisms of working memory in the mouse is an important step in determining the relevance of such models to cognitive tasks studied in humans. Exploring these mechanisms in mice carrying schizophrenia-predisposing mutations uses this understanding to identify the behaviorally relevant neural consequences of these mutations. The end goal of this work is to develop an integrative model of schizophrenia pathogenesis and pathophysiology that demonstrates how these genetic lesions alter neural cells, circuits and systems to disrupt cognitive function.

DESCRIPTION (provided by applicant): The current proposal is aimed at understanding the neurobiological mechanisms underlying anxiety disorders. Furthering the understanding of anxiety disorders remains a key unmet public health goal, as these disorders represent a large burden to society in morbidity and related costs. Our previous studies with wild-type and serotonin 1A- receptor knockout (5-HT1AR KO) mice have implicated a circuit consisting of the ventral hippocampus (vHPC), the basolateral amygdala (BLA), and the medial prefrontal cortex (mPFC) in regulating anxiety-like behavior in various paradigms. Most notably, we have shown that these three regions functionally interact during anxiety, and that the strength of these interactions (1) correlates with anxiety and (2) is greater in the highly anxious 5- HT1AR KO mice than in wild-type littermates. Furthermore, our data suggest that the mPFC uses these interactions to construct a map of the aversiveness of the environment, which in turn is used to guide behavior. However, these observations are primarily correlative in nature. In this renewal application, we propose to directly test the hypothesis that the vHPC and BLA drive neural representations of aversiveness and anxiety-related behavior via their interactions with each other and with the mPFC. We will use a variety of pharmacological, optogenetic and pharmacogenetic tools to silence the vHPC and/or BLA, combined with in vivo neurophysiology to probe the role of these regions in the neural representations of aversiveness within the mPFC as well as anxiety-like behavior. In parallel, we will use emerging technologies aimed at silencing specific projections from and between these brain regions to determine whether and how these specific projections are required. These experiments will be performed in both wild-type and 5-HT1AR KO mice to test their relevance to pathological as well as physiological anxiety mechanisms. Addressing these issues will clarify the mechanisms by which these brain structures modulate anxiety-like behavior, and may help identify specific patterns of connectivity and activity that underly anxiety, providing novel functional targets for therapeutic intervention.

DESCRIPTION (provided by applicant): This proposal aims to continue and improve upon a residency training research track with the explicit goal of recruiting MD/PhD and medical graduates with a track record in conducting research. The program provides early exposure to clinical research to stimulate interest in translational research among our basic science trainees. There are 7 months of exposure to translational research in both inpatient and outpatient clinical research settings, and 14.5 months of protected time for a mentored research project. These months will be augmented by intensive mentoring, overseen by the PIs, functioning as meta-mentors, as well as preceptorships focused on ethics, statistics, research design and principles of translational research. All this will be attained while meeting ACGME requirements so that graduates will be board eligible. We already have early evidence that such a 4-year program permits research track residents to jump start their research career while still residents, rendering them better prepared for research fellowships and the K award process, ultimately leading to careers as independent investigators. Because the program leads to board eligibility, we offer our trainees a no-risk path towards enhanced likelihood of success as independent investigators. This approach is intended to remedy the current state of affairs wherein MD, PhDs often are faced with re-starting their research after a hiatus created by the need for clinical training. We anticipate educating physician-scientists to enhance the pipeline of translational investigators, a key goal of the NIMH.