Rodney Samaco, Ph.D. - US grants

DESCRIPTION (provided by applicant): The overarching goal of this proposal is to gain insight into the plasticity of social behavior, and to identify the neuroanatomical and molecular determinants that contribute to social behavior. Social behavior is governed by both genetic and environmental factors, yet the genetic basis for normal social behavior remains poorly explored in spite of a need to better understand it for human health. This is underscored by numerous recent findings implicating dozens of susceptibility loci in autism spectrum disorders (ASDs), whose core features include marked deficits in social interaction. To gain insight into the underpinnings of social behavior, we propose to study abnormal social behavior in two mouse models of syndromic autism, the Tsc1 and Fmr1 mouse models. Single gene mutations account for a subset of syndromic ASD and mouse models of these disorders provide the opportunity to experimentally test and understand how these genes contribute to autism- like phenotypes. We hypothesize that social behavior is sensitive to the temporal requirement of either Tsc1 or Fmr1 gene function. We further hypothesize that specific neuronal populations are responsive to social stimuli, and that the loss of Tsc1 or Fmr1 may disrupt the pattern of neuronal activation in specific brain regions due to an underlying defect in common molecular targets. The Specific Aims of the proposed work are i) investigate the temporal requirement of Tsc1 and Fmr1 for normal social behavior and the plasticity of social behavior by deleting and restoring the expression of these genes'functions in the adult mouse brain using conditionally inducible mouse models, ii) identify the neuronal populations responsive to social stimuli and examine alterations in their activity in Tsc1 and Fmr1 mouse models by analyzing the pattern of immediate early gene expression during social interaction, iii) elucidate the molecular determinants of abnormal social behavior in Tsc1 and Fmr1 mouse models using RNA sequencing, two-dimensional liquid chromatography and mass spectrometry, and protein antibody microarray platforms. Because ASDs are a prominent public health concern with a current prevalence rate of 60 cases per 10,000 children, and in some populations more than 110 cases per 10,000 children, the proposed work is designed to determine if social behavior can be modified, and possibly corrected, in neuropsychiatric conditions during the adult stage of life. The research aims will also inform us of the neuroanatomical determinants and molecular targets that may be critical in the manifestation of social behavior phenotypes. Together, our findings will provide the foundation for future work designed to improve social behavior phenotypes in humans by either genetic or pharmacological means. PUBLIC HEALTH RELEVANCE: ASDs constitute a prevalent and devastating group of neuropsychiatric disorders affecting as many as 1:100 - 1:150 children. The proposed work will determine if social behavior deficits, such as those characteristic of ASDs, are reversible in adulthood, and will identify the neuroanatomical and molecular pathways that determine healthy social interactions. Defining the fundamental neuronal and molecular changes related to social behavior impairments has far-reaching benefits for human health, given that ASDs are a rising, prominent public health concern.

? DESCRIPTION (provided by applicant): The Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (BCM IDDRC) was established August 1, 1988, and has been continuously funded with the last renewal of funding July 1, 2009. The BCM IDDRC is committed to advancing research in intellectual and developmental disabilities (IDD) to address the problems encountered by individuals with IDD and their families. Specifically, the mission of the BCM IDDRC are to identify as many causes of intellectual and developmental disability as possible, to understand the mechanisms mediating these disorders, to prevent these disorders, and to provide interventions that can improve the quality of life of affected individuals and ameliorate their disability whenever possible. The specific objectives are: 1) To enhance IDD research activities at BCM by encouraging and focusing research efforts on etiology, diagnosis, prevention, mechanism of pathogenesis, and the development of therapies to treat IDD, 2) To develop and provide innovative and critical core facilities to enhance IDD research at BCM, 3) To promote a multidisciplinary approach to IDD research by improving interactions between Center investigators and recruiting new investigators into the field of IDD research, and 4) To promote scientific and collaborative interactions with investigators outside BCM who have demonstrated a major commitment to study and treat IDD. The BCM IDDRC is structured around the major themes of discovering the genetic and genomic basis of IDD, developing disease models of IDD, performing detailed pathogenesis studies of IDD, and developing novel therapies for IDD. The mission and goals of the BCM IDDRC will be accomplished by providing innovative, important, and cost-effective research core services to support high quality investigators and research projects aligned with the mission, goals, and objectives of the IDDRC. The BCM IDDRC proposes A) an Administrative Core, B) a Clinical Translational Core, C) a Rodent Neurobehavioral Core, D) a Neurovisualization Core which includes Neuropathology, Confocal, and RNA in situ, and (E) a Neuroconnectivity Core which includes Viral Production, Optogenetics, and In vivo Physiology. Additionally, the BCM IDDRC will support an innovative preclinical research project entitled Steps towards a paternal gene activation therapy for Angelman syndrome that will develop novel, genetically based treatments for that neurodevelopmental disorder. These core resources will support 45 investigators and 56 NIH funded research projects. Over the last 25 years the BCM IDDRC has been remarkably successful in fostering the discovery of the causes of IDD, determining the pathophysiology of IDD, and developing treatments for IDD. Ongoing funding will allow the Center to continue to support and expand these efforts at BCM.

The primary goal of the Preclinical & Clinical Outcomes (PCO) Core is to provide the infrastructure, expertise and resources to support bi-directional translational efforts spanning animal and human research. Combining the expertise of neurobehavioral tools in animal models and neuropsychiatric assessment methods in humans will ensure the use and development of maximally relevant tasks and measures, helping to address challenges in translational research in IDD. The PCO Core will provide investigators with a battery of validated assays for rodents and humans, with a focus on creating a translational pipeline, as well as harmonizing measures across studies. In addition, the PCO Core will provide access and training on the use of additional behavioral assays that will allow IDDRC investigators to perform critical secondary or follow-up studies to better understand the nature of any behavioral abnormality detected with a primary behavioral test battery. The Animal Phenotyping & Preclinical Endpoints sub-core provides resources for investigators to perform behavioral assessment across various domains in rodent models. This core also focuses on development of robust preclinical outcome measures for assessment of potential interventions, serving as surrogate endpoints in treatment paradigms for potential therapies. The animal phenotyping sub-core provides high quality, cost effective behavioral assessments in rodent models, expert consultation for experimental design and data analysis and training investigators to conduct behavior assessments independently. It also offers educational workshops on various topics and data analysis, technical issues, trouble-shooting and development of novel assays as preclinical outcome measures. The Human Phenotyping and Neuropsych Measures sub-core provides neurobehavioral and neuropsychiatric assessment tools, comprising questionnaire-based methods, structured clinical interviews, and task-based measures. Some of the innovative approaches provided by the human phenotyping sub-core includes a novel computer vision-based technique for quantifying dynamics of facial expression, posture, and gaze (automated multimodal analysis), and bio-behavioral sensing, to move beyond traditional assessment approaches. Investigators can access consultation and guidance regarding developing phenotyping batteries, which may involve the creation or utilization of novel approaches. They can also access training and/or supervision in implementing and analyzing varied tasks, together with quality assurance resources. The human phenotyping sub-core will also provide direct service in implementing tailored phenotyping approaches for mental health conditions frequently prevalent in IDD. Finally, investigators can access consultation regarding building animal to human models of disease state to facilitate translation. Thus, the PCO Core's set of unique resources and broad expertise provides IDDRC Investigators a cost- effective and flexible means for conducting cross-species translational research in IDD. .