Garet P Lahvis, Ph.D. - US grants

The Ahr knockout mouse allows us to answer many questions about the mechanisms by which TCDD induces toxicity and potentiates carcinogenicity. Further, this animal will give us great insight to the endogenous function of the AHR. This insight will likely provide us with new ways to understand the toxicology of TCDD. However, apparent differences in the phenotypes of two independently derived Ahr knockout mice obfuscate studies of the AHR. Disparate phenotypes between the Ahr null mice may result from variations in investigator protocol, environmental or genetic background, or targeting strategy. We propose to examine both Ahr null mice under identical environmental and genetic contexts to determine if the phenotypes remain different. If differences remain, then we will examine the effects of different targeting strategies on expression of the targeted allele and adjacent loci. As we reconcile differences between null animals, we will also examine variables that may affect their phenotypes, such as pathogen and pollutant exposure, with the hopes of identifying genes that modify responses to the targeted Ahr allele. Finally, we will pursue two endpoints, neonatal survival of null mice and liver size, to unravel some of the interactions between the Ahr and other mouse genes. It is hoped that through this work, we will gain much greater understanding of the interactions of the AHR with other gene products and thus identify other susceptibility genes for TCDD-induced toxicity and cancer potentiation.

DESCRIPTION (provided by applicant): Many neurodevelopmental disorders, including autism, fragile X syndrome, and schizophrenia, feature aberrant social behavior as a core characteristic. These disorders include a broad array of social impairments, ranging from deficits in shared attention, to communication delays, to social withdrawal. The underlying genetic causes of these social impairments remain largely unknown. Mouse models have tremendous value for elucidating the roles of genes in development. To more fully understand the genetics of social behavior, the investigators propose an expanded panel of mouse behavioral tests that allow them to explore small functional units of social behavior, or social endophenotypes. Specifically, three features of social functioning will be evaluated: the extent to which a social stimulus affects a trained goal-directed behavior, the extent to which social interaction can serve as reward or reinforcement, and the degree that a social stimulus can serve as a spatial cue for learning and memory. We propose to determine if these endophenotypes can be distinguished in five common inbred mouse strains. We then propose to determine if these endophenotypes are anomalous in knockout mice with known deficits in social behavior, including oxytocin and fosB knockout mice, and the N-methyl-D-aspartate receptor 1 hypomorphic mouse. It is expected that some of the knockout mice will exhibit more profound deficits in these measures than both wild-type littermates and the five inbred strains. By developing new measures of mouse social endophenotypes, the investigators can more precisely delineate the roles of particular genes in social functionality. In future projects, this work is likely to provide greater understanding of the neurobiological mechanisms underlying the social impairments that are associated with developmental disorders, such as autism.

[unreadable] DESCRIPTION (provided by applicant): Drug addiction is one of the most costly and devastating health problems in the United States. Adolescents are particularly susceptible to drugs of abuse, in part because they are motivated to take risks and they seek the social approval among their peers. While the neurobiology underlying the affiliative social behaviors of adults has been extensively studied over last few years, there neurobiology of adolescent social behaviors is not well understood and may represent distinct genetic influences. In support of this concept, we find that social approach behaviors among two strains of juvenile mice (BALB/c and C57BL/6) exhibit strain- dependent differences that are not influenced by gender. As these mice mature, strain-specific differences are displaced by the emergence of gender-specific differences in social behavior, suggesting distinct underlying genetics and neurobiology of adolescent and adult social behavior. The central hypothesis of this proposal is that drugs of abuse may co-opt social reward pathways of the adolescent phenotype. Opioids can interfere with adolescent social interactions and we find higher sensitivity towards opioids in the juvenile mouse strain that shows greater pro-social tendencies. We propose to examine (a) how natural rewards, such as access to social interactions and highly palatable foods, affect reward pathways in the adolescent mouse brain, (b) how the social environment affects the neural and behavioral response to morphine, (c) how morphine influences social approach and arousal and (d) the extent to which social reward is influenced by the concurrent manipulation of opioid receptors. With this foundation for understanding the adolescent mouse brain and behavior, we can envision a long-term research program that employs genetic and genomic strategies to elucidate the interplay between drugs of abuse and social approach during this unique period of development. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): There is a fundamental gap between human psychological experiences and how we study them in animal models. Humans typically learn and experience emotions within a variety of social contexts. By contrast, animal models are typically studied within an isolated environment. This discontinuity in social context imposes an obstacle to the development of treatments for psychological disorders. We propose a series of experiments that examine learning within the context of social interaction. The proposed experiments will allow us to develop and characterize new procedures for studying fear conditioning and extinction in the rodent laboratory, resulting in a novel conceptual framework for understanding the environmental, genetic, and molecular mechanisms that underlie learning and memory. To evaluate the interplay between learning and psychosocial experience, we need an environment sufficiently robust to impart translational relevance, yet simple enough to be accessible to multiple laboratories for routine assessments of genetically modified mice. Through a novel integration of readily available experimental tools, our model will focus on how different shared social experiences and non-social stimuli modulate the acquisition and extinction of fearful behaviors. In Aim 1, we propose to determine how two critical features of social interaction, familiarity and social motivation, influence the capacity for vicarious fear learning. In the proposed experimental paradigm, a subject mouse observes an object mouse receive cued fear conditioning, repeated trials in which a tone is paired with a shock. Depending upon the strain of mice tested, C57BL/6J (B6), BALB/cJ (BALB), or FVB/NJ (FVB), the subject mouse then expresses a conditioned fear response to the tone. We ask whether the capacity of a subject mouse to learn from an object mouse is sensitive to its social motivation and its familiarity with the animal undergoing the tone-shock contingency. In Aim 2, we ask how these same social variables, social motivation and familiarity, moderate the ability of a mouse to suppress a fearful memory; how social factors moderate fear extinction. We propose to examine juvenile mice of the B6, BALB, and FVB strains because they show robust fear conditioning yet differ in key social behaviors. B6 mice express greater levels of social interaction, social reward and vicarious fear learning relative to BALB mice. By comparing these three strains, we gain substantial insight to the role of social motivation in learning and extinction. We envision the proposed study will lead to a larger research program that reveals how social mechanisms enhance memory formation and extinction and that it will lead to novel models for a range of disorders that involve memory and social components, including PTSD, addiction, and autism.