The diathesis for suicidal behavior plays a major role in determining risk and includes aggressive and impulsive traits. Low serotonergic activity correlates with greater aggressive impulsivity. Genetic factors play a role in determining aggressive-impulsive traits and serotonergic activity. While suicidal behavior is unique to humans, certain associated behaviors such as aggression, impulsivity, novelty seeking and risk taking behaviors in animals may be of direct relevance to suicide-related behaviors in humans. Studies are proposed to examine the hypothesis that alterations in neurodevelopment may result in enduring impairment in the serotonergic system and an increase in impulsivity, novelty seeking and aggression in animals. To further understand these genetic-biological-behavioral relationships, three studies using different, but complementary, strategies are proposed. Study 1 (AGGRESSION IN SEROTONIN RECEPTOR KNOCKOUT MICE, R. Hen) will identify differences in aggressive behavior, serotonin receptor (serotonin transporter, 5-HT/1A, 5-HT/2A) concentrations, and differential gene expression in the brain of 5-HT/1B knockout mice (more aggressive) and compare them with less aggressive 5-HT1A knockout mice and wild type control animals. The genes that produce candidate proteins will be rescued in specific brain regions, and the resulting effects on aggressive behaviors will be determined. Behavioral genetics will be examined in two populations. One population, the vervet monkey component of Study 2 (SEROTONIN SYSTEM NEURODEVELOPMENT, M. Underwood), proposes studies of neurodevelopment to understand the conditions under which genetic factors influence behavioral outcomes. In this work, and in parallel experiments in knockout mice, candidate genes and the morphometry of serotonergic neurons in the dorsal raphe nucleus are examined. Study 3 (GENETICS OF TEMPERAMENT AND CENTRAL MONOAMINERGIC ACTIVITY IN PEDIGREED BABOONS, J. Kaplan) examines the second population, baboons, in a linkage study of candidate genes, aggression, novelty seeking and neurobiology (CSF indices). It offers the possibility of identifying the genetic loci of other genes possibly contributing to the aggression or the level of central monoaminergic activity.
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