[P113]: High anxiety/aggressive mice exhibit serotonergic developmental deficits that persist into adulthood

Mouse models of human affective disorders are consistently associated with deficient serotonergic function, as manifested by reduced serotonin (5-HT) immunoreactive (IR) neurons and 5-HT contents. Adult ICR mice selectively bred for highaggression (NC900) reproduce common behavioral, pharmacological and neurological traits of human anxiety compared to mice selectively bred for low-aggression (NC100). Here, we examined whether NC900 mice also reproduce what is considered to be a primary etiologic feature of affective disorders, alterations in serotonin development. First, we evaluated whether embryonic day 13.5 (E13.5) NC900 mice exhibited decreased numbers of 5-HT IR neurons and reduced 5-HT contents by HPLC-EC, relative to NC100 mice and unselected ICR mice, and determined whether these deficits persisted into adulthood. Second, we determined whether our 5-HT neuronal measures were negatively correlated with adult anxiety-like behaviors and aggression. E13.5 NC900 animals exhibited dramatic reductions in the number of 5-HT IR neurons compared to NC100 mice, and these deficits persisted into adulthood (Fig. 1). NC900 mice also show reduced 5-HT contents in ventral striatum and amygdala, primary brain sites of motivation and emotion. Moreover, NC900 reliably expressed more anxiety-like and aggressive behaviors than NC100 animals. Taken together, these results, obtained from a forward, behavioral genetic mouse model, corroborate results obtained from a reverse genetic model of anxiety and aggression (Hendricks et al., 2003). Our findings provide further support for the notion that deficient serotonergic development is a primary pathogenic feature of affective disorders, like anxiety and aggression. Fig. 1. (A) E13.5 NC900 mice express deficits in number of 5-HT IR cells relative to NC100 mice, (B) which persist into adulthood.