Susceptibility to neurobehavioral disorders, temperament, and stress responses arise from a complex interplay between genetic endowment and environmental factors, such as the mother/infant interaction. In both humans and rodent models, mother/infant interactions have been demonstrated to produce long-term effects on stress responsiveness, anxiety-like behavior and psychostimulant response. Many of these effects are thought to result from influences on the development and function of central dopamine systems. The availability of serotonin 5-HT2C receptor mutant mice affords a unique opportunity to dissect the role of the serotonin neurotransmitter system in influencing gene/environment interactions on neural substrates of stress responses and dopaminergic neurotransmission. Serotonin 5-HT2C receptor mutants exhibit alterations in the regulation of maternal behavior, novelty responses and enhanced dopaminergic neurotransmission (Preliminary Results). This proposal will test the hypothesis that the 5-HT2C receptor is an important mediator of serotonergic influences on mother/infant interactions and their long-term impact on offspring behavior. The proposal consists of three specific aims:
Aim 1. Examination of the effects of a 5- HT2C receptor null mutation on maternal and pup behavior.
Aim 2. Examination of the influence of maternal and offspring serotonin 5-HT2C receptor genotype on neural substrates of offspring stress responsiveness. This will be examined through fostering studies in which wild type and mutant pups are fostered to wild type, heterozygous and homozygous mutant mothers. Adult offspring will be examined using neuroendocrine, neuroanatomical and behavioral approaches.
Aim 3. Examination of the influence of maternal and offspring 5-HT2C receptor genotype on offspring dopamine system function. Several approaches will be applied to examine central dopamine systems in adult offspring of the fostering groups described in Aim 2. Neuroanatomical assessment of genes implicated dopaminergic neurotransmission will be performed, and in vivo microdialysis procedures will be used to assess extracellular dopamine levels in awake, behaving mice. ? ? ?
