Exposure to early life stress (ELS) including neglect, abuse, maternal separation or loss carries an increased risk for the development of anxiety and mood disorders. The overarching goal in my proposal is to examine gene expression profiles in a novel circuit through the primate amygdala that is implicated in persistent anxiety, and to determine how ELS may alter gene expression in this path. Neural networks involving the amygdala may exert effects on long-lasting anxiety behaviors through inputs to the bed nucleus of the stria terminalis (BNST). Recent work in rodents shows that the BNST important for the long-lasting ('tonic') effects of unconditioned stressors. In monkeys, BNST activity is correlated with individual differences in anxious temperament, a stable pattern of response to threatening stimuli. Our preliminary data indicate that a unique amygdala nucleus, known as the paralaminar nucleus (PL), may be a novel afferent input to the BNST in primates.
Aim 1 will determine if the PL has direct connections to the BNST, thus forming a conduit by which the amygdala influences long-lasting anxiety responses in the primate. The PL in both human and nonhuman primates contains a unique subpopulation of immature-appearing neurons not found in other amygdala regions, suggesting a special role in circuits through the region. Our preliminary immunocytochemical and molecular data suggest that the PL has capabilities for neural growth not seen in other amygdala regions. This suggests that the PL has unique plastic properties that may be important in the afferent regulation of BNST targets, particularly during development.
Aim 2 will examine the extent to which the PL is a distinct amygdala subregion based on enrichment in gene transcripts involved in neuronal development. Stress, including ELS, alters the maturation and survival of developing neurons. While classic studies on stress effects have largely focused on hippocampal development, changes in gene expression in the developing primate amygdala are also observed. Our preliminary data show that immature-appearing neurons in the PL constitutively express high levels of activated (CREB), a transcript known to be altered in ELS. We hypothesize that normal CREB expression in the PL has downstream effects on many transcripts involved in neural development, and is disrupted by ELS. Specifically, I hypothesize that ELS will alter the transcription of genes involved in CREB-related pathways that are involved in neural differentiation, growth, and migration.
Aim 3 will examine changes in PL gene transcripts in young monkeys exposed to ELS, focusing on CREB-mediated pathways.
Depression and anxiety disorders cause significant suffering and impairment, however current treatments are limited by our lack of understanding of the pathogenesis underlying these illnesses. Early life stress has been associated with the development of these disorders, as has dysfunction of the amygdala and one of its main output regions, the BNST. This project examines the hypothesis that the paralaminar nucleus (PL), an overlooked nucleus of the amygdala, is a site of neuronal development, is vulnerable to early life stress, and is a key input to the BNST.
