Cellular and Molecular Basis of Hippocampal Atrophy in Depressed Female Monkeys
Clinical and experimental studies suggest that hippocampal volumes may be smaller in individuals with depression, although the cellular mechanisms underlying this relationship are unclear. Stressful life events are associated with an increased risk of depression, and animal models, exposed to chronic stress have been used previously to investigate hippocampal shrinkage in depression. Although the data from preclinical stress models are compelling, the degree to which stress responses in animal models are relevant to human depression remains controversial, particularly since women are at two-fold greater risk of depression and the animal models are mostly male rodents. Evaluation of the causes of reduced hippocampal volume in an experimental model that more closely resembles human depression would be valuable. We have developed a primate model of depression in adult female cynomolgus monkeys which closely resembles human depression, and recently observed that depressed monkeys have relatively small anterior hippocampi. The overall goal of this proposal is to evaluate hippocampal morphologic, cellular, and molecular characteristics in depressed and nondepressed female monkeys to determine whether the smaller hippocampi of depressed female monkeys are accompanied by reductions in neuropil and synaptic, spinous, and dendritic integrity. We have a unique and valuable collection of fixed, frozen hippocampi derived from the population of adult female monkeys in which the behavioral and physiological characteristics of depression were studied premortem for 4 years. Using the tissue from 8 depressed and 8 nondepressed monkeys we will determine astrocyte, pyramidal, and granule neuron size and number, and protein and mRNA levels of markers of synaptic, spinous, and dendritic integrity in the cornu ammonis (CA) CA1, CA2, CA3, and DG of the anterior and posterior HC of behaviorally depressed and nondepressed monkeys. The results of this study will establish the use of the model in future investigations of the mechanisms of depression and the efficacy of interventions for depression. The research is particularly responsive to the FOA entitled "Advancing Novel Science in Women's Health Research" (PAS-07-381). The results of the proposed study will be used in support of a competitive NIH application. PUBLIC HEALTH RELEVANCE: Depression is a significant health problem in the US, particularly in women, as 20% of reproductive-aged women experience clinically significant depression. Unfortunately very little research has been conducted in female animal models of depression. The use of the first primate model of adult depression in females proposed here, which has greater similarity to human neurobiology and depression than rodent models, will advance our understanding of the neurobiology of depression especially in women.