Our group has developed a nonhuman primate model of adverse early rearing which results in long-standing anxiety-like behaviors accompanied by a range of biochemical alterations including alterations of concentrations of cerebrospinal fluid (CSF) neuropeptides, such as corticotrophin-releasing factor (CRF) and somatostatin (SOM), and monoamine metabolites of serotonin [5-hydroxy-indole-acetic acid (5-HIAA)] as well as dopamine [homovanillic acid (HVA)]. For this model, genetically random monkeys are reared as infants by mothers exposed to unpredictable variability in foraging demand (VFD). Of note, the neurochemical alterations observed in the VFD-reared primates bear resemblance to certain aspects of biogenic amine, neuropeptide and neuroendocrine disturbances observed in a number of clinical conditions. Our primary focus is that prefrontal cortical efferents, either directly or via thalamic nuclei efferents, utilize the glutamate neurotransmitter system and are hypothesized to be a primary source for neuronal stimulation of the """"""""fear"""""""" neurocircuitry. This fear network originates from the central nucleus of the amygdala (CeN) and bed nucleus of the stria terminalis (BNST). Both of these limbic structures contain particularly dense concentrations of CRF-producing neurons. We propose that excessive glutamatergic discharge consequent to adverse early rearing may provide a key contribution towards the hyper-excitation of these key neuronal populations which are involved in the behavioral manifestations of anxiety. Reduction in glutamatergic neurotransmission should therefore reduce anxiety levels and the concomitant biochemical alterations associated with VFD rearing. The major aim of this proposal is the pharmacological reduction of the anxious behavioral profile associated with VFD rearing through attenuation of the glutamatergic system, using a normative or low foraging demand (LFD)-reared control group. Ongoing neurochemical and behavioral assessments will provide extensive longitudinal documentation of the effects of such reductions.
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