Aaron M. Jasnow - US grants

Many species experience social stressors during their lifetimes. This is especially true for humans, whose overwhelming source of conflict and stress is social in nature. A large body of evidence suggests that exposure to traumatic events or persistent high levels of stress are linked to the development and expression of a number of stress-related disorders (i.e. PTSD, depression, anxiety disorders). Animal models of stress-related disorders have provided important information about the neurobiological basis of many psychopathologies. Very few models, however, have examined these disorders in a biologically relevant paradigm. Conditioned defeat in Syrian hamsters provides an ideal model for studying the neurobiological basis of stress-related disorders in an ecologically relevant context. The goal of the current proposal is to explore the neuroanatomical and neurochemical basis of conditioned defeat by using site-specific microinjections into specific brain nuclei. The present proposal will test the hypothesis that the brain areas and neurochemicals that are involved in fear, anxiety and behavioral responses to stressors, in general, are also critical in the acquisition and expression of conditioned defeat. The results of the current proposal will provide important insight into the underlying physiological mechanisms of conditioned defeat. Additionally, these data will contribute to our knowledge about the neurobiological basis of human stress-related disorders.

DESCRIPTION (provided by applicant): Natural fluctuations in estrogens have been associated with a number of affective disorders in humans. In particular, low levels of circulating estrogens are associated with increased symptoms of depression, anxiety and cognitive dysfunction, which can often be ameliorated with hormone replacement therapy. Little is known about the mechanisms or the sites of action through which estrogen is influencing emotion, however, they likely occur within the amygdala. Therefore, a comprehensive analysis of the effects of estrogen within the amygdala is needed to further our understanding of how this steroid hormone influences the development of neuropsychiatric disorders in humans. The goal of the current proposal is to (I) determine the genomic and neurochemical actions of estrogen within the amygdala and (II) how they influence fear and anxiety in female rodents. This will be accomplished by examining estrogen-induced changes in gene expression within each region of the amygdala using quantitative-real-time-PCR (Q-PCR). These experiments will be followed by functional studies in which gene function knockdown with a novel antisense oligonucleotide moiety will be used to examine how estrogen-regulated genes influence fear and anxiety. These data will contribute to our knowledge of the hormonal mechanisms underlying fear and anxiety.

PROJECT SUMMARY/ABSTRACT Excessive associative fear is a hallmark symptom of many anxiety disorders and phobias. These disorders frequently co-occur with substance abuse or mood dysregulation, severely complicating treatment and the recovery process. The nucleus accumbens (NAc), critically involved in reward and substance abuse, is also implicated in aversive processing (ie., fear). Yet how the NAc is regulated by the amygdala and the infralimbic cortex (IL), two critical regions implicated in controlling fear responses, is not clear. Robust glutamatergic axons from the basolateral amygdala (BLA) and the IL innervate both shell and core NAc subregions. To evaluate how fear responses are modulated by these glutamatergic inputs into the NAc, we use an associative fear conditioning paradigm in mice. This involves having mice associate a previously neutral conditioned stimulus (CS; auditory tone) with an unconditioned stimulus (US; mild foot shock) that produces a threat response, quantified by measuring the natural freezing of mice (higher freezing indicates more fear). This associative fear response is reduced by repeated CS-alone presentations, a process called extinction that has major implications for exposure therapy in humans. We have previously shown that optogenetic activation of specific glutamatergic BLA neurons promoted the consolidation of extinction without affecting fear expression. Our pilot data here demonstrate that optogenetic stimulation of BLA terminals in the NAc enhances the consolidation of fear extinction. In addition, we show that inhibiting group I metabotropic glutamate receptors (mGluRs) significantly impairs the consolidation of extinction but has no effect on fear expression. Blocking AMPA receptors, however, reduces fear expression without altering extinction learning. The BLA and IL are critical nodes involved in fear acquisition, expression, and extinction. The NAc is a target of BLA and IL axon terminals and both circuits are important for modulating aversive behaviors. To evaluate if BLA-NAc and IL-NAc glutamatergic projections modulate fear expression and extinction learning, we propose to optogenetically activate or inhibit BLA or IL neurons that project specifically to the NAc during fear testing or extinction (Aim 1). In Aim 2 we will pharmacologically evaluate the roles that AMPA receptors and mGluR1 in the NAc play in fear expression and extinction learning. Next, we will extend characterization of this circuit by further determining which glutamate receptors are responsible for BLA or IL driven fear responses. These novel experiments will improve understanding of the circuitry involved in associative fear processing within the NAc. Because this brain region is also implicated in mood and substance abuse disorders, these experiments will contribute a critical framework for investigations into the mechanisms of co-morbidity.