Critical Periods in Development of Amygdala Inhibition: Effect of Prenatal Stress

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DESCRIPTION (provided by applicant): Anxiety disorders are widespread, particularly in juveniles, and are increasingly considered disorders of development. These disorders often emerge during developmental "critical periods," windows when brain circuits are highly plastic. One region which plays a central role in the expression and treatment of anxiety, the basolateral amygdala (BLA), experiences a postnatal critical period that may contribute to the emergence of anxiety disorders. Fearful and anxious behaviors are regulated by a balance between excitatory and inhibitory neurotransmission in the BLA, in particular by activity of 3-aminobutyric acid A (GABAA) receptors. The functional properties of GABAA receptors are determined by their expression of different subunits, and changes in expression of 1-subunits during development leads to drastic changes in the effects of this neurotransmitter system. Expression of the 11 subunit, which emerges postnatally, not only influences GABAA receptors, but also plays a vitally important role to organize the timing of critical periods. Because it plays such an important role in brain development and in the normal function of the BLA, the 11 subunit may be a point of vulnerability in the developing BLA. Interestingly, manipulations of 11 expression early in life significantly impact emotional behavior, but manipulations in adulthood do not. In this proposal we will characterize the normal development of 11 expression in the BLA, determine its effects on BLA neurotransmission, and identify whether manipulating 11 expression in the developing BLA has long-term effects on BLA neurotransmission and anxiety-like behaviors. Furthermore, we will test whether prenatal stress, which is a well-documented risk factor for anxiety disorders that has numerous effects on BLA development, influences the expression of 11 in the developing BLA. In summary, these studies aim to identify how 11-subunit expression influences development of the BLA and of emotional behaviors. Because this subunit plays a critical role in shaping neurotransmission of the BLA and organizing neural development, it is a prime candidate to regulate emotional development. Expression of the 11-subunit is sensitive to various environmental factors, including stress, so influencing 11 may be a mechanism by which early-life experiences alter neural development to promote or prevent anxiety disorders. If successful, these experiments will identify this protein as a potential target for preventative treatments for anxiety disorders, as well as identify developmental changes in the BLA that may contribute to normal emotional maturation. PUBLIC HEALTH RELEVANCE: Early-life stress is a well-documented risk factor for anxiety disorders, but the developmental changes that underlie this effect are unknown. These experiments are designed to study the effects of early-life stress on the development of a brain region that processes emotion, the amygdala. We will use a rat model of prenatal stress to explore how stress-induced changes in the developing amygdala can impact the maturation of emotional behavior and promote later-life anxiety.