Childhood anxious temperament (AT) is a key risk factor for developing anxiety and comorbid depression. In primates, AT is evident early in life, stable, and associated with increased threat reactivity. Early adversity is known to increase the risk of developing extreme AT. While adversity is common, the neural mechanisms linking it to AT are not understood. This understanding would permit identification of novel therapeutic targets with the potential for developing neuroscientifically-informed interventions. This proposal builds on work validating the AT phenotype and identifying the neural circuit underlying AT. Recent microarray and RNA sequencing (RNA-seq) work suggests the hypothesis that extreme AT reflects neuroplasticity deficits in the lateral division of the central nucleus of the amygdala (CeL), a key regulator of amygdalar outflow to regions that give rise to signs of anxiety, and the region most predictive of AT in our imaging work. This proposal aims to understand how peer rearing (PR), a controlled early adversity manipulation, causes extreme AT in primates, something not possible in human studies. The use of primates increases the likelihood that discoveries will translate to at-risk children. PR and maternally reared (MR) animals will be longitudinally assessed, testing adversity's impact on the development of AT. Repeated multimodal imaging will assess adversity's impact on the development of amygdala reactivity and prefrontal-amygdala anxiety regulation circuits. Importantly, the primate model affords an opportunity to test whether adversity's harmful effects on AT are mediated by alterations in CeL neuroplasticity pathways. Immunohistochemical and RNA-seq analyses will be performed on CeL microdissected neurons. This novel synthesis of tools promises new insights into how adversity-induced molecular alterations manifest in brain function, connectivity, and structure, and how these macroscopic changes contribute to extreme AT? insights not readily available from molecular-level rodent or systems-level human studies. Further, a stem cell model of CeL GABAergic neurons will be created and compared to neurons from CeL. A valid stem cell model would enhance understanding of AT's molecular bases and accelerate the screening of new therapeutics.

Public Health Relevance

: Unfortunately, early adversity is common and markedly increases risk for psychiatric disorders. This is likely due to adversity's harmful influence on the development of an extreme emotional disposition, termed Anxious Temperament. This proposal, which integrates advanced multimodal imaging and molecular methods in developing primates exposed to an adversity manipulation, has the potential to yield new mechanistic insights and set the stage for developing novel neuroscientifically-informed interventions.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1-ERB-L (02))
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University of Wisconsin Madison
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