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.
: 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.
|Dean 3rd, Douglas C; Planalp, Elizabeth M; Wooten, William et al. (2018) Association of Prenatal Maternal Depression and Anxiety Symptoms With Infant White Matter Microstructure. JAMA Pediatr 172:973-981|
|Fox, Andrew S; Oler, Jonathan A; Birn, Rasmus M et al. (2018) Functional Connectivity within the Primate Extended Amygdala Is Heritable and Associated with Early-Life Anxious Temperament. J Neurosci 38:7611-7621|
|Huo, Hai-Qin; Qu, Zhuang-Yin; Yuan, Fang et al. (2018) Modeling Down Syndrome with Patient iPSCs Reveals Cellular and Migration Deficits of GABAergic Neurons. Stem Cell Reports 10:1251-1266|
|Zhao, Gengyan; Liu, Fang; Oler, Jonathan A et al. (2018) Bayesian convolutional neural network based MRI brain extraction on nonhuman primates. Neuroimage 175:32-44|
|Kalin, Ned H (2018) Corticotropin-Releasing Hormone Binding Protein: Stress, Psychopathology, and Antidepressant Treatment Response. Am J Psychiatry 175:204-206|
|Dean 3rd, Douglas C; Planalp, E M; Wooten, W et al. (2018) Investigation of brain structure in the 1-month infant. Brain Struct Funct 223:1953-1970|
|Van Hulle, Carol A; Lemery-Chalfant, Kathryn; Hill Goldsmith, H (2018) Parent-Offspring Transmission of Internalizing and Sensory over-Responsivity Symptoms in Adolescence. J Abnorm Child Psychol 46:557-567|
|Jones, Jeffrey R; Kong, Linghai; Hanna 4th, Michael G et al. (2018) Mutations in GFAP Disrupt the Distribution and Function of Organelles in Human Astrocytes. Cell Rep 25:947-958.e4|
|Sarkisian, Katherine L; Van Hulle, Carol A; Hill Goldsmith, H (2018) Brooding, Inattention, and Impulsivity as Predictors of Adolescent Suicidal Ideation. J Abnorm Child Psychol :|
|Kecskemeti, Steven; Samsonov, Alexey; Velikina, Julia et al. (2018) Robust Motion Correction Strategy for Structural MRI in Unsedated Children Demonstrated with Three-dimensional Radial MPnRAGE. Radiology 289:509-516|
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