Alterations in neuroplasticity are strongly implicated in stress-related psychopathology. This proposal will use nonhuman primates (NHP) to investigate the extent to which altered neuroplasticity systems in the central nucleus of the amygdala (Ce) underlie anxious temperament (AT), the early risk phenotype for anxiety and depressive disorders. We will also investigate the effects of increasing neuroplasticity via an understudied, direct prefrontal cortex to Ce pathway, which will inform the development of pathway specific treatments focused on modulating Ce function. Anxiety disorders (ADs) commonly emerge during childhood, are highly prevalent, result in significant disability, and childhood onset predicts more severe and prolonged symptomatology. Despite current treatments, many individuals with ADs continue to be highly symptomatic and interventions aimed at mechanisms mediating the childhood onset of ADs would be ideal. To gain insights into the mechanisms underlying childhood ADs, and to conceptualize more effective interventions, we developed a NHP model of AT that is directly translatable to humans. Our studies demonstrate remarkable similarities between human and monkey AT, have elaborated AT?s neural circuit, and using RNA sequencing (RNA-Seq) have characterized molecular alterations in the Ce. To facilitate molecular, mechanistic studies, we developed intraoperative real-time MRI methods to reliably deliver viral vectors to select neural targets, including the Ce. Our work led us to posit a neurodevelopmental hypothesis suggesting that reduced neuroplasticity mechanisms in the Ce serve to maintain high levels of AT and its ultimate conversion to anxiety and depressive disorders. While much is known from rodent studies about the BDNF (brain-derived neurotrophic factor)-TrkB system in mediating fear, depressive behaviors, and antidepressant effects, our RNA-Seq and viral vector overexpression data from young primates also points to alterations in NT3 (neurotrophin 3)-TrkC signaling within the Ce as a pathway that contributes to pathological anxiety. To further explore the role of Ce NT3/TrkC and BDNF/TrkB systems in early-life pathological anxiety, we will use viral vectors to modulate neuroplasticity systems in the Ce and in a prefrontal pathway that directly regulates Ce. To assess effects we will use a unique combination of measures including: behavioral, neuroimaging, postmortem analyses, and RNA-Seq. Paralleling the in vivo experiments, we will use Ce-like neurons derived from rhesus induced pluripotent stem cells (iPSCs), to investigate mechanisms at a cellular level. The experiments in this proposal will provide evidence in primates for the involvement of altered Ce neuroplasticity in mediating early-life anxiety and will establish a translational rationale for exploring new therapeutic approaches in patients with anxiety and depression.

Public Health Relevance

An anxious disposition (anxious temperament) early in life greatly increases the risk of developing anxiety disorders and depression during adolescence and adulthood. We are using a cutting-edge combination of molecular genetic, stem cell and brain imaging technologies to better understand the differences in brain systems involved in mediating the early-life risk to develop anxiety and depression. The experiments in this proposal are the next step towards developing new, neuroscientifically-informed, treatment strategies designed to boost neuronal changes that may reduce suffering and prevent the risk of developing anxiety and depressive disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Prabhakar, Janani
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University of Wisconsin Madison
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United States
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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
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
Shackman, A J; Fox, A S; Oler, J A et al. (2017) Heightened extended amygdala metabolism following threat characterizes the early phenotypic risk to develop anxiety-related psychopathology. Mol Psychiatry 22:724-732
Oler, Jonathan A; Tromp, Do P M; Fox, Andrew S et al. (2017) Connectivity between the central nucleus of the amygdala and the bed nucleus of the stria terminalis in the non-human primate: neuronal tract tracing and developmental neuroimaging studies. Brain Struct Funct 222:21-39
Kalin, Ned H (2017) Mechanisms underlying the early risk to develop anxiety and depression: A translational approach. Eur Neuropsychopharmacol 27:543-553
Fox, Andrew S; Oler, Jonathan A; Shackman, Alexander J et al. (2015) Intergenerational neural mediators of early-life anxious temperament. Proc Natl Acad Sci U S A 112:9118-22
Cavanagh, James F; Shackman, Alexander J (2015) Frontal midline theta reflects anxiety and cognitive control: meta-analytic evidence. J Physiol Paris 109:3-15
Fox, Andrew S; Oler, Jonathan A; Tromp, Do P M et al. (2015) Extending the amygdala in theories of threat processing. Trends Neurosci 38:319-29
Fox, Andrew S; Kalin, Ned H (2014) A translational neuroscience approach to understanding the development of social anxiety disorder and its pathophysiology. Am J Psychiatry 171:1162-73

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