# Brain Mechanisms Mediating Genetic Risk For Anxiety And Depression

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $726,995

## Abstract

PROJECT SUMMARY/ABSTRACT
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.

## Key facts

- **NIH application ID:** 9890860
- **Project number:** 5R01MH081884-12
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Ned H Kalin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $726,995
- **Award type:** 5
- **Project period:** 2008-09-17 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9890860

## Citation

> US National Institutes of Health, RePORTER application 9890860, Brain Mechanisms Mediating Genetic Risk For Anxiety And Depression (5R01MH081884-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9890860. Licensed CC0.

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