# Brain Mechanisms Mediating Genetic Risk for Anxiety and Depression

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $778,409

## Abstract

PROJECT SUMMARY – Pathological anxiety commonly emerges during childhood and is a prominent risk
factor for the later development of anxiety and depression. To gain insights into mechanisms underlying the
risk to develop stress-related psychopathology, we developed a non-human primate (NHP) model, termed
anxious temperament (AT). This model allows for mechanism-based studies focused on the well-developed
prefrontal cortex (PFC) shared by NHPs and humans. In this regard, we demonstrated involvement of PFC
regions such as the dorsolateral PFC (dlPFC) in pathological anxiety, along with the amygdala and other
subcortical AT-related regions. Neuroimaging research points to hypoactivation of the dlPFC in anxiety and
depression. The dlPFC is involved in emotion regulation, working memory, and cognitive control, and
modulates activity of limbic regions, such as the basolateral amygdala (BLA). Importantly, the dlPFC serves as
a treatment target for neuromodulation strategies such as repetitive transcranial magnetic stimulation (rTMS)
and is thought to be involved in mediating the effects of various cognitive therapies. Because of the
evolutionary relatedness between NHPs and humans, especially manifested in PFC development, NHPs are
ideally suited for investigations of the role of the PFC in psychopathology. As a translational bridge, our
laboratory employs methods that provide an in-depth mechanistic understanding of brain alterations associated
with extreme anxiety, including behavioral phenotyping, functional and structural neuroimaging, RNA
sequencing and viral vector-mediated gene delivery. The focus of this proposal is to characterize the molecular
substrates of the dlPFC in relation to AT, to understand how its top-down regulatory influences impact the BLA,
a mediator of AT, and to explore the dlPFC as a treatment target. Our laboratory is uniquely suited for this
endeavor as we use an integrative strategy in NHPs with behavioral phenotyping, multimodal imaging,
chemogenetics, electron microscopy and single nuclear RNA sequencing (snRNA-Seq).

## Key facts

- **NIH application ID:** 10863816
- **Project number:** 5R01MH081884-16
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Ned H Kalin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $778,409
- **Award type:** 5
- **Project period:** 2023-06-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863816

## Citation

> US National Institutes of Health, RePORTER application 10863816, Brain Mechanisms Mediating Genetic Risk for Anxiety and Depression (5R01MH081884-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10863816. Licensed CC0.

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