# Limbic-midbrain interactions in defense and emotional arousal

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2022 · $617,634

## Abstract

Exaggerated emotional reactivity, impaired social function, aberrant regulation of defense behaviors, and
autonomic dysregulation are a constellation of debilitating symptoms that are present in a range of anxiety
disorders. Anxiety disorders, as a group, impact about 20% of the US population and treatments for anxiety
disorders are only partially effective and often associated with side effects. While most attention has focused
on fronto-limbic circuitry, a current gap in knowledge is the contribution of hindbrain circuits. A second major
gap is how hindbrain and forebrain sites interact. Moreover, the vast majority of circuit-level characterization
has occurred in rodent models, which leads to the third major gap in knowledge: the functional organization of
these circuits in non-human primates. Indeed, as evidenced by findings in our lab and by others, the primate
brain is organized in often surprisingly different manners than the rodent brain. Thus, understanding the
organization of these circuits in the primate brain is essential to understanding the organization of the human
brain. We have previously found that acute disinhibition of the deep layers of the superior colliculus (DLSC), a
midbrain structure, by focal infusions of the GABAA antagonist, bicuculline, precipitated a state of exaggerated
defensive and emotional reactivity (DER). Concurrent inhibition of the basolateral amygdala (BLA) reduced
some but not all of the defense responses, suggesting differential circuitry underlying individual components of
the defensive response. In this application, we propose to determine the circuit architecture by which hindbrain
(DLSC, PAG) and forebrain (BLA, central nucleus of the amygdala, pulvinar) regions interact to produce
defensive emotional reactions, unconditioned fear, dysregulation of social behavior, and autonomic arousal. In
the two proposed specific aims, we will test the hypotheses that induced inhibition of the limbic components will
attenuate the DER evoked from the midbrain structures and that induced inhibition of midbrain structures will
attenuate the DER evoked from the forebrain. Using MRI-guided intracerebral microinfusions, we will
transiently activate and inactivate components of this network and determine the resulting impact on anxiety-
relevant behavioral responses. Following these experiments, we will employ anatomical tracer techniques to
characterize projection pathways of interest. We will also perform validation experiments using Designer
Receptors Exclusively Activated by Designer Drugs (DREADDs), which have grown in use in rodents, but
remain rarely used in primates, to help move this translational technology forward. We expect that our data will
have implications for understanding the pathology of anxiety disorders.

## Key facts

- **NIH application ID:** 10312050
- **Project number:** 5R01MH120638-03
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Patrick Alexander Forcelli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $617,634
- **Award type:** 5
- **Project period:** 2020-02-03 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312050

## Citation

> US National Institutes of Health, RePORTER application 10312050, Limbic-midbrain interactions in defense and emotional arousal (5R01MH120638-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10312050. Licensed CC0.

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