# Dysregulation of Appetitive & Aversive Amygdala Circuits in Bipolar Disorder

> **NIH NIH R01** · MCLEAN HOSPITAL · 2021 · $770,531

## Abstract

Bipolar disorder (BD) is characterized by profound affective dysregulation. Periods of aversive symptoms
(depression, anxiety, decreased appetitive drive), alternate with mania (a state of enhanced appetitive drive for
reward and pleasure). The clinical manifestation is heterogeneous, with diverse patterns of predominant
symptoms, severity and duration. Notably, there are no current robust neurocircuit models to account for these
clinical manifestations. Imaging and postmortem studies point to the amygdala, a nucleus embedded in circuits
involved in threat and reward responses. Recent breakthroughs from our group and others are beginning to
characterize molecularly identifiable, functionally divergent sets of amygdala neurons, which separately encode
and regulate aversive and appetitive behaviors. Specifically, distinct neuronal types within the mouse amygdala
promote aversive/fear responses (`FEAR-ON' neurons), vs. appetitive/reward responses (`APPT-ON' neurons).
Our preliminary data using single-cell RNA sequencing show that analogous molecularly defined neuronal
populations are present in human amygdala. Our overarching hypothesis is that neuronal populations
impacting valence encoding and motivated behavior (FEAR-ON vs. APPT-ON neurons), are disrupted in BD,
contributing to depression, anxiety and mania.
What factors may regulate the functions of FEAR-ON and APPT-ON circuitry in health and disease states? An
answer may lie within the distinctive molecular signatures of these neurons, consistent with their opposing
functions. First, FEAR-ON and APPT-ON neurons express distinct molecular factors known to regulate
fear/threat and reward processing within the amygdala, including anxiogenic (e.g. corticotropic releasing
hormone [CRH]) and anxiolytic (e.g. neurotensin receptor 2 [NTSR2]) factors, respectively. Second, a well-
validated distinguishing feature of amygdala FEAR-ON and APPT-ON neurons is their distinct expression pattern
of Wnt/β catenin signaling molecules. This feature indicates that Wnt/β catenin pathways differentially regulate
FEAR-ON and APPT-ON neurons. Pilot data also show altered expression of key molecules, including Wnt7a
and CRH in the amygdala of people with BD. Our specific hypothesis is that cell-specific FEAR-ON and APPT-
ON molecular factors modulating stress/anxiety and reward/appetitive behaviors are altered in BD, and that
disruption of Wnt/β catenin pathways contributes to distinct abnormalities FEAR-ON and APPT-ON neurons.
Human postmortem studies combining single-cell RNAseq, multiplex mRNA/protein cell labeling and quantitative
analyses of RDoC clinical domains will test the hypothesis that quantifiable clinical `fingerprints' in BD are
predictive of distinct patterns of molecular changes in FEAR-ON and APPT-ON neurons (Aims 1 and 2). Causal
manipulation in mouse genetic models will mechanistically test the hypothesis that a disruption of Wnt signaling
causally alters expression of reward- and stress- related mo...

## Key facts

- **NIH application ID:** 10168644
- **Project number:** 5R01MH120991-02
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** Sabina Berretta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $770,531
- **Award type:** 5
- **Project period:** 2020-05-20 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168644

## Citation

> US National Institutes of Health, RePORTER application 10168644, Dysregulation of Appetitive & Aversive Amygdala Circuits in Bipolar Disorder (5R01MH120991-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10168644. Licensed CC0.

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