# Discrete Functions of Basal Forebrain Cholinergic Signaling to Amygdala and Orbitofrontal Cortex in Reversal Learning

> **NIH NIH K08** · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · 2024 · $197,235

## Abstract

This proposal describes a four-year research career development program for an MD/PhD studying the
circuit physiology of cognitive flexibility, which has relevance for a largely unaddressed symptom domain seen
in schizophrenia (SCZ), autism spectrum disorder (ASD), post-traumatic stress disorder (PTSD), and other
conditions. The proposed studies build upon the candidate’s foundation in rodent behavior and advanced cell
and molecular biology techniques, but they will require training to develop new, complementary skills in two
key dimensions: A) computational modeling of combined neural and behavioral data sets, and B) using
synapse-specific optogenetic and pharmacologic manipulations together with state-of the-art markerless
behavioral tracking tools to perform behavioral experiments with real-time interventions. These training goals
are reflected in the expertise of the involved co-mentors (Drs. Christoph Kellendonk and Kiyohito Iigaya),
tailored seminars and didactics, and the strong neuroscience training environment at New York State
Psychiatric Institute and Columbia University. Completing the proposed studies and multi-faceted training plan
will position the candidate with a sought-after combination of skills that will facilitate transitioning into a
productive, independent physician-scientist studying cognitive dysfunctions in mental disorders.
 Acetylcholine (ACh)-releasing neurons of the basal forebrain (BF) are implicated in associative learning
and behavioral flexibility, as measured via the paradigm of reversal learning. However, the timing and
behaviorally relevant effects of ACh input to BF target regions involved in reversal learning, including the
basolateral amygdala (BLA) and lateral orbitofrontal cortex (LO), remain largely unexplored. Probing these
mechanisms has translational importance, as reversal learning deficits are measurable in people with SCZ,
ASD, and PTSD, though it is unclear how much these findings are generalizable to disparate learning contexts.
The proposed studies investigate the hypothesis that stimulus-associated changes in BF-derived ACh input to
the BLA and LO regulate discrete behavioral parameters underlying reward-based reversal learning depending
on the associative context used—whether Pavlovian or operant, deterministic or probabilistic. In Aim 1,
computational analysis will be used on simultaneous recordings of ACh activity in the BLA and LO during
reversal learning tasks to discern the specific behavioral parameters, such as prediction error or learning rate,
encoded through each target area and their interactions. In Aim 2, optogenetic control of BF projection neurons
and intravital microinfusions of pharmacologic inhibitors will be employed to demonstrate the necessity of ACh
release in the BLA and LO for the different learning contexts tested, and computational models will be tested
against each other to assess their interpretability and predictive power. These studies and their future
directions ...

## Key facts

- **NIH application ID:** 10985270
- **Project number:** 1K08MH135164-01A1
- **Recipient organization:** NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
- **Principal Investigator:** Joseph Manuel Villarin
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $197,235
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985270

## Citation

> US National Institutes of Health, RePORTER application 10985270, Discrete Functions of Basal Forebrain Cholinergic Signaling to Amygdala and Orbitofrontal Cortex in Reversal Learning (1K08MH135164-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10985270. Licensed CC0.

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