# Molecular and Circuit Mechanisms of Neurexin1-Mediated Goal-Directed Dysfunction

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $727,248

## Abstract

PROJECT SUMMARY
Studies in humans suggest that Neurexin1α (Nrxn1α), a presynaptically expressed organizer of synaptic
structure, is a key genetic risk factor for multiple neuropsychiatric diseases, all of which exhibit impairments in
goal-directed processing. Given the pernicious effects of goal-directed dysfunction on daily quality of life, a better
understanding of the underlying neurobiology – both at the molecular and neural circuit level - is strongly
warranted. Our prior work has developed quantitative behavioral and in vitro electrophysiological approaches
while demonstrating that mice with mutations in Nrxn1α are an excellent system to study alterations in neural
circuit activity driving impaired goal-directed behavior. Efficient goal-directed behavior relies on reinforcement,
whereby outcomes shape future actions, as well as flexibility, the ability to adapt to changes in contingencies or
context. Both processes are thought to occur in part within the striatum, where excitatory inputs representing
choice-relevant information interact with neuromodulators, such as dopamine (DA) and acetylcholine (ACh),
which signal information about rewards, surprise, and uncertainty from the external world. Nrxn1 is broadly
expressed in these cortico-striatal-thalamic circuits including the presynaptic terminals of striatal-targeting
cortical and thalamic neurons, as well as within striatal cholinergic interneurons and striatal-targeting
dopaminergic projections from the midbrain. Here we examine how Nrxn1 functions within midbrain dopamine
neurons and striatal cholinergic interneurons, the major sources of striatal dopamine and acetylcholine,
respectively. We employ cell type specific Nrxn1 deletion together with acute slice recordings to mechanistically
address how Nrxn1 contributes to the striatal release of these key neuromodulators. In parallel, we use in vivo
imaging of novel sensors for dopamine and acetylcholine to investigate how these modulators are altered during
value-based choice tasks in both circuit-specific and brain-wide Nrxn1 KOs. We will correlate abnormal
neuromodulatory signals with abnormalities in choice behavior, focusing on reinforcement processes and choice
flexibility. To probe the functional relevance of altered neuromodulatory signals for behavior, we optogenetically
impose abnormal ACh and DA signals in WT mice and observe impacts on choice selection and flexibility. Finally,
we examine how Nrxn1 mutations impact striatal processing during selection of actions via in vivo recordings
in wildtype and Nrxn1 KO mice. The proposed work will inform us of how mutations in Nrxn1 alter striatal
cholinergic and dopaminergic signals and striatal processing of goal-directed actions, while providing a
framework to understand the diversity of goal-directed dysfunction seen across neuropsychiatric disorders.

## Key facts

- **NIH application ID:** 11050459
- **Project number:** 1R01MH136354-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Marc V Fuccillo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $727,248
- **Award type:** 1
- **Project period:** 2024-09-25 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11050459

## Citation

> US National Institutes of Health, RePORTER application 11050459, Molecular and Circuit Mechanisms of Neurexin1-Mediated Goal-Directed Dysfunction (1R01MH136354-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11050459. Licensed CC0.

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