# A novel circuit underlying amotivation in a mouse model of 22q11DS

> **NIH NIH K99** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $88,374

## Abstract

Project Summary
Schizophrenia is a multifaceted neurodevelopmental disorder characterized by positive, cognitive, and negative
symptom categories. One particular negative symptom, amotivation, generates a major impact on public health,
yet the treatment options for this symptom remain sparse. This proposal seeks to investigate a novel circuit
underlying the amotivation phenotype in a mouse model of 22q11 deletion syndrome (22q11DS), one of the
most robust genetic contributors to schizophrenia. Data derived from this study stand to provide novel treatment
options aimed at rectifying amotivation. Despite being implicated in motivational states, the dorsal striatum is
largely overlooked when studying motivated behavior. Moreover, disruptions in thalamic nuclei are involved in
all facets of schizophrenia symptomology, but the role of the thalamus in amotivation remains unknown. My
preliminary results demonstrate amotivation in 22q11DS mice, as well as a deficit in synaptic transmission in the
thalamostriatal pathway. Information flow through this circuit is modulated by intra-striatal cholinergic
interneurons. In 22q11DS mice, I find that there is an increase in the number of spontaneously active cholinergic
interneurons and that blocking cholinergic transmission rescues the thalamostriatal synaptic deficit. These
findings are the first to implicate the thalamostriatal circuit and cholinergic signaling in motivated behaviors. To
study this further, I propose to use cutting-edge approaches in three aims of investigation: 1) to determine the
role of striatal cholinergic interneuron activity in amotivation, 2) to elucidate the cholinergic mechanism underlying
weakened thalamostriatal synaptic transmission, and 3) to identify the contribution of distinct striatal microcircuits
in amotivation. The results of this study stand to significantly enhance our understanding of the neural circuits
underlying motivated behaviors and provide important insight into the disruption of motivation that occurs in
neuropsychiatric disorders such as schizophrenia, depression, and addiction.

## Key facts

- **NIH application ID:** 10753583
- **Project number:** 5K99MH129617-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Mary H. Patton
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $88,374
- **Award type:** 5
- **Project period:** 2022-12-12 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10753583

## Citation

> US National Institutes of Health, RePORTER application 10753583, A novel circuit underlying amotivation in a mouse model of 22q11DS (5K99MH129617-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10753583. Licensed CC0.

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