# Ciliary melanin concentrating hormone receptors and the link to cognitive dysfunction in mice

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $43,223

## Abstract

Project Abstract
The hypothalamic neuropeptide melanin-concentrating hormone (MCH) is a cyclic peptide expressed almost
exclusively in the lateral hypothalamus (LH) and zona incerta (ZI) but projects throughout the central nervous
system. The MCH system has been implicated as a regulator of energy homeostasis and food intake but also
of sleep, stress, mood, aggression, reward and cognition. MCH exerts its action through interacting with a G
protein-coupled receptor, MCHR1, which has a widespread distribution in the brain, particularly in the frontal
cortex, amygdala, nucleus accumbens, and hippocampus providing an anatomical basis for an MCH role in the
modulation of social, emotional, and cognitive functions. MCHR1 is one of a few GPCRs that are located to the
primary neuronal cilia, small microtubule backbones, hair-like structures that protrude from the plasma
membrane of almost every cell including neurons. Cilia act as cells' antennas and play crucial roles in cell
signaling through detecting and transducing external stimuli, and regulating the proper cell differentiation and
migration. Mutations in 87 of cilia genes have been associated with disruptions in ciliary structure and functions
clinical disorders, termed ciliopathies. Among these genes, 77 genes have been associated with neurological
deficits, such as cognitive deficits and intellectual disability. We recently found that MCHR1 mRNA levels are
significantly lower in the prefrontal cortex (PFC) of subjects with schizophrenia. We also showed that the
disruption of MCH system by either germline deletion of MCHR1 or conditional ablation of MCH expressing
neurons led to behavioral abnormalities mimicking certain symptoms relevant to schizophrenia: social and
cognitive deficits, and sensorimotor gating deficits. This evidence from human and animal studies supports a
role for the MCH system in neurological disoders such as schizophrenia. Given these preliminary findings the
goal of this project is to understand whether the MCHR1 localization on cilia membranes is the basis of the
uniqueness of these receptors in the ciliary singling, through converging different sensory signals in the
extracellular environment, and transmitting these signals into the cell. This is supported by the fact that the
activation of MCHR1 causes shortening of the cilia length in in vitro experiments through cytoskeleton-related
regulation. My results will provide new insights into understanding the role that ciliary MCH receptors plays in
cognitive deficits via methods such as single guide RNA for CRISPR-Cas9 coupled with Cre-loxP recombinase
technology, as well as deleting IFT88, a cilia gene responsible for cilia function and structure, from neurons
that express MCHR1 or MCH. We will also design MCH analogues to reverse the effects seen in our animal
models. The results of this study will potentially demonstrate the role of ciliary MCHR1 in cognitive
dysfunctions seen in psychiatric disorders.

## Key facts

- **NIH application ID:** 10488061
- **Project number:** 5F31MH126565-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Wedad S Alhassen
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $43,223
- **Award type:** 5
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488061

## Citation

> US National Institutes of Health, RePORTER application 10488061, Ciliary melanin concentrating hormone receptors and the link to cognitive dysfunction in mice (5F31MH126565-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10488061. Licensed CC0.

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