# Project 2

> **NIH NIH P50** · JOHNS HOPKINS UNIVERSITY · 2024 · $417,210

## Abstract

Project 2 Abstract
Pathological changes of the olfactory epithelium (OE) and smell deficits are reproducibly reported in
schizophrenia (SZ) patients. Notably, smell deficits are tightly correlated with negative symptoms (e.g.,
avolition, anhedonia; due to impaired positive valence systems) and social cognitive deficits, but not with
positive symptoms (e.g., hallucination, delusion) in SZ. However, a conceptual framework for explaining the
impact of the olfactory system on higher brain functions (e.g., motivation, social process, and cognition)
remains lacking. Olfactory sensory neurons (OSNs) in the OE project their axons to the olfactory bulb (OB),
which then transmits the information to several olfactory cortices, including the anterior olfactory nucleus/taenia
tecta (AON for simplicity) and the piriform cortex (Pir). These olfactory cortical regions subsequently project to
the prefrontal cortex (PFC), which may participate in in emergence of negative symptoms as well as in deficits
of social cognition in SZ and related disorders. Our preliminary results show that chronic local OE inflammation
leads to reduced excitatory synaptic inputs into PFC pyramidal neurons (PNs), we propose that the olfactory-
prefrontal circuits provide the causal link between OE perturbation and PFC functionality to impact higher brain
functions. Because adolescence/young adulthood is a critical period for PFC maturation, which depends on its
excitatory inputs, we will test the central hypothesis that chronic local OE perturbation during this period
leads to prolonged PFC dysfunction through the olfactory-prefrontal circuits. Specifically, we will pursue
three aims. First, we will determine the impact of OE perturbation on functional properties of PFC PNs in two
inducible OE perturbation mouse models [in collaboration with Project 1 (P1) and P3]. Using patch clamp
recordings, we will examine the effects of OE inflammation or OSN inactivation in two time windows covering
adolescence to adulthood on intrinsic electrophysiological properties and synaptic connections of PFC PNs
and aim to reverse the effects by chemogenetic activation of olfactory-prefrontal circuits. Second, we will
determine the impact of OE perturbation on PFC activity (both olfactory cortical PN terminals in PFC and PFC
PNs) via fiber photometry recording during specific mouse behaviors that assess motivation and social
recognition (in collaboration with Project 1). Third, in collaboration with Core B and Core C, we will determine
the impact of OE perturbation on functional connectivity of olfactory-prefrontal circuits in mice via in vivo
electrophysiology and compare functional connectivity between control mice and human healthy subjects (via
resting-state functional magnetic resonance imaging) to evaluate cross-species similarity. Overall, this project
will fill a significant knowledge gap by establishing olfactory-prefrontal circuits as a novel contributory link
between OE pathology and negative sym...

## Key facts

- **NIH application ID:** 10862177
- **Project number:** 1P50MH136297-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Minghong Ma
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $417,210
- **Award type:** 1
- **Project period:** 2024-04-15 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862177

## Citation

> US National Institutes of Health, RePORTER application 10862177, Project 2 (1P50MH136297-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10862177. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*