# Project 1

> **NIH NIH P50** · JOHNS HOPKINS UNIVERSITY · 2024 · $615,123

## Abstract

Project 1 Abstract
Smell deficits have been reproducibly shown to be associated with negative symptoms and impaired social
cognitive processes in schizophrenia (SZ). Smell deficits are found from the early stage of SZ. Olfactory
epithelium (OE) pathology including molecular and cellular changes (e.g., immune/inflammatory changes in
association with redox imbalance) are directly associated with smell deficits, olfactory bulb (OB) volume
reduction, and negative symptoms in SZ. Nevertheless, it is not yet known how OE perturbation induces
pathological signatures of the OE and OB changes, which may lead to negative symptoms and impaired social
cognition. In the OE, olfactory sensory neurons (OSNs) can be continuously produced from stem cells such as
horizontal basal cells (HBCs) even in adulthood. OSNs transmit sensory information to the OB via direct
neuronal connections, which projects to the primary olfactory cortical regions. These brain regions directly
connect with the prefrontal cortex (PFC) that regulate higher brain functions. Using a mouse model, we have
previously reported that OE inflammation affects cell cycle/fate control of HBCs, leading to OSN dysfunction.
Our preliminary data also show that OE inflammation leads to a volume reduction and layer structure changes
of the OB, reduced excitatory synaptic inputs to the OB and PFC principal neurons, and deficits in motivation
and social recognition. Based on these findings, we hypothesize that chronic local OE perturbation during
adolescence/young adulthood, a critical period for PFC maturation, induces pathological signatures of the OE,
which may be a contributory factor to impair olfactory-prefrontal circuits, leading to behavioral deficits in
positive valence systems and social processes. To address these hypotheses, we will leverage our mouse
models to produce local OE perturbation. Using the inducible OE inflammation model and inducible OSN
inactivation model, we will identify the impact of OE perturbation (i.e., OE inflammation and OSN inactivation)
on pathological signatures of the OE and OB changes (Aim 1). We will also identify the impact of OE
perturbation on behavioral outcomes (Aim 2). Finally, we will determine specific molecules that contribute to
the impact of OE pathological signatures on OB changes and behavioral phenotypes (Aim 3). Overall, this
project will identify molecular and cellular mechanisms underlying the impact of chronic local OE perturbation
during adolescence/young adulthood on the olfactory-prefrontal circuits (focusing on the OB) and behavioral
domains in positive valence systems and social processes.

## Key facts

- **NIH application ID:** 10862176
- **Project number:** 1P50MH136297-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** ANDREW P LANE
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $615,123
- **Award type:** 1
- **Project period:** 2024-04-15 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862176

## Citation

> US National Institutes of Health, RePORTER application 10862176, Project 1 (1P50MH136297-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10862176. Licensed CC0.

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