# Neuronal Circuits and Molecular Mechanisms Underlying Early Social Isolation-Potentiated Heroin Seeking

> **NIH NIH K01** · UNIVERSITY OF KANSAS LAWRENCE · 2024 · $134,231

## Abstract

Abstract
Heroin addiction is characterized by compulsive craving, drug seeking and re-occurrence of relapse, and is
considered to be one of the most problematic public health concerns. Heroin relapse is significantly affected by
stress. Human studies suggest that exposure to life stressors is correlated with compulsive drug abuse and
relapse to drugs during periods of abstinence. More importantly, environmental stress during early life is
related to bigger risk for developing addiction and increased relapse vulnerability. Early social isolation (during
adolescence, ESI), as one of the widely used models for early life stress, causes many behavioral
abnormalities that related to mental health issues including increased vulnerability for relapse. My preliminary
data confirmed that ESI potentiates cue-induced heroin seeking after forced abstinence from heroin self-
administration (SA). However, the underlying neurobiological mechanisms are largely understudied.
 Prefrontal cortex (PFC) is involved in the regulation of drug relapse. PFC hypofunction has been identified
in opioid abusers. Preclinical studies indicate that PFC, which projects to subcortical regions such as NAc and
VTA, is critical for heroin relapse. As ESI induces irreversible synaptic dysfunction in the PFC, it is likely that
ESI potentiates heroin seeking by exacerbating PFC malfunction. Moreover, due to the heterogeneous of PFC
projecting neurons (PFC-VTA and PFC-NAc projection have distinct distribution and molecular signatures), it
remains unclear what are the neuronal circuit-specific molecular mechanisms for heroin relapse vulnerability.
Therefore, my central hypothesis is that hypofunction of PFC (PFC-VTA/PFC-NAc) projecting neurons is
involved in ESI-potentiates heroin seeking, and this effect is accompanied by gene transcriptional changes
within the PFC-VTA and/or PFC-NAc projecting neurons.
 To test my hypothesis, I will incorporate state-of-the-art electrophysiology, chemogenetic strategies
(DREADDs), and projection-specific molecular profiling (TRAP [translating ribosome affinity purification])
technologies into my study. I propose to measure excitatory synaptic transmission in PFC-NAc and PFC-VTA
projecting neurons after forced abstinence from heroin SA. Chemogenetic tools will be used to test the
functional role of PFC-VTA and PFC-NAc projecting neurons in ESI-intensified heroin seeking. TRAP methods
(using GFPL10 transgenic mice) will be applied to isolate projection-specific neurons for RNA-seq to identify
potential molecular mechanisms for ESI-potentiated heroin seeking. Fulfillment of my Research Plan and
Training Plan will allow me to independently pursue my long-term career goals: study neuronal circuit-specific
molecular mechanisms for heroin seeking to ultimately contribute to the development of pharmacotherapies for
heroin relapse.

## Key facts

- **NIH application ID:** 10892916
- **Project number:** 5K01DA050908-05
- **Recipient organization:** UNIVERSITY OF KANSAS LAWRENCE
- **Principal Investigator:** Zijun Wang
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $134,231
- **Award type:** 5
- **Project period:** 2020-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892916

## Citation

> US National Institutes of Health, RePORTER application 10892916, Neuronal Circuits and Molecular Mechanisms Underlying Early Social Isolation-Potentiated Heroin Seeking (5K01DA050908-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10892916. Licensed CC0.

---

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