# Hormonal Programming of the Mesocorticolimbic Circuit During Adolescent Development

> **NIH NIH R21** · MICHIGAN STATE UNIVERSITY · 2024 · $235,500

## Abstract

Abstract
Adolescence is a critical period for the development of a range of mental health conditions in females and
males, particularly those marked by impairments in cognitive control. This research is focused on adolescent
maturation of the mesocorticolimbic dopamine (DA) circuit, which is functionally linked to motivation, reward,
and cognitive control. A unique feature of adolescent development of this circuit is the long-distance outgrowth
of ventral tegmental area (VTA) DA axons from their prepubertal location in the nucleus accumbens (NAc) to
the medial prefrontal cortex (mPFC), thereby strengthening connectivity between subcortical and cortical
regions regulating cognitive control. The adolescent outgrowth of axons from the NAc to the mPFC coincides
with the pubertal rise in gonadal steroid hormones, primarily estrogen in females and testosterone in males.
Both hormones organize the nervous system during critical periods of development, including adolescence,
resulting in structural and functional sex differences. The proposed studies will test the hypotheses that: Aim 1)
gonadal hormones program the adolescent outgrowth of dopaminergic axons from the NAc to the mPFC; and
Aim 2) adolescence is a sensitive period for hormone-dependent organization of the mesocorticolimbic circuit.
A unique combination of virally mediated tract tracing techniques will be used to identify the synaptic
varicosities of VTA neurons that extend their axons from the NAc to the mPFC during adolescence in female
and male rats that either do or do not experience gonadal hormones during adolescence. The first hypothesis
predicts that prepubertal gonadectomy will result in reduced DA innervation of the mPFC in both females and
males and that hormone replacement (estrogen in females, testosterone in males) during adolescence will
restore innervation. The second hypothesis predicts that hormone replacement in prepubertally
gonadectomized rats in adulthood will not restore DA innervation of the mPFC. Because these exploratory
studies predict hormonal effects in both females (estrogen) and males (testosterone), analyses will focus on
within-sex comparisons of hormone status during adolescence or adulthood, rather than sex differences. This
research will advance fundamental understanding of the developmental plasticity of the mesocorticolimbic
dopamine circuit and how it is influenced by gonadal hormones in females and males. It will reveal not only
how typical maturation occurs and within what developmental window(s) it can occur, but also how it can go
awry (e.g., atypical timing of puberty onset). Knowing how typical maturation can go awry will provide novel
insights into the developmental processes during puberty and adolescence that could lead to the emergence of
psychopathology marked by deficits in cognitive control.

## Key facts

- **NIH application ID:** 10869226
- **Project number:** 1R21MH136442-01
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Alexander W. Johnson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $235,500
- **Award type:** 1
- **Project period:** 2024-08-07 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10869226

## Citation

> US National Institutes of Health, RePORTER application 10869226, Hormonal Programming of the Mesocorticolimbic Circuit During Adolescent Development (1R21MH136442-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10869226. Licensed CC0.

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