# Aging of Emotion Circuitry: Impact of Sex, Depression, and Fetal Immune Origins

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $704,392

## Abstract

PROJECT SUMMARY/ABSTRACT
Maintaining emotional stability in the face of negative life experiences is critical for healthy aging. Maladaptive
responses to negative affective stimuli (“NAffecS”) are implicated in psychiatric disorders, including major
depressive disorder (MDD). In fact, there are shared brain regions involved in responses to NAffecS and MDD
pathophysiology, including: hypothalamus (HYPO), amygdala (AMYG), hippocampus (HIPP), anterior cingulate
cortex (ACC), and ventromedial, ventrolateral, dorsolateral, and orbital prefrontal cortices (PFC), areas that are
among the most sexually dimorphic. Activity in this circuitry is physiologically associated with cortisol response,
loss of parasympathetic cardiac tone, and immune responses, including TNF-α, IL-1β, IL-6, responses that
differ by sex. We will test here that immune pathway abnormalities, beginning in fetal development, are
associated with sex-dependent impacts on HYPO, HIPP, AMYG and PFC, resulting in maladaptive negative
emotion processing and MDD in early midlife. Further, aging of NAffec circuitry (i.e., decline) into later midlife
will be accelerated by MDD in early midlife, resulting in greater deficits in negative emotion processing in later
midlife, that we predict will differ by sex, i.e. women worse than men. We are uniquely poised to examine this
for the first time in humans using data from our prenatal cohort prospectively followed since 2nd/3rd trimesters
and assessed at ages 44-50 in a previous NIH study, in which we investigated fetal programming of sex
differences in MDD. We will re-recruit over 5 years 180 of these offspring (equally divided by sex; half with
recurrent MDD) who, 11 years later, will be ages 55-61. We will relate maternal prenatal immune activity (TNF-
α, IL-1β, IL-6) to sex differences in NAffec circuitry deficits and maladaptive negative emotion regulation at
ages 55-61 and decline from ages 44-50. We will use the same multimodal imaging approach as previously
(structural, functional imaging (sMRI/fMRI)) coupled with hormones, autonomic and immune physiology, and
emotion regulation measures. Novel transcriptomic analyses in the offspring's peripheral blood mononuclear
cells will be used to measure abnormalities in innate immune gene expression in response to prenatal
maternal immune exposures and related to adult midlife outcomes. Our lifespan perspective is an innovative
approach to identify potential immunotherapeutic targets for maintaining healthy emotion processing that are
sex-dependent and can be applied prior to functional decline. This will contribute to RDoC Negative Affect and
Arousal phenotypes, physiology and genotypes, and impact of mood and sex.

## Key facts

- **NIH application ID:** 10116240
- **Project number:** 5R01AG057505-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JILL M GOLDSTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $704,392
- **Award type:** 5
- **Project period:** 2018-06-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116240

## Citation

> US National Institutes of Health, RePORTER application 10116240, Aging of Emotion Circuitry: Impact of Sex, Depression, and Fetal Immune Origins (5R01AG057505-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10116240. Licensed CC0.

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