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Early childhood stress is associated with blunted development of ventral tegmental area functional connectivity.

ABSTRACT: Early life stress increases risk for later psychopathology, due in part to changes in dopaminergic brain systems that support reward processing and motivation. Work in animals has shown that early life stress has a profound impact on the ventral tegmental area (VTA), which provides dopamine to regions including nucleus accumbens (NAcc), anterior hippocampus, and medial prefrontal cortex (mPFC), with cascading effects over the course of development. However, little is known about how early stress exposure shifts the developmental trajectory of mesocorticolimbic circuitry in humans. In the current study, 88 four- to nine-year-old children participated in resting-state fMRI. Parents completed questionnaires on their children's chronic stress exposure, including socioeconomic status (SES) and adverse childhood experiences (ACEs). We found an age x SES interaction on VTA connectivity, such that children from higher SES backgrounds showed a positive relationship between age and VTA-mPFC connectivity. Similarly, we found an age x ACEs exposure interaction on VTA connectivity, such that children with no ACEs exposure showed a positive relationship between age and VTA-mPFC connectivity. Our findings suggest that early stress exposure relates to the blunted maturation of VTA connectivity in young children, which may lead to disrupted reward processing later in childhood and beyond.

SUBMITTER: Park AT

PROVIDER: S-EPMC7785957 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Early childhood stress is associated with blunted development of ventral tegmental area functional connectivity.

Park Anne T AT Tooley Ursula A UA Leonard Julia A JA Boroshok Austin L AL McDermott Cassidy L CL Tisdall M Dylan MD Mackey Allyson P AP

Developmental cognitive neuroscience 20201225

Early life stress increases risk for later psychopathology, due in part to changes in dopaminergic brain systems that support reward processing and motivation. Work in animals has shown that early life stress has a profound impact on the ventral tegmental area (VTA), which provides dopamine to regions including nucleus accumbens (NAcc), anterior hippocampus, and medial prefrontal cortex (mPFC), with cascading effects over the course of development. However, little is known about how early stress ...[more]

PMID: 33395612

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Project description:Decades of research have revealed the remarkable complexity of the midbrain dopamine (DA) system, which comprises cells principally located in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Neither homogenous nor serving a singular function, the midbrain DA system is instead composed of distinct cell populations that (1) receive different sets of inputs, (2) project to separate forebrain sites, and (3) are characterized by unique transcriptional and physiological signatures. To appreciate how these differences relate to circuit function, we first need to understand the anatomical connectivity of unique DA pathways and how this connectivity relates to DA-dependent motivated behavior. We and others have provided detailed maps of the input-output relationships of several subpopulations of midbrain DA cells and explored the roles of these different cell populations in directing behavioral output. In this study, we analyze VTA inputs and outputs as a high dimensional dataset (10 outputs, 22 inputs), deploying computational techniques well-suited to finding interpretable patterns in such data. In addition to reinforcing our previous conclusion that the connectivity in the VTA is dependent on spatial organization, our analysis also uncovered a set of inputs elevated onto each projection-defined VTADA cell type. For example, VTADA→NAcLat cells receive preferential innervation from inputs in the basal ganglia, while VTADA→Amygdala cells preferentially receive inputs from populations sending a distributed input across the VTA, which happen to be regions associated with the brain's stress circuitry. In addition, VTADA→NAcMed cells receive ventromedially biased inputs including from the preoptic area, ventral pallidum, and laterodorsal tegmentum, while VTADA→mPFC cells are defined by dominant inputs from the habenula and dorsal raphe. We also go on to show that the biased input logic to the VTADA cells can be recapitulated using projection architecture in the ventral midbrain, reinforcing our finding that most input differences identified using rabies-based (RABV) circuit mapping reflect projection archetypes within the VTA.

Project description:The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of μ-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders.The μ-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R heteromer can explain previous results showing antagonistic galanin-opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder.

Dataset Information

Early childhood stress is associated with blunted development of ventral tegmental area functional connectivity.

Publications

Early childhood stress is associated with blunted development of ventral tegmental area functional connectivity.

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