Reduced Ventral Tegmental Area–Hippocampal Connectivity in Children and Adolescents Exposed to Early Threat

Abstract

Background Preclinical data suggest that early life stress has detrimental effects on the brain’s dopaminergic system, particularly the mesocorticolimbic pathway. Altered dopamine function is thought to contribute to the development of stress-related pathologies; yet, little is known about the impact of early stress on dopamine systems during childhood and adolescence, when stress-related disorders frequently emerge. Here, we evaluate the impact of early threat exposure (violence, abuse) on functional connectivity of putative dopaminergic midbrain regions, the ventral tegmental area (VTA) and substantia nigra (SN), giving rise to mesocorticolimbic and nigrostriatal pathways, respectively. Methods Resting-state functional magnetic resonance imaging scans were completed in 43 trauma-exposed and 43 matched comparison youth (ages 7–17). Functional connectivity of the VTA and SN were compared between groups. Results The trauma group demonstrated lower functional connectivity between the VTA and hippocampus. No group differences in SN connectivity were observed. Across all participants, there were age-related decreases in connectivity of both VTA and SN with the hippocampus, suggesting that age-related attenuations in VTA-hippocampal circuitry may be exacerbated in trauma-exposed youth. Higher levels of anxiety symptomology were associated with reduced SN–nucleus accumbens connectivity. Conclusions Prior research suggests that VTA-hippocampal circuitry is critical for the gating of new information into long-term memory. Lower connectivity in this circuitry suggests a novel mechanism that may serve to adaptively prevent the overwriting of a previously stored trauma memory, but at the same time contribute to the broad range of cognitive and emotional difficulties linked to early stress exposure.

Resilience to adversity is associated with increased activity and connectivity in the VTA and hippocampus

“…Furthermore, high resilience in subjects with high adversity experiences was associated with less negative functional interactions between VTA, VS and HP, suggesting a compensatory or protective mechanism counteracting the effects of adversity. In line with this, reduced resting-state connectivity between VTA and HP in adolescents exposed to early threat has been shown in a previous fMRI study (Marusak et al, 2017).…”

Endophenotype Potential of Nucleus Accumbens Functional Connectivity: Effects of Polygenic Risk for Schizophrenia Interacting with Childhood Adversity

“…No main effect of CA was observed at the FCD or NAcc seed level which calls into attention that for mediation of some environmental factors, high genetic risk could be a prerequisite. We see a potential link between our result and epidemiological data that report previously trauma exposed children and adolescents [40], and amygdalastriatal FC changes were reported in male drug cocaine users with a history of CA [41]. In experimental animals, early life-adversity was identified as factor influencing GABAergic functions of the NAcc [70].…”

“…FC analysis revealed an association between early life stress and altered amygdala/DLPFC and amygdala/rostral ACC connectivity that mediated stress response patterns in adulthood [39]. A relevant connection between early life stress and the mesocorticolimbic dopaminergic system has been detected using FC analysis of the VTA, identifying age-related attenuation of VTA/hippocampal connectivity [40]. Altered amygdala-striatal connectivity has been identified as a specific trait in male cocaine users with a history of CA [41], and impaired GABA signalling in the NAcc has been observed in animal models of early-life adversity [39].…”

Brain and behavioral correlates of insulin resistance in youth with depression and obesity

“…In the combined phenotype of depression and insulin resistance (Androutsos et al, 2014;Ryan et al, 2012), maladaptive behaviors such as inactivity and compensatory overeating may be represented by neurobiological disruptions in function, structure, and connectivity in the reward network; these disruptions lead, in turn, to subsequent worsening of depressive symptoms. We posit that such disruptions are localized to two central regulatory regions in the neural reward network: the anterior cingulate cortex (ACC) (Foland-Ross et al, 2015, p.;Pruessner et al, 2010;Ryan et al, 2012;Teh et al, 2010;Wozniak et al, 2012) and the hippocampus (Chantiluke et al, 2012;Hulvershorn et al, 2011;Keding and Herringa, 2015;Marusak et al, 2017), which each play key roles in emotion, stress, and insulin regulation.…”