Affective neuroscience research suggests that maturational changes in reward circuitry during adolescence present opportunities for new learning, but likely also contribute to increases in vulnerability for psychiatric disorders such as depression and substance abuse. Basic research in animal models and human neuroimaging has made progress in understanding the normal development of reward circuitry in adolescence, yet, few functional neuroimaging studies have examined puberty-related influences on the functioning of this circuitry. The goal of this study was to address this gap by examining the extent to which striatal activation and cortico-striatal functional connectivity to cues predicting upcoming rewards would be positively associated with pubertal status and levels of pubertal hormones (dehydroepiandrosterone, testosterone, estradiol). Participants included 79 adolescents (10-13 year olds; 47 girls) varying in pubertal status who performed a novel reward cue processing task during fMRI. Pubertal maturation was assessed using sex-specific standardized composite measures based on Tanner staging (self-report and clinical assessment) and scores from the Pubertal Development Scale. These composite measures were computed to index overall pubertal maturation as well as maturation of the adrenal and gonadal axes separately for boys and girls. Basal levels of circulating pubertal hormones were measured using immunoassays from three samples collected weekly upon awakening across a three-week period. Results indicated greater striatal activation and functional connectivity between nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) to reward cue (vs. no reward cue) on this task. Also, girls with higher levels of estradiol showed reduced activation in left and right caudate and greater NAcc-putamen connectivity. Girls with higher levels of testosterone showed greater NAcc connectivity with the anterior cingulate cortex and the insula. There were no significant associations in boys. Findings suggest that patterns of activation and connectivity in cortico-striatal regions are associated with reward cue processing, particularly in girls. Longitudinal follow-up neuroimaging studies are needed to fully characterize puberty-specific effects on the development of these neural regions and how such changes may contribute to pathways of risk or resilience in adolescence.
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Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity
Autism spectrum disorder (ASD) is more prevalent in males than in females, but the neurobiological mechanisms that give rise to this sex-bias are poorly understood. The female protective hypothesis suggests that the manifestation of ASD in females requires higher cumulative genetic and environmental risk relative to males. Here, we test this hypothesis by assessing the additive impact of several ASD-associated
- NSF-PAR ID:
- 10154434
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Translational Psychiatry
- Volume:
- 10
- Issue:
- 1
- ISSN:
- 2158-3188
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Executive function is a quintessential human capacity that emerges late in development and displays different developmental trends in males and females. Sex differences in executive function in youth have been linked to vulnerability to psychopathology as well as to behaviors that impinge on health, wellbeing, and longevity. Yet, the neurobiological basis of these differences is not well understood, in part due to the spatiotemporal complexity inherent in patterns of brain network maturation supporting executive function. Here we test the hypothesis that sex differences in impulsivity in youth stem from sex differences in the controllability of structural brain networks as they rewire over development. Combining methods from network neuroscience and network control theory, we characterize the network control properties of structural brain networks estimated from diffusion imaging data acquired in males and females in a sample of 879 youth aged 8–22 years. We summarize the control properties of these networks by estimating average and modal controllability, two statistics that probe the ease with which brain areas can drive the network towards easy versus difficult-to-reach states. We find that females have higher modal controllability in frontal, parietal, and subcortical regions while males have higher average controllability in frontal and subcortical regions. Furthermore, controllability profiles in males are negatively related to the false positive rate on a continuous performance task, a common measure of impulsivity. Finally, we find associations between average controllability and individual differences in activation during an n-back working memory task. Taken together, our findings support the notion that sex differences in the controllability of structural brain networks can partially explain sex differences in executive function. Controllability of structural brain networks also predicts features of task-relevant activation, suggesting the potential for controllability to represent context- specific constraints on network state more generally.more » « less
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Abstract Introduction In humans, satisfying sexual activity within a pair‐bond plays a significant role in relationship quality and maintenance, beyond reproduction. However, the neural and genetic correlates for this basic species‐supporting function, in response to a pair‐bonded partner, are unknown.
Methods We examined the neural correlates of oxytocin‐ (
Oxtr rs53576) and vasopressin‐ (Avpr 1a rs3) receptor genotypes with sexual satisfaction and frequency, among a group of individuals in pair‐bonds (M relationship length = 4.1 years). Participants were scanned twice (with functional MRI), about 1‐year apart, while viewing face images of their spouse and a familiar, neutral acquaintance.Results Sex satisfaction scores showed significant interactions with
Oxtr andAvpr variants associated with social behaviors in a broad network of regions involved in reward and motivation (ventral tegmental area, substantia nigra [SN], and caudate), social bonding (ventral pallidum), emotion and memory (amygdala/hippocampus), hormone control (hypothalamus); and somatosensory and self‐other processing (SII, frontal, and temporal lobe). Sexual frequency interactions also showed activations in the SN and paraventricular hypothalamus forAvpr , and the prefrontal cortex forOxtr .Conclusions Satisfying sexual activity in pair‐bonds is associated with activation of subcortical structures that support basic motivational and physiological processes; as well as cortical regions that mediate complex thinking, empathy, and self‐other processes highlighting the multifaceted role of sex in pair‐bonds.
Oxtr andAvpr gene variants may further amplify both basic and complex neural processes for pair‐bond conservation and well‐being. -
The nonapeptide system modulates numerous social behaviors through oxytocin and vasopressin activation of the oxytocin receptor (OXTR) and vasopressin receptor (AVPR1A) in the brain. OXTRs and AVPR1As are widely distributed throughout the brain and binding densities exhibit substantial variation within and across species. Although OXTR and AVPR1A binding distributions have been mapped for several rodents, this system has yet to be characterized in the spiny mouse (Acomys cahirinus). Here we conducted receptor autoradiography and in situ hybridization to map distributions of OXTR and AVPR1A binding and Oxtr and Avpr1a mRNA expression throughout the basal forebrain and midbrain of male and female spiny mice. We found that nonapeptide receptor mRNA is diffuse throughout the forebrain and midbrain and does not always align with OXTR and AVPR1A binding. Analyses of sex differences in brain regions involved in social behavior and reward revealed that males exhibit higher OXTR binding densities in the lateral septum, bed nucleus of the stria terminalis, and anterior hypothalamus. However, no association with gonadal sex was observed for AVPR1A binding. Hierarchical clustering analysis further revealed that co-expression patterns of OXTR and AVPR1A binding across brain regions involved in social behavior and reward differ between males and females. These findings provide mapping distributions and sex differences in nonapeptide receptors in spiny mice. Spiny mice are an excellent organism for studying grouping behaviors such as cooperation and prosociality, and the nonapeptide receptor mapping here can inform the study of nonapeptide-mediated behavior in a highly social, large group-living rodent.more » « less
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Abstract Adolescence is an important period for HPA axis development and synapse maturation and reorganization in the prefrontal cortex (PFC). Thus, stress during adolescence could alter stress‐sensitive brain regions such as the PFC and may alter the impact of future stressors on these brain regions. Given that women are more susceptible to many stress‐linked psychological disorders in which dysfunction of PFC is implicated, and that this increased vulnerability emerges in adolescence, stress during this time could have sex‐dependent effects. Therefore, we investigated the effects of adolescent social instability stress (SIS) on dendritic morphology of Golgi‐stained pyramidal cells in the medial PFC of adult male and female rats. We then examined dendritic reorganization following chronic restraint stress (CRS) with and without a rest period in adult rats that had been stressed in adolescence. Adolescent SIS conferred long‐term alterations in prelimbic of males and females, whereby females show reduced apical length and basilar thin spine density and males show reduced basilar length. CRS in adulthood failed to produce immediate dendritic remodeling in SIS rats. However, CRS followed by a rest period reduced apical dendritic length and increases mushroom spine density in adolescently stressed adult males. Conversely, CRS followed by rest produced apical outgrowth and decreased mushroom spine density in adolescently stressed adult females. These results suggest that stress during adolescence alters development of the PFC and modulates stress‐induced dendritic changes in adulthood.
