Faculty Bibliography

Early life is a sensitive period in which enhanced neural plasticity allows the developing brain to adapt to its environment. This plasticity can also be a risk factor in which maladaptive development can lead to long-lasting behavioral deficits. Here, we test how early-life exposure to the selective-serotonin-reuptake-inhibitor, fluoxetine, affects motivation and dopaminergic signaling in adulthood. We show for the first time that mice exposed to fluoxetine in the early postnatal period exhibit a reduction in effort-related motivation. These mice also show blunted responses to amphetamine and reduced dopaminergic activation in a sucrose reward task.Interestingly, we find that the reduction in motivation can be rescued in the adult by administering bupropion, a dopamine-norepinephrine reuptake inhibitor used as an antidepressant and a smoke cessation aid, but not by fluoxetine. Taken together, our studies highlight the effects of early postnatal exposure of fluoxetine on motivation and demonstrate the involvement of the dopaminergic system in this process.Significance StatementThe developmental period is characterized by enhanced plasticity. During this period, environmental factors have the potential to lead to enduring behavioral changes. Here we show that exposure to the SSRI fluoxetine during a restricted period in early-life leads to a reduction in adult motivation. We further show that this reduction is associated with decreased dopaminergic responsivity. Finally, we show that motivational deficits induced by early-life fluoxetine exposure can be rescued by adult administration of bupropion but not by fluoxetine.

BACKGROUND:Mind-body integrative health (MBIH) interventions to improve adolescent sleep are lacking. The study characterized sleep quality and bedtime-related psychosocial stressors among urban minority adolescents, explored associations between demographics factors, stressors and sleep quality, and gauged interest in a MBIH sleep intervention. MATERIALS AND METHODS/METHODS:167 school-based health center (SBHC) patients (mean age = 16.3; 64% female; 68% Latino) participated in a needs assessment as part of a quality improvement project. They reported bedtime-related psychosocial stressors using items from the Adolescent Sleep Hygiene Scale (ASHS), sleep quality using the Pittsburgh Sleep Quality Index (PSQI), and interest in a MBIH-based sleep intervention. Chi-square and logistic regression examined associations between demographics, stressors, sleep quality, and interest in the intervention. RESULTS:67% had poor sleep quality. Females, compared to males, had 2.23 higher odds (95% Confidence Interval [CI]: 1.12, 4.42) of having poor sleep quality. Nearly 80% experienced bedtime-related stressors (25% experienced one stressor, 17% two stressors and 37% three or more stressors); relative to those reporting no stressors, those reporting 3+ stressors had 3.15 higher odds (95% CI: 1.27, 7.84) of having poor sleep quality. Most (77%) reported they would participate in an SBHC-based intervention that utilized MBIH modalities preferring both one-on-one and group sessions. CONCLUSIONS:Urban, predominantly Hispanic and Black, SBHC adolescent patients have poor sleep quality and report bedtime-related psychosocial stressors. Their interest in MBIH interventions to address sleep problems represents a unique opportunity for practitioners and complementary therapists to offer MBIH interventions to a population at high-risk for poor sleep quality.

The social and economic situation in Europe seems to play a role in the migratory flow of doctors and other health professionals within the continent. However, little is known about the particular reality of workforce migration in Spain. The objective of this study was to explore the factors that motivate migration among junior doctors training in psychiatry in Spain. A semistructured questionnaire of 61 items was circulated to psychiatric trainees in Spain to explore the extent and the factors that influence the decisions regarding workforce migration. A total of 95 psychiatric trainees participated in the survey. More than two-thirds (n = 71, 74.7%) had "ever" considered migrating to another country, and more than one-fourth (n = 21, 29.5%) had already taken "practical steps" to go abroad. The main reasons to consider leaving the country were financial (n = 82, 86%) and the opportunity to progress professionally (n = 82, 84%). However, nearly half of the trainees (n = 47, 49%) were satisfied with their current income. While the majority of the psychiatric trainees in this survey had considered migrating abroad, these potential future migrations could lead to a loss of human capital with an important sociosanitary impact.

Convergence insufficiency (CI) is the most common binocular vision problem, associated with blurred/double vision, headaches, and sore eyes that are exacerbated when doing prolonged near work, such as reading. The Convergence Insufficiency Neuro-mechanism Adult Population Study (NCT03593031) investigates the mechanistic neural differences between 50 binocularly normal controls (BNC) and 50 symptomatic CI participants by examining the fast and slow fusional disparity vergence systems. The fast fusional system is preprogrammed and is assessed with convergence peak velocity. The slow fusional system optimizes vergence effort and is assessed by measuring the phoria adaptation magnitude and rate. For the fast fusional system, significant differences are observed between the BNC and CI groups for convergence peak velocity, final position amplitude, and functional imaging activity within the secondary visual cortex, right cuneus, and oculomotor vermis. For the slow fusional system, the phoria adaptation magnitude and rate, and the medial cuneus functional activity, are significantly different between the groups. Significant correlations are observed between vergence peak velocity and right cuneus functional activity (p = 0.002) and the rate of phoria adaptation and medial cuneus functional activity (p = 0.02). These results map the brain-behavior of vergence. Future therapeutic interventions may consider implementing procedures that increase cuneus activity for this debilitating disorder.

The dentate gyrus (DG) of the hippocampus is important for cognition and behavior. However, the circuits underlying these functions are unclear. DG mossy cells (MCs) are potentially important because of their excitatory synapses on the primary cell type, granule cells (GCs). However, MCs also activate GABAergic neurons which inhibit GCs. We used viral delivery of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in mice to implement a gain- and loss of function study of MCs in diverse behaviors. Using this approach, manipulations of MCs could bidirectionally regulate behavior. The results suggest that inhibiting MCs can reduce anxiety-like behavior and improve cognitive performance. However, not all cognitive or anxiety-related behaviors were influenced, suggesting specific roles of MCs in some but not all types of cognition and anxiety. Notably, several behaviors showed sex-specific effects, with females often showing more pronounced effects than the males. We also used the immediate early gene c-Fos to address whether DREADDs bidirectionally regulated MC or GC activity. We confirmed excitatory DREADDs increased MC c-Fos. However, there was no change in GC c-Fos, consistent with MC activation leading to GABAergic inhibition of GCs. In contrast, inhibitory DREADDs led to a large increase in GC c-Fos, consistent with a reduction in MC excitation of GABAergic neurons, and reduced inhibition of GCs. Taken together, these results suggest that MCs regulate anxiety and cognition in specific ways. We also raise the possibility that cognitive performance may be improved by reducing anxiety.SIGNIFICANCE STATEMENT: The dentate gyrus (DG) has many important cognitive roles as well as being associated with affective behavior. This study addressed how a glutamatergic DG cell type called mossy cells (MCs) contributes to diverse behaviors, which is timely because it is known that MCs regulate the activity of the primary DG cell type, granule cells (GCs), but how MC activity influences behavior is unclear. We show, surprisingly, that activating MCs can lead to adverse behavioral outcomes, and inhibiting MCs have an opposite effect. Importantly, the results appeared to be task-dependent and showed that testing both sexes was important. Additional experiments indicated what MC and GC circuitry was involved. Taken together, the results suggest how MCs influence behaviors that involve the DG.

BACKGROUND:Youth in the justice system (YJS) are more likely than youth who have never been arrested to have mental health and substance use problems. However, a low percentage of YJS receive SUD services during their justice system involvement. The SUD care cascade can identify potential missed opportunities for treatment for YJS. Steps along the continuum of the cascade include identification of treatment need, referral to services, and treatment engagement. To address gaps in care for YJS, we will (1) implement a learning health system (LHS) to develop, or improve upon, alliances between juvenile justice (JJ) agencies and community mental health centers (CMHC) and (2) present local cascade data during continuous quality improvement cycles within the LHS alliances. METHODS/DESIGN/METHODS:ADAPT is a hybrid Type II effectiveness implementation trial. We will collaborate with JJ and CMHCs in eight Indiana counties. Application of the EPIS (exploration, preparation, implementation, and sustainment) framework will guide the implementation of the LHS alliances. The study team will review local cascade data quarterly with the alliances to identify gaps along the continuum. The study will collect self-report survey measures longitudinally at each site regarding readiness for change, implementation climate, organizational leadership, and program sustainability. The study will use the Stages of Implementation Completion (SIC) tool to assess the process of implementation across interventions. Additionally, the study team will conduct focus groups and qualitative interviews with JJ and CMHC personnel across the intervention period to assess for impact. DISCUSSION/CONCLUSIONS:Findings have the potential to increase SUD need identification, referral to services, and treatment for YJS.

PURPOSE OF REVIEW/OBJECTIVE:Despite increased literature on the impact of racism in the past decades, relatively few studies have focused on the effects of racism on younger children. This article reviews research from the past 5 years focusing on the impact of racism on infant and early childhood mental health and socioemotional development. RECENT FINDINGS/RESULTS:Longitudinal studies provide evidence that very young children are highly influenced by exposure to multiple and interconnecting levels of racism and discrimination. These forms of exposure (structural and personally mediated, which can be further divided into direct and indirect exposure) are particularly nefarious to young children's socioemotional development and have implications for adolescent and adult mental health with lasting sequelae. Furthermore, the effects of racism on parenting practices and maternal/caregiver mental health appear to indicate mechanisms through which racism affects young children. Although more studies are needed in this area, recent literature indicates that racism is a social determinant of health that adversely impacts infant and early childhood socioemotional, and behavioral development. Future studies should focus on understanding the mechanisms through which racism impacts early childhood development and health, and interventions to prevent and mitigate the effects of racism.

BACKGROUND:Examining social networks, characterized by interpersonal interactions across family, peer, school, and neighborhoods, offer alternative explanations to suicidal behaviors and shape effective suicide prevention. This study examines adolescent social networks predicting suicide ideation and attempt trajectories transitioning to adulthood, while revealing differences across racial/ethnic, sex, sexual identity, and socioeconomic status. METHODS:Participants included 9421 high school students (Mage = 15.30 years; 54.58% females, baseline) from Waves I-IV of the National Longitudinal Study of Adolescent to Adult Health, 1994-2008. Latent class growth analyses were conducted to identify suicide ideation and attempt trajectories. Multivariate multinomial logistic regressions examined the relationships between social network characteristics during adolescence and suicidal trajectories. Interaction terms between social networks and sociodemographic characteristics were included to test moderation effects. RESULTS:Three suicidal ideation trajectories (low-stable, high-decreasing, moderate-decreasing-increasing) and two suicide attempt trajectories (low-stable, moderate-decreasing) were identified. Greater family cohesion significantly reduced the probability of belonging to high-decreasing (Trajectory 2) and moderate-decreasing-increasing (Trajectory 3) suicidal ideation trajectories, and moderate-decreasing (Trajectory 2) suicide attempt trajectory. Race/ethnicity, sex, and sexual identity significantly moderated the associations between social networks (household size, peer network density, family cohesion, peer support, neighborhood support) and suicidal trajectories. CONCLUSIONS:Social networks during adolescence influenced the odds of belonging to distinct suicidal trajectories. Family cohesion protected youth from being in high-risk developmental courses of suicidal behaviors. Social networks, especially quality of interactions, may improve detecting adolescents and young adults at-risk for suicide behaviors. Network-based interventions are key to prevent suicidal behaviors over time and suicide intervention programming.

BACKGROUND:Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data. METHODS:We addressed this gap by using a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 males, 166 females; 7-18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics (voxel-level Z > 3.1, cluster-level P < 0.01, gaussian random field corrected). Secondary analyses assessed the robustness of the results to different pre-processing approaches and their replicability in two independent samples: the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research. RESULTS:Discovery analyses in ABIDE revealed significant main effects of diagnosis and sex across the intrinsic functional connectivity of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples-EU-AIMS LEAP. LIMITATIONS:Given the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability. CONCLUSIONS:Atypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies.