Faculty Bibliography

Adult hippocampal neurogenesis (AHN) is a key process for certain types of hippocampal-dependent learning. Alzheimer's disease (AD) is accompanied by memory deficits related to alterations in AHN. Given that the increased activity of GSK-3β has been related to alterations in the population of hippocampal granule neurons in AD patients, we designed a novel methodology by which to induce selective GSK-3β overexpression exclusively in newborn granule neurons. To this end, we injected an rtTA-IRES-EGFP-expressing retrovirus into the hippocampus of tTO-GSK-3β mice. Using this novel retroviral strategy, we found that GSK-3β caused a cell-autonomous impairment of the morphological and synaptic maturation of newborn neurons. In addition, we examined whether GSK-3β overexpression in newborn neurons limits the effects of physical activity. While physical exercise increased the number of dendritic spines, the percentage of mushroom spines, and the head diameter of the same in tet-OFF cells, these effects were not triggered in tet-ON cells. This observation suggests that GSK-3β blocks the stimulatory actions of exercise. Given that the activity of GSK-3β is increased in the brains of individuals with AD, these data may be relevant for non-pharmacological therapies for AD.

Significance Statement:The extracellular protein Reelin has an important role in neurological diseases, including epilepsy, Alzheimer's disease and psychiatric diseases, targeting hippocampal circuits. Here we address the role of Reelin in the development of synaptic contacts in adult-generated granule cells (GCs), a neuronal population that is crucial for learning and memory and implicated in neurological and psychiatric diseases. We found that the Reelin pathway controls the shapes, sizes, and types of dendritic spines, the complexity of multisynaptic innervations and the degree of the perisynaptic astroglial ensheathment that controls synaptic homeostasis. These findings show a pivotal role of Reelin in GC synaptogenesis and provide a foundation for structural circuit alterations caused by Reelin deregulation that may occur in neurological and psychiatric disorders.

The articles in this Special Issue are devoted to integrating the fields of disaster mental health and positive psychology. Their focus on resilience building, individual and community preparation, meaning making, and posttraumatic growth represents an important new development in disaster mental health. The overarching goal of this effort is to inform strategies to help both individuals-including children, adolescent, adult disaster survivors, and relief workers-and communities prepare for, respond to, recover from, and possibly even grow stronger in the face of adversity. To achieve this goal, this body of literature suggests that it is important for disaster mental health workers to partner with community leaders, organizations, and the population at large to understand community vulnerabilities, take advantage of existing strengths, and respect cultural factors implicated in disaster recovery. It further suggests that an effective community-based approach to disaster recovery will make psychosocial support and skill-building programs available to large numbers of survivors, which is critical for responding to future national and international disasters. Continued high-quality research that is comprehensive and considers not only relevant psychological, social, cultural, and biological factors but also interrelations between individuals, organizations and communities is needed to advance this relatively new and important direction of the disaster mental health field.

Only a limited literature focuses on solid organ transplant outcomes using an integrated care approach connecting the transplant team with psychiatry, other medical specialties, and importantly, the patient's social supports. We present the case of a man with heart failure whom we treated for symptoms of anxiety and depression both precardiac and postcardiac transplant. The patient was managed by a multidisciplinary team for his complex medical, psychiatric, family, and social issues. Most notably, the role and involvement of his primary caregiver at home changed during the crucial period between his pretransplant evaluation and clinical care during the year following his cardiac transplant. Unfortunately our patient succumbed to a poor outcome both socially and medically, dying 1 year posttransplant. Our experience with this patient led us to explore the cardiac transplant presurgical and postsurgical assessment and management process, focusing on the key role of social support in the patient care team.

IMPORTANCE:The increased risk of major depression in the offspring of depressed parents is well known. Whether the risk is transmitted beyond 2 generations is less well known. To our knowledge, no published study with direct interviews of family members and the generations in the age of risk for depression has evaluated beyond 2 generations. This information is important for detecting individuals at highest risk who may benefit from early intervention. OBJECTIVE:To examine the familial aggregation of psychiatric disorder and functioning in grandchildren by their biological parents' and grandparents' depression status. DESIGN, SETTING, AND PARTICIPANTS:Longitudinal retrospective cohort family study of 251 grandchildren (generation 3 [mean age, 18 years]) interviewed a mean of 2.0 times and their biological parents (generation 2) interviewed a mean of 4.6 times and grandparents (generation 1) interviewed up to 30 years. The study dates were January 1982 (wave 1) to June 2015 (wave 6). MAIN OUTCOMES AND MEASURES:Cumulative rates of psychiatric disorders and functioning collected for all generations by clinically trained interviewers and best-estimate diagnosis made blind to diagnoses in members of previous generations. RESULTS:There were 91 families (G1) in the original sample, of whom 77 were eligible for inclusion (had a grandchild older than 5 years), and 80.5% (62 of 77) participated in the study. When first examining only 2 generations, the biological children (generation 3) of depressed compared with nondepressed parents (generation 2) had 2-fold increased risk for major depressive disorder (MDD) (hazard ratio [HR], 2.02; 95% CI, 1.08-3.79; P = .03), any disruptive disorder (HR, 1.70; 95% CI, 1.05-2.75; P = .03), substance dependence (HR, 2.96; 95% CI, 1.24-7.08; P = .01), any suicidal ideation or gesture (HR, 2.44; 95% CI, 1.28-4.66; P = .007), and poor functioning (F = 38.25, P < .001). When 3 generations were examined stratified by parental and grandparental depression status, association of a parent's MDD on the grandchild's MDD but not other disorders varied with the grandparent's depression status: grandchildren with both a depressed parent and grandparent (n = 38) were at highest risk for MDD. Among grandchildren without a depressed grandparent, those with (n = 14) vs without (n = 74) a depressed parent had overall poorer functioning (F = 6.31, P = .01) but not higher rates of any of the disorders. Potential confounding variables did not have a meaningful effect on the association between grandchild outcomes and parental or grandparental depression. CONCLUSIONS AND RELEVANCE:In this study, biological offspring with 2 previous generations affected with major depression were at highest risk for major depression, suggesting the potential value of determining family history of depression in children and adolescents beyond 2 generations. Early intervention in offspring of 2 generations affected with moderate to severely impairing MDD seems warranted. The specificity of the transmission of depression across 3 generations may make this group a homogeneous sample for biological marker studies.

The amygdalo-nigrostriatal (ANS) network plays an essential role in enhanced attention to significant events. Interval timing requires attention to temporal cues. We assessed rats having a disconnected ANS network, due to contralateral lesions of the medial central nucleus of the amygdala (CEm) and dopaminergic afferents to the lateral striatum, as compared to controls (sham and ipsilateral lesions of CEm and dopaminergic afferents to LS) in a temporal bisection task. ANS disconnection induced poorer temporal precision and increased response latencies to a short duration. The present results reveal a role of the ANS network in temporal processing.

Cognitive deficits associated with Huntington disease (HD) are generally dominated by executive function disorders often associated with disinhibition and impulsivity/compulsivity. Few studies have directly examined symptoms and consequences of behavioral disinhibition in HD and its relation with decision-making. To assess the different forms of impulsivity in a transgenic model of HD (tgHD rats), two tasks assessing cognitive/choice impulsivity were used: risky decision-making with a rat gambling task (RGT) and intertemporal choices with a delay discounting task (DD). To assess waiting or action impulsivity the differential reinforcement of low rate of responding task (DRL) was used. In parallel, the volume as well as cellular activity of the amygdala was analyzed. In contrast to WT rats, 15 months old tgHD rats exhibited a poor efficiency in the RGT task with difficulties to choose advantageous options, a steep DD curve as delays increased in the DD task and a high rate of premature and bursts responses in the DRL task. tgHD rats also demonstrated a concomitant and correlated presence of both action and cognitive/choice impulsivity in contrast to wild type (WT) animals. Moreover, a reduced volume associated with an increased basal cellular activity of the central nucleus of amygdala indicated a dysfunctional amygdala in tgHD rats, which could underlie inhibitory dyscontrol. In conclusion, tgHD rats are a good model for impulsivity disorder that could be used more widely to identify potential pharmacotherapies to treat these invasive symptoms in HD.

BACKGROUND:Transition-age youth have elevated rates of mental disorders, and they often do not receive services. This is a serious public health concern, as mental health conditions persist into adulthood. Continuing to engage this population has been a pervasive challenge for the mental health care system worldwide. Few mental health interventions have been developed for transition-age youth, and even fewer have been found to be effective over the transition to adulthood. Cornerstone, a theoretically guided intervention has shown promise for addressing the mental health and psychosocial needs of this population as they emerge into adulthood. Cornerstone provides case management, trauma-focused cognitive behavioral therapy, mentoring/peer support, community-based in vivo practice, and groups to address stigma, mistrust, and practical skill development to improve the transition to independence among transition-age youth with serious mental health conditions. METHODS/DESIGN:This study utilizes a hybrid research design and focuses on examining feasibility, acceptability and preliminary impact, along with factors that influence implementation, to maximize new knowledge. The study combines qualitative methods and a randomized controlled trial, using data to inform and refine protocols and manuals, while testing the preliminary impact of the intervention, compared to best available services (treatment as usual, TAU) at a partnering outpatient mental health clinic (n = 60). Contributors to the intervention development research (n = 20) are national experts on mental health services, clinic administrators and staff and young adults with direct experience. The intervention involves intensive staff training and 18 months of ongoing service provision, monitoring and supervision. Quantitative survey data will be collected at baseline, 3 months, 6 months, and 9 months measuring mental health and practical life outcomes via self-report measures. Medical records will be used to triangulate self-report data (i.e., primary diagnosis, treatment planning and attendance). Qualitative data focuses on the intervention development process and implementation research and will use constant comparison coding techniques. In this intention-to-treat analysis, we will conduct basic omnibus analyses to examine whether Cornerstone leads to improved outcomes relative to TAU utilizing t tests across treatment conditions for each outcome measure specified. We will likewise examine whether changes in the proposed mediating variables differ across groups. DISCUSSION:The aim of this study is to refine Cornerstone through an intensive preliminary trial, learning through collaboration with clinic staff, project team members, and leaders in New York State and nationwide on how to best serve transition-age youth with serious mental health conditions. Cornerstone has the potential to fill a large gap in the service system for transition-age youth with serious mental health conditions, and may enhance the menu of care options for those who have been recently diagnosed with a serious mental health condition, and yet, have a long life to live. The program is recovery-oriented, builds on the best evidence to date, and is in line with both local and national health care reform efforts. TRIAL REGISTRATION:This trial was registered with ClinicalTrials.gov (Identifier: NCT02696109 ) on 22 April 16 as Protocol Record R34-MH102525-01A1MRM, as New York University, Cornerstone program for transition-age youth with serious mental illness: study protocol for a randomized controlled trial.