Faculty Bibliography

The dentate gyrus (DG) principal cells are glutamatergic granule cells (GCs), and they are located in a compact cell layer. However, GCs are also present in the adjacent hilar region, but have been described in only a few studies. Therefore, we used the transcription factor prospero homeobox 1 (Prox1) to quantify GCs at postnatal day (PND) 16, 30, and 60 in a common mouse strain, C57BL/6J mice. At PND16, there was a large population of Prox1-immunoreactive (ir) hilar cells, with more in the septal than temporal hippocampus. At PND30 and 60, the size of the hilar Prox1-ir cell population was reduced. Similar numbers of hilar Prox1-expressing cells were observed in PND30 and 60 Swiss Webster mice. Prox1 is usually considered to be a marker of postmitotic GCs. However, many Prox1-ir hilar cells, especially at PND16, were not double-labeled with NeuN, a marker typically found in mature neurons. Most hilar Prox1-positive cells at PND16 co-expressed doublecortin (DCX) and calretinin, markers of immature GCs. Double-labeling with a marker of actively dividing cells, Ki67, was not detected. These results suggest that, surprisingly, a large population of cells in the hilus at PND16 are immature GCs (Type 2b and Type 3 cells). We also asked whether hilar Prox1-ir cell numbers are modifiable. To examine this issue, we conditionally deleted the proapoptotic gene BAX in Nestin-expressing cells at a time when there are numerous immature GCs in the hilus, PND2-8. When these mice were examined at PND60, the numbers of Prox1-ir hilar cells were significantly increased compared to control mice. However, deletion of BAX did not appear to change the proportion that co-expressed NeuN, suggesting that the size of the hilar Prox1-expressing population is modifiable. However, deleting BAX, a major developmental disruption, does not appear to change the proportion that ultimately becomes neurons.

Despite the critical importance of patient-physician trust, it may be compromised among vulnerable patients, such as (1) incarcerated patients and (2) those patients who have been victims of trauma. The purpose of this study was to examine patient-physician trust among forensic and civilian psychiatric inpatient populations and to explore whether it varied based on a patient's history of incarceration and/or victimization. A trust survey (WFPTS) and a trauma instrument (LEC-5) were administered to 93 patients hospitalized on forensic and civilian psychiatric hospital units in a large, urban public hospital. Results showed no difference in patient-physician trust between incarcerated and civilian patients. Similarly, there was no effect of a history of physical assault or sexual assault on ratings of patient-physician trust. However, the hospitalized civilian and forensic patients who reported being the victim of weapons assault had significantly lower patient-physician trust scores than their counterparts.

What an animal needs to learn to survive is altered dramatically as they change from dependence on the parent for protection to independence and reliance on self-defense. This transition occurs in most altricial animals, but our understanding of the behavioral neurobiology has mostly relied on the infant rat. The transformation from dependence to independence occurs over three weeks in pups and is accompanied by complex changes in responses to both natural and learned threats and the supporting neural circuitry. Overall, in early life, the threat system is quiescent and learning is biased towards acquiring attachment related behaviors to support attachment to the caregiver and proximity seeking. Caregiver-associated cues learned in infancy have the ability to provide a sense of safety throughout lifetime. This attachment/safety system is activated by learning involving presumably pleasurable stimuli (food, warmth) but also painful stimuli (tailpinch, moderate shock). At about the midway point to independence, pups begin to have access to the adult-like amygdala-dependent threat system and amygdala-dependent responses to natural dangers such as predator odors. However, pups have the ability to switch between the infant and adult-like system, which is controlled by maternal presence and modification of stress hormones. Specifically, if the pup is alone, it will learn fear but if with the mother it will learn attachment (10-15 days of age). As pups begin to approach weaning, pups lose access to the attachment system and rely only on the amygdala-dependent threat system. However, pups learning system is complex and exhibits flexibility that enables the mother to override the control of the attachment circuit, since newborn pups may acquire threat responses from the mother expressing fear in their presence. Together, these data suggest that the development of pups' threat learning system is not only dependent upon maturation of the amygdala, but it is also exquisitely controlled by the environment. Most notably the mother can switch pup learning between attachment to threat learning in a moment's notice. This enables the mother to navigate pup's learning about the world and what is threatening and what is safe.

Caregiver report is the most common measure of change in pediatric psychiatry. Yet, placebo response rates pose significant challenges to reliably detect a treatment response. The present study simulated an eight-week clinical trial protocol for Autism Spectrum Disorder (ASD) for the purpose of testing the feasibility and validity of several outcome measures. Twenty caregivers answered questions about their child's behavior on their smartphone each week and completed a battery of paper questionnaires during weeks one and eight. No treatment was administered. Caregivers reported a significant decrease in problem behaviors on the Aberrant Behavior Checklist (ABC) (29% decrease) and general ASD behaviors on the Social Responsiveness Scale (SRS) (7% decrease). There was also a trend of behavior improvement from smartphone questions but no significant changes in clinical ratings of core diagnostic features of ASD. Participation in a comprehensive protocol in the absence of a particular treatment significantly influenced how caregivers perceived the severity of their children's problem behaviors. These placebo-like effects represent substantial challenges for randomized controlled trials (RCTs) that use treatment as usual and have implications for future behavioral and pharmacological treatment trial designs. Autism Res 2017, 10: 1567-1572. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

The immediate and long-term effects of exposure to early life stress (ELS) have been documented in humans and animal models. Even relatively brief periods of stress during the first 10 days of life in rodents can impact later behavioral regulation and the vulnerability to develop adult pathologies, in particular an impairment of cognitive functions and neurogenesis, but also modified social, emotional, and conditioned fear responses. The development of preclinical models of ELS exposure allows the examination of mechanisms and testing of therapeutic approaches that are not possible in humans. Here, we describe limited bedding and nesting (LBN) procedures, with models that produce altered maternal behavior ranging from fragmentation of care to maltreatment of infants. The purpose of this paper is to discuss important issues related to the implementation of this chronic ELS procedure and to describe some of the most prominent endpoints and consequences, focusing on areas of convergence between laboratories. Effects on the hypothalamic-pituitary adrenal (HPA) axis, gut axis and metabolism are presented in addition to changes in cognitive and emotional functions. Interestingly, recent data have suggested a strong sex difference in some of the reported consequences of the LBN paradigm, with females being more resilient in general than males. As both the chronic and intermittent variants of the LBN procedure have profound consequences on the offspring with minimal external intervention from the investigator, this model is advantageous ecologically and has a large translational potential. In addition to the direct effect of ELS on neurodevelopmental outcomes, exposure to adverse early environments can also have intergenerational impacts on mental health and function in subsequent generation offspring. Thus, advancing our understanding of the effect of ELS on brain and behavioral development is of critical concern for the health and wellbeing of both the current population, and for generations to come.

In this pilot study, we examined training effects of a computerized working memory program on resting state functional magnetic resonance imaging (fMRI) measures in children with neurofibromatosis type 1 (NF1). We contrasted pre- with post-training resting state fMRI and cognitive measures from 16 participants (nine males; 11.1 +/- 2.3 years) with NF1 and documented working memory difficulties. Using non-parametric permutation test inference, we found significant regionally specific differences (family-wise error corrected) in two of four voxel-wise resting state measures: fractional amplitude of low frequency fluctuations (indexing peak-to-trough intensity of spontaneous oscillations) and regional homogeneity (indexing local intrinsic synchrony). Some cognitive task improvement was observed as well. These preliminary findings suggest that regionally specific changes in resting state fMRI indices may be associated with treatment-related cognitive amelioration in NF1. Nevertheless, current results must be interpreted with caution pending independent controlled replication.

Increased resting-state functional connectivity (rsFC) between the default mode network (DMN) and subgenual anterior cingulate cortex (sgACC) is consistently reported in adults and youth with psychopathologies related to affect dysregulation (e.g. depression, posttraumatic stress disorder). This pattern of increased rsFC is thought to underlie ruminative thought patterns through integration of negative affect (via sgACC) into self-referential operations supported by the DMN. Neurobiological studies in adults show that behavioral activation system (BAS) sensitivity is a potential protective factor against the development of psychopathology, particularly in the context of stress and trauma exposure. However, whether BAS sensitivity is associated with variation in DMN-sgACC stress-vulnerability circuitry in youth, particularly those at risk for affect dysregulation, has not yet been studied. This association was tested in a sample of ninety-eight children and adolescents (ages 6-17) at high sociodemographic risk for psychopathology (i.e., urban, lower income, high frequency of violence and abuse exposure). Participants underwent a six-minute resting-state functional magnetic resonance imaging scan. Using a targeted, small-volume corrected approach, we found that youth with higher BAS sensitivity demonstrated lower DMN-sgACC rsFC, suggesting a potential link between the purported protective effects of BAS sensitivity and stress-vulnerability circuitry. This work suggests that interventions that augment BAS sensitivity, such as behavioral activation therapy, may protect against the development of stress-related psychopathology by modifying a critical rumination circuitry in the brain. Such interventions may be especially important for bolstering resiliency in at-risk urban youth, who are disproportionately burdened by early stress and associated psychopathology.

Valproate is the best choice drug for a variety of medical conditions. As with any other drug, it has adverse effects, and it is important to emphasize the possibility of those adverse effects to prevent complications. We present the case history of a 44-year-old male with valproate-induced hyperammonemic encephalopathy, despite having normal liver function tests. This case includes a detailed literature review of this rare adverse event. In the light of this case report, we illustrate the importance of checking ammonia levels in all psychiatric patients receiving valproate as a treatment who present with new onset neurological symptoms or altered mental status.

PURPOSE OF REVIEW/OBJECTIVE:Imaging research has sought to uncover brain structure, function, and metabolism in women with postpartum depression (PPD) as little is known about its underlying pathophysiology. This review discusses the imaging modalities used to date to evaluate postpartum depression and highlights recent findings. RECENT FINDINGS/RESULTS:Altered functional connectivity and activity changes in brain areas implicated in executive functioning and emotion and reward processing have been identified in PPD. Metabolism changes involving monoamine oxidase A, gamma-aminobutyric acid, glutamate, serotonin, and dopamine have additionally been reported. To date, no studies have evaluated gray matter morphometry, voxel-based morphometry, surface area, cortical thickness, or white matter tract integrity in PPD. Recent imaging studies report changes in functional connectivity and metabolism in women with PPD vs. healthy comparison women. Future research is needed to extend these findings as they have important implications for the prevention and treatment of postpartum mood disorders.