National Institute of Mental Health Five-Year Strategic Plan for Reducing Health Disparities

The NIMH has a long history of concern and action related to health disparities and ethnic minority groups as well as other underrepresented groups (i.e. women, children, and disabled persons). In 1980, NIMH established the position of Associate Director for Special Populations and subsequently established an Office for Special Populations (OSP) to oversee NIMH activities concerning underrepresented groups, including ethnic minorities. Recently, NIMH in collaboration with consultants and public comment has developed a five-year Strategic Plan to address mental health outcome disparities through research that aims to describe, understand, and remedy the disproportionate impact on minority populations of mental disorders and behaviorally influenced physical health conditions such as HIV/AIDS. The research takes into consideration relevant contextual frameworks, including interpersonal, socio-cultural, and organizational factors

Childhood mental health: an ecological analysis of the effects of neighborhood characteristics

Research on childhood mental illness traditionally examines risk factors most proximal to the child. However, current trends reflect growing interest in how broader contextual factors contribute to psychopathology risk. In this study, we examined neighborhood‐level indicators as potential sources of chronic strain in a sample of 156 mother–child dyads; children were 8 to 12 years old. For most neighborhood indicators, data were collected at the level of census tracts using publicly available data sets. We hypothesized that these indicators would be both associated with greater overall mental health symptoms and specifically predictive of childhood symptoms of depression. We also examined potential mediators (maternal functioning and family cohesion) and moderators (maternal depression). Neighborhood indicators correlated with parents’ ratings of children's overall mental health problems, but did not correlate with children's self‐report of depression symptoms. Maternal functioning mediated neighborhood effects on children's overall mental health problems. Implications and directions for future research are presented.The current work was supported by the following grants from the National Institutes of Health, National Institute of Mental Health MH066077, MH082861, PI: Martha C. Tompson, Ph.D. and MH082861S1, PI: Gail N. Kemp, M.A., M.P.H. (MH066077 - National Institutes of Health, National Institute of Mental Health; MH082861 - National Institutes of Health, National Institute of Mental Health; MH082861S1 - National Institutes of Health, National Institute of Mental Health)Published versio

Increased AT 1 receptor expression and mRNA in kidney glomeruli of AT 2 receptor gene-disrupted mice

The proposed feedback between angiotensin II AT2 and AT1 receptors prompted us to study AT1 receptor expression in kidneys of male AT2 receptor-gene disrupted mice (agtr2 −/y). In wild-type (agtr2 +/y) mice, AT1 receptor binding and mRNA is abundant in glomeruli, and AT1 receptor binding is also high in the inner stripe of the outer medulla. AT2 receptors are scarce, primarily associated to cortical vascular structures. In agtr2 −/y mice, AT1 receptor binding and mRNA were increased in the kidney glomeruli, and AT1 receptor binding was higher in the rest of the cortex and outer stripe of the outer medulla, but not in its inner stripe, indicating different cellular regulation. Although AT2 receptor expression is very low in male agtr 2 +/y mice, their gene disruption alters AT1 receptor expression. AT1 upregulation alone may explain the AT2 gene-disrupted mice phenotype such as increased blood pressure, higher sensitivity to angiotensin II, and altered renal function. The indirect AT1/AT2 receptor feedback could have clinical significance because AT1antagonists are widely used in medical practice.Fil: Saavedra, Juan M.. National Institute of Mental Health; Estados UnidosFil: Häuser, Walter. National Institute of Mental Health; Estados UnidosFil: Ciuffo, Gladys Maria. National Institute of Mental Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Egidy, Giorgia. National Institute of Mental Health; Estados UnidosFil: Hoe, Kwang Lae. National Institute of Mental Health; Estados UnidosFil: Jöhren, Olaf. National Institute of Mental Health; Estados UnidosFil: Sembonmatsu, Takaaki. Vanderbilt University; Estados UnidosFil: Inagami, Tadashi. Vanderbilt University; Estados UnidosFil: Armando, Inés. National Institute of Mental Health; Estados Unido

Segregation of cortical head direction cell assemblies on alternating theta cycles

High-level cortical systems for spatial navigation, including entorhinal grid cells, critically depend on input from the head direction system. We examined spiking rhythms and modes of synchrony between neurons participating in head direction networks for evidence of internal processing, independent of direct sensory drive, which may be important for grid cell function. We found that head direction networks of rats were segregated into at least two populations of neurons firing on alternate theta cycles (theta cycle skipping) with fixed synchronous or anti-synchronous relationships. Pairs of anti-synchronous theta cycle skipping neurons exhibited larger differences in head direction tuning, with a minimum difference of 40 degrees of head direction. Septal inactivation preserved the head direction signal, but eliminated theta cycle skipping of head direction cells and grid cell spatial periodicity. We propose that internal mechanisms underlying cycle skipping in head direction networks may be critical for downstream spatial computation by grid cells.We kindly thank S. Gillet, J. Hinman, E. Newman and L. Ewell for their invaluable consultations and comments on previous versions of this manuscript, as well as M. Connerney, S. Eriksson, C. Libby and T. Ware for technical assistance and behavioral training. This work was supported by grants from the National Institute of Mental Health (R01 MH60013 and MH61492) and the Office of Naval Research Multidisciplinary University Research Initiative (N00014-10-1-0936). (R01 MH60013 - National Institute of Mental Health; MH61492 - National Institute of Mental Health; N00014-10-1-0936 - Office of Naval Research Multidisciplinary University Research Initiative)Accepted manuscrip

GABAergic interneuron origin of schizophrenia pathophysiology

Hypofunction of N-methyl-d-aspartic acid-type glutamate receptors (NMDAR) induced by the systemic administration of NMDAR antagonists is well known to cause schizophrenia-like symptoms in otherwise healthy subjects. However, the brain areas or cell-types responsible for the emergence of these symptoms following NMDAR hypofunction remain largely unknown. One possibility, the so-called "GABAergic origin hypothesis," is that NMDAR hypofunction at GABAergic interneurons, in particular, is sufficient for schizophrenia-like effects. In one attempt to address this issue, transgenic mice were generated in which NMDARs were selectively deleted from cortical and hippocampal GABAergic interneurons, a majority of which were parvalbumin (PV)-positive. This manipulation triggered a constellation of phenotypes-from molecular and physiological to behavioral-resembling characteristics of human schizophrenia. Based on these results, and in conjunction with previous literature, we argue that during development, NMDAR hypofunction at cortical, PV-positive, fast-spiking interneurons produces schizophrenia-like effects. This review summarizes the data demonstrating that in schizophrenia, GABAergic (particularly PV-positive) interneurons are disrupted. PV-positive interneurons, many of which display a fast-spiking firing pattern, are critical not only for tight temporal control of cortical inhibition but also for the generation of synchronous membrane-potential gamma-band oscillations. We therefore suggest that in schizophrenia the specific ability of fast-spiking interneurons to control and synchronize disparate cortical circuits is disrupted and that this disruption may underlie many of the schizophrenia symptoms. We further argue that the high vulnerability of corticolimbic fast-spiking interneurons to genetic predispositions and to early environmental insults-including excitotoxicity and oxidative stress-might help to explain their significant contribution to the development of schizophrenia.Fil: Nakazawa, Kazu. National Institute of Mental Health; Estados UnidosFil: Zsiros, Veronika. National Institute of Mental Health; Estados UnidosFil: Jiang, Zhihong. National Institute of Mental Health; Estados UnidosFil: Nakao, Kazuhito. National Institute of Mental Health; Estados UnidosFil: Kolata, Stefan. National Institute of Mental Health; Estados UnidosFil: Zhang, Shuqin. National Institute of Mental Health; Estados UnidosFil: Belforte, Juan Emilio. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Mol Psychiatry

Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells, neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation because of dysregulation of a \u3b2-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by insulin growth factor 1 (IGF-1), a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.KL2 TR000099/NCATS NIH HHS/National Center for Advancing Translational Sciences/United StatesDP2 OD006495/ODCDC CDC HHS/Office of the Director/United StatesR01 MH113924/NIMH NIH HHS/National Institute of Mental Health/United StatesR01 MH100175/NIMH NIH HHS/National Institute of Mental Health/United StatesR01 MH094753/NIMH NIH HHS/National Institute of Mental Health/United StatesR00 MH101634/NIMH NIH HHS/National Institute of Mental Health/United StatesU19 MH107367/NIMH NIH HHS/National Institute of Mental Health/United States2017-05-23T00:00:00Z27378147PMC52159916525vault:3354

Translating Glutamate: From Pathophysiology to Treatment

The neurotransmitter glutamate is the primary excitatory neurotransmitter in mammalian brain and is responsible for most corticocortical and corticofugal neurotransmission. Disturbances in glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders—including schizophrenia, drug abuse and addiction, autism, and depression—that were until recently poorly understood. Nevertheless, improvements in basic information regarding these disorders have yet to translate into Food and Drug Administration–approved treatments. Barriers to translation include the need not only for improved compounds but also for improved biomarkers sensitive to both structural and functional target engagement and for improved translational models. Overcoming these barriers will require unique collaborative arrangements between pharma, government, and academia. Here, we review a recent Institute of Medicine–sponsored meeting, highlighting advances in glutamatergic theories of neuropsychiatric illness as well as remaining barriers to treatment development.National Institute of Mental Health (U.S.) (grant R37MH49334)National Institute of Mental Health (U.S.) (Intramural Research Program)National Institute of Mental Health (U.S.) (R01DA03383)National Institute of Mental Health (U.S.) (P50MH086385)National Institutes of Health (U.S.)FRAXA Research FoundationHoward Hughes Medical InstituteSimons Foundatio

Temporal Organization of Spoken Language

This study was supported by PHS Research Grant No. 1 R03 MH-18122-01 from the National Institute of Mental Health

Linguistics

Contains research objectives.National Institutes of Health (Grant 5 TO1 HD00111-09)National Institute of Mental Health (Grant 5 PO1 MH13390-07

Linguistics

Contains reports on two research projects.National Institutes of Health (Grant 5 TO1 HD00111-08)National Institute of Mental Health (Grant 2 PO1 MH13390-06