2002 — 2011 |
Benes, Francine M. |
R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Limbic Lobe in Schizophrenia and Bipolar Disorder
DESCRIPTION (provided by applicant): This is a resubmission of a competitive renewal application (ROl MH42261-14) for postmortem studies of the limbic lobe in relation to schizophrenia (SZ) and bipolar disorder (BD). Recent work from this laboratory has demonstrated a series of microscopic anomalies in layer II of the anterior cingulate cortex (ACCx-ll) and sectors CA3 and CA2 of the hippocampal formation (HIPP) in SZs and BDs. These changes have included reductions in interneurons, although an overt loss of GABA cells now appears to be a striking feature of GD, but not SZ. Even so, both SZs and BDs show evidence for a decrease of GABAergic function in ACCx-ll and HIPP. Specific Aim I will test the hypothesis that discrepancies in cell counting data in ACCx and HIPP of SZs and/or BDs can be explained in part by differences in sampling window size employed in 2D vs 3D counting. Specific Aim II will test the hypothesis that there will be a reduction in cells positive for GAD in HIPP sectors CA3 and CA2, as well as layers II and Ill of ACCx in BDs, but not SZs or their family members. In addition, it is also postulated that dopaminergic inputs to GABA cells are in increased in ACCx-ll of SZs, but not BDs. Specific Aim Ill will test the hypothesis that in ACCx and HIPP of SZs and their first degree relatives there will be a decrease of the kainate receptor in PNs, while the NMDA receptor will be decreased in NPs. Specific Aim IV will test the hypothesis that neurons in SZs will show less evidence of apoptosis than patients with BD and this will be especially apparent in interneurons. Taken together, the proposed studies are seeking to identify specific aspects of limbic circuitry that may be involved in the induction of neuronal pathology in SZ and BD. By learning more about the possible role of oxidative stress, novel forms of pharmacotherapy for the major neuropsychiatric disorders may eventually be developed.
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0.907 |
2007 — 2011 |
Benes, Francine M. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gene Expression in Hippocampal Circuits of Bipolars and Schizophrenics
DESCRIPTION (provided by applicant): The studies described in this proposal are a logical follow-up to our earlier work showing subtle alterations of intrinsic neural circuitry in the hippocampus (HIPP) of schizophrenic (SZ) and bipolar disorder (BD) subjects. Some of these abnormalities have suggested that cellular and molecular changes in pathways associated with cell viability may lead to cell death in BDs and, to a lesser degree, SZs. We recently tested this hypothesis using gene expression profiling (GEP), together with a novel post hoc analysis of GenMapp biopathways/clusters. A pronounced upregulation of genes associated with calcium channels, monoamine and peptide G-coupled protein receptors (GPCRs) and multiple signaling pathways including apoptosis, TFG-p and Wnt has been observed in BDs. In SZs, these same pathways are affected, but in the opposite direction, suggesting that at least some of these changes may be related to susceptibility genes for each of the disorders. To learn more about cellular regulatory mechanisms in the HIPP of BDs and SZs, we are proposing to use two cohorts, one composed of a well-characterized set of normal controls, SZs and BDs called the McLean 66 and another consisting of first degree relatives of SZs (SZ-F) and matched controls. In Specific Aim I, a combination of GEP, laser capture microdissection (LCM) and quantitative RT-PCR will be used to determine whether these changes are present in particular subregions, sublaminae and cellular subtypes in sectors CA3/2 versus CA1 in HIPP of BDs and SZs. In later studies, we will perform GEP in the SZ-F cohort to determine whether there are similarities in the expression profiles in SZs. In addition, data from our 'partial'rodent model of SZ in which picrotoxin is acutely and chronically infused in the amygdala will also be used to evaluate whether genes showing overlapping changes in BDs, SZs and PICRO-treated rats may be related to amygdalar activation of the HIPP. In Specific Aim II, we will validate and extend the GEP results by using double in situ hybridization (DISH) to co-localize mRNA from several target genes associated with apoptosis and other GenMapp pathways/clusters with GAD65 mRNA to determine whether key changes are preferentially occurring in GABAergic or non-GABAergic neurons. Overall, the proposed studies are seeking to replicate, validate and extend our GEP studies in critical ways that will provide a more detailed understanding of where pivotal changes in gene expression may be occurring within discrete aspects of HIPP circuitry and whether such changes may be related to genetic or environmental factors associated with the psychotic disorders.
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0.907 |
2012 |
Benes, Francine M. |
S10Activity Code Description: To make available to institutions with a high concentration of NIH extramural research awards, research instruments which will be used on a shared basis. |
Confocal Imaging For Neuropsychiatric Research
DESCRIPTION (provided by applicant): The Mailman Research Center (MRC) at McLean Hospital is a critical component to our translational studies of the causes and treatments of neuropsychiatric disorders. The MRC Imaging Facility must replace our outmoded Leica confocal microscope with a state-of-the-art instrument. This will enhance our ability to perform co- localization studies of cellular and molecular mechanisms within neuronal subpopulations that regulate complex neural circuits involved in emotion and cognition. Ongoing work in the MRC focuses on corticolimbic circuits believed to be dysfunctional in patients with major psychoses, mood and anxiety disorders, post-traumatic stress, development disorders and neurodegenerative diseases. This proposal describes the need for a Leica TCS SP5 confocal microscope. This instrument will provide MRC investigators with a broad array of imaging capabilities. We currently have JEOL 1200EX electron microscope and a Leica confocal microscope; both were purchased with funds awarded through two separate NIH Shared Instrumentation Grants. In 1985, when the EM was procured, we established a Users Committee and this has served as a governing body for the Imaging Facility since that time. If this application is successful, our Users Committee will coordinate the use and maintenance of the new confocal microscope. Since 1985, a financial plan for the support of our Imaging Facility has been in place and will be amended to cover the new instrumentation. Historically, McLean Hospital has provided additional support for this facility and will continue to do so. The procurement of the proposed equipment will ensure that the MRC at McLean Hospital will be able to maintain a cutting edge research program for the study of neuropsychiatric disorders. PUBLIC HEALTH RELEVANCE: McLean Hospital has a multidisciplinary research program directed at the study of psychosis, mood and anxiety disorders, post-traumatic stress, development disorders and neurodegenerative diseases. The productivity of this program is dependent upon the availability of state-of-the-art imaging technology for visualizing neuronal circuitry both structurally and functionally. This proposal describes our need for a new sophisticated confocal imaging instrument that will allow us to function at the cutting edge of psychiatric neuroscience where it will be possible to develop innovative new approaches to the treatment of neuropsychiatric disorders.
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0.907 |