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2012 Research Awards

Mechanisms of Cognitive Impairment in Multiple Sclerosis

PI: Charles J. Duffy, M.D., Ph.D.
Co-Investigators: Matthew Bellizzi, M.D., Ph.D.; Giovanni Schifitto, M.D.

This proposal represents the product of a new collaboration among URMC faculty to bridge their previous independent areas of focus: cognitive sciences (Duffy), neuro-imaging (Schifitto), and neuro-immunology (Bellizzi).The proposed project will:

  1. Establish collaborative interactions for innovative multi-modal studies of MS
  2. Validate our paradigm for linking the neuro-behavioral features of MS to its neuro-imaging characteristics, and cellular mechanisms of disease
  3. Demonstrate the feasibility of linking these modalities to distinguish between WM and GM lesions in MS

Our goal is to create a new approach to MS diagnosis, therapeutic monitoring, and individualized treatment based-on a refined understanding of the mechanisms of cognitive impairment in these patients. This is an area of significant unmet need in MS care. This study will provide the preliminary data need to support applications for investigator initiated extramural support, including NIH R01 funding and potential for a center grant from the MS Society.

Proteomic Investigation of CGRP-Receptor Component Protein (RCP)

PI: Ian M. Dickerson, Ph.D.
Co-Investigator: Alan Eric Friedman, Ph.D.

Calcitonin gene-related peptide (CGRP) is a neuropeptide synthesized in neurons with broad distribution in brain and spinal cord. In the CNS CGRP is involved in migraine, neuroinflammation, and tolerance to opiates. The effects of CGRP are mediated through an unusual G protein-coupled receptor named calcitonin-like receptor (CLR), which requires two accessory proteins for function, named receptor activity modifying protein (RAMP1) and CGRPreceptor component protein (RCP). CGRP binds to the CLR/RAMP1 dimer, and RCP couples CLR/RAMP1 to the cellular signaling pathway. We have identified RCP in sub-cellular pools without CLR, and have observed RCP movement within the cell, suggesting that RCP does not always interact with CLR. Our hypothesis is that RCP has additional roles in neuronal physiology, and that these roles are mediated via molecular interactions with additional proteins. The specific aims of this proposal are to:

  1. Identify proteins that directly interact with RCP
  2. Test interactions of newly discovered proteins in cell culture

Identification of these additional proteins will be the first step in elucidating further roles for RCP, and determining if cross-talk between the CGRP receptor and these interacting proteins via RCP identifies new roles for CGRP in neuroendocrine regulation.

Amygdala Neurogenesis and Behavior in Adolescent Rats

PI: Julie Fudge, M.D.
Co-Investigators: Margot Mayer-Pröschel, Ph.D., Christoph Pröschel, Ph.D., Dana L. Helmreich, Ph.D.

The amygdala is integral part of the limbic system circuitry that mediates emotional learning and social behavior. The amygdala can become dysregulated in individuals with mood and anxiety disorders; it is both hyperactive and relatively small in size. Current hypotheses suggest that mental disorders may, in part, be neuro-developmental disorders. This hypothesis, in concert with the knowledge that mood and anxiety disorders can be triggered by stress, suggests that stress during development may create individuals predisposed to developing mood or anxiety disorders as adults. In the current experiments, we propose an animal model that will allow testing of these hypotheses. One mechanism underlying the observations of decreased amygdala size in anxiety disorders may be decreased amygdalar cell proliferation and/or survival during critical growth periods, such as adolescence. Cell proliferation and neurogenesis within the hippocampus are decreased by stress. To date, cell proliferation and neurogenesis within the amygdala have received scant attention, but our preliminary data from male rats suggest that there is cell proliferation during adolescence in the rodent amygdala, and that it is decreased by stress. Our proposed model examines the hypothesis that adolescent stress has consequences for subsequent amygdala volume and cell survival, adult behavioral inhibition, and glucocorticoid responses. We further hypothesize that similar stress exposure during adulthood—outside the critical adolescent period—is relatively benign. In Aim 1, we will use established protocols with the thymidine analogue, bromo-deoxyuracil (BrdU), to determine the number of adolescent proliferating cells that survive into adulthood, and compare this to the number and phenotype of adult proliferating cells that survive further into adulthood. We will further characterize these cells as neurons or glia. In Aims 2 and 3, we will then determine if this rate of cell/proliferation and survival is altered by stress. In conjunction, we will also assess if adolescent stress alters adult amygdala volume, neophobic/neophilic behavior (‘behavioral inhibition’), and corticosterone reactivity. We hypothesize that stress will have greater effects in adolescent compared to adult animals. If so, this would support the idea that adolescence is a sensitive period in which the amygdala is particularly vulnerable to the effects of stress.

The Consequences of Postnatal Bisphenol A Exposure on Cortical Development

PI: Anna Majewska, Ph.D.
Co-Investigators: Lisa Opanashuk, Ph.D.; Cindi Rittenhouse, Ph.D.

Bisphenol A (BPA), an organic compound used in the production of plastics, can cause significant negative health effects by mimicking estrogen in the body. Of particular concern is that growing scientific evidence suggests harmful and significant consequences of exposure to BPA during early development. Yet, exposure to BPA is virtually unavoidable. Children are exposed through plastic in baby bottles, canned food linings, plastic toys and numerous other sources. Although much of the developmental BPA research has focused on the effects of prenatal exposure on development of the reproductive system, studies examining the brain also suggest widespread deleterious repercussions. The effects of BPA on early mammalian postnatal development may be particularly profound because wiring of neuronal networks during this period is critically dependent upon sensory experience. Insults during this developmental window are likely to disrupt synaptic wiring and could result in serious cognitive consequences. We hypothesize that BPA exposure disrupts cortical structure, function and plasticity during early postnatal development, a time when the brain is highly susceptible to alterations in sensory-driven activity. To test this, we propose to examine the effects of BPA exposure on ocular dominance plasticity in the visual system, one of the best studied models of cortical activity-dependent plasticity. Our preliminary findings suggest that BPA at a lower daily exposure than that currently deemed acceptable by the United States Environmental Protection Agency disrupts ocular dominance plasticity in the mouse. Thus, it is imperative that the full health impact on human health of this omnipresent compound be determined and used to help direct clinical practice and public policy. We will address the following scenario: early BPA exposure alters cortical development and synapse morphogenesis resulting in long-term changes in cortical function and plasticity (Aim1). These changes are mediated through estrogenic signaling pathways (Aim2). We will use a combination of in vivo functional and structural 4D imaging to provide unique insights into the effects of BPA on cortical development.