Skip to main content
Explore URMC

Del Monte Neuroscience Institute

menu

2014 Research Awards

Interdisciplinary Research Projects

The Role of Oxytocin in Face Processing Regions of the Prefrontal Cortex

PI: Liz Romanski, Ph.D.
Co-Investigators: Julie Fudge, M.D.

In this grant we will combine Dr. Fudge’s expertise in neuroanatomy of limbic brain regions with my own expertise in frontal lobe neurophysiology investigating the processing of social communication stimuli. We will examine the effect of Oxytocin on the neurophysiological responses of prefrontal eurons to face and vocalization stimuli in awake, behaving primates. Oxytocin is a peptide produced in the hypothalamus that has gained popularity as a potential treatment for social cognition impairments in autism spectrum disorders. After face responsive regions of the prefrontal cortex have been localized we will place anatomical tracers into the prefrontal face responsive regions and then subsequently localize oxytocin receptor mRNA binding in these physiologically characterized face-vocalization regions, and in afferent and efferent connections including the amygdala. We have previous experience performing all of the work described. I have previously recorded and localized multisensory neurons responsive to faces and vocalizations in ventrolateral and orbitofrontal cortex while Dr. Fudge has expertise in all of the anatomical assays to be conducted. Our proposal is novel in that few studies combine neurophysiology and anatomical analysis in the same animals and even fewer have examined the primate prefrontal cortex. In addition, while the effects of oxytocin on face processing have been studied, the effects of oxytocin on the ventrolateral prefrontal cortex and its effects on multisensory face-vocalization cells have not been previously examined. We plan to use this data as pilot data towards a larger R01.vestibular function.


Lipid Droplets in Motor Neuron Pathology: A Nematode Model

PI: Doug Portman, Ph.D.
Co-Investigator: Michael Welte, Ph.D.

We outline an exciting new collaboration to investigate the pathogenesis of the Hereditary Spastic Paraplegias (HSPs), a heterogeneous set of motor disorders characterized by the degeneration of lower-limb corticospinal motor axons. Interestingly, recent work on the genetics of HSP has implicated several factors involved in the biology of lipid droplets, small lipid storage organelles that have garnered much recent attention. However, the function of lipid droplets in the nervous system, and their potential roles in motor neuron (dys)function, remain almost completely obscure. To close this gap, we propose to combine Michael’s expertise in lipid droplet biology with my expertise in the neurobiology of the nematode C. elegans to develop a powerful new model to investigate the role of lipid droplets in neuronal development, homeostasis and pathology. We see a clear path from these foundational studies to a competitive, hypothesis-driven R21/R01 application on the cellular pathogenesis of HSP.


Lung-brain coupling in neutrophil-dependent injury after global ischemia

PI: Marc Halterman, M.D., Ph.D.
Co-Investigators: Michael O'Reilly, Ph.D.

This project represents the culmination of collaborative work between Drs. Marc Halterman, (Associate Professor of Neurology) and Dr. Michael O’Reilly (Professor of Pediatrics), with additional support from both Dr. Minsoo Kim (Associate Professor of Microbiology and Immunology) and Dr. Alison Elder (Associate Professor of Environmental Medicine). Recent reports indicating that hypothermia may not, in fact, provide neuroprotection in the setting of cardiac arrest, underscores the importance of finding alternate therapeutic strategies. The experiments outlined in this proposal brings together expertise in pre-clinical stroke modeling (Halterman), lung biology (O’Reilly, Elders) and neutrophil (Kim) biology to test the hypothesis that the lung is a therapeutic target in global cerebral ischemia through its effects on modulating innate immunity. This is an exciting collaboration and progress in this area could have important implications in a number of CNS disorders. Support from the Schmitt award will allow us to obtain preliminary data required to prepare a multi-PI submission to the NINDS.


Visual-haptic object perception at multiple levels of the sensory hierarchy

PI: Robert Jacobs, Ph.D.
Co-Investigators: Brad Mahon, Ph.D.

This project is a research collaboration between Robert Jacobs (Department of Brain & Cognitive Sciences) and Brad Mahon (Department of Brain & Cognitive Sciences and Department of Neurosurgery). The research combines behavioral experiments and brain imaging (fMRI) to study visual, haptic, and visual-haptic object perception at multiple levels of the sensory hierarchy. The research project is directly relevant to two of the three areas targeted by the Schmitt Program: The Senses and Behavior and Learning, Plasticity, and Memory. Because the project studies visual and haptic perception, the research will contribute to our understanding of perception and behavior. Because it studies perceptual learning (Aim #2), the research will also contribute to our understanding of learning and neural plasticity. Professors Greg DeAngelis, Robert Jacobs, David Knill, and Brad Mahon (all members of the Department of Brain & Cognitive Sciences) have been meeting on a regular basis to discuss a planned National Institutes of Health (NIH) program project grant proposal on the topic of multisensory perception. This proposal will include three components, one component studying visual and vestibular signals to motion perception (to be written by Greg DeAngelis), a second component studying visual and kinesthetic signals to motion perception (to be written by David Knill), and a final component studying how sensory (visual, haptic), action, and conceptual information contribute to object perception. This last component will be co-written by Robert Jacobs and Brad Mahon.


Post-Doc Award

Role of platelet activating factor (PAF) underlying synaptic damage and cognitive decline in disorders involving neuroinflammation

Post-Doc Fellow: Jennetta Hammond, Ph.D.
Faculty Advisor: Handy Gelbard, M.D., Ph.D.

The overarching goal of my research is to determine how platelet activating factor (PAF), an inflammatory mediator alters neurotransmission leading to synaptic damage and cognitive decline in disorders involving neuroinflammation. Specifically I work within the field of neuroAIDS, where even with combination antiretroviral therapy up to 50% of people infected with HIV have some degree of neurological impairment [1]. PAF’s increased concentration in the CNS of patients with HAND [2] and its known dual role as an inflammatory mediator and modulator of neurotransmission have made it a molecule of enduring interest in the context of HAND. In vitro data shows PAF can exacerbate the inflammatory environment by stimulating monocyte and neutrophil chemotaxis, adhesion and activation [3, 4], and stimulating the production of TNF[5] and reactive oxygen species [6]. In healthy brain, PAF enhances long-term potentiation (LTP) [7, 8] and performance in learning and memory tasks [9]. However, PAF also directly increases neurons vulnerability to excitotoxic injury [2, 10]. High doses of PAF induce neuronal apoptosis [2, 10]. Sub-lethal doses cause dendritic beading, loss of spines, failure of LTP, and mitochondrial dysfunction in an NMDA, calcium, and caspase dependent manner [11, 12]. These sub-lethal neuronal effects may be most relevant to HAND as cognitive decline is associated with synaptic and dendritic injury rather than complete neuronal loss [13-15]. PAFs ability to modulate synaptic strength is likely key to the neuronal injury associated with neuroinflammation; yet, there is much about the mechanisms of PAF signaling at the synapse that we do not understand including whether it occurs primarily in the presynaptic or postsynaptic compartment or both.


Pre-Doc Award

The Critical Role of Microglial P2Y12 in Synaptic Plasticity

Pre-Doc Fellow: Grayson Sipe
Faculty Advisor: Ania Mayewska, Ph.D.

Microglia are immunocompetent cells in the brain with wide-ranging roles in both normal and abnormal neurophysiology. Nearly every neurological disorder has been linked to changes in microglial physiology1,2 including neurodevelopmental disorders where the newly discovered role of microglial synaptic pruning is critical for proper network maturation3,4. However, the mechanistic mediators underlying these non-inflammatory functions are poorly understood. I have recently started to unravel the molecular underpinnings of microglial actions on synapses by showing that purinergic signaling through the P2Y12 receptor in microglia is critical for ocular dominance plasticity. Here I propose to further delineate the underlying molecular pathway through two critical experiments examining microglial gene expression and phagocytosis in the absence of P2Y12 signaling. In Aim 1, I will determine whether microglia from P2Y12 knockouts (KOs) have significantly transformed gene expression using whole-transcriptome RNA sequencing analysis. Deviations in expression signature may give mechanistic insight into the causes of the plasticity deficit observed in the absence of P2Y12 signaling. In Aim 2, I will determine whether P2Y12 KO microglia have defective synaptic phagocytosis compared to wildtype animals. Through these aims, I will begin to understand the molecular pathways orchestrated by P2Y12 signaling and how they contribute to normal and abnormal synaptic development. Through these insights, avenues will be improved for future therapeutics targeting neurodevelopmental disorders.