Molecular Mechanisms Responsible for Functional Cortical Plasticity During Development and after Focal Ischemic Brain Injury

The cerebral cortex is organized into functional representations, or maps, defined by increased activity during specific tasks. In addition, the brain exhibits robust spontaneous activity with spatiotemporal organization that defines the brain’s functional architecture (termed functional connectivity). Task-evoked representations and functional connectivity demonstrate experience-dependent plasticity, and this plasticity may be important in neurological development and disease. An important case of this is in focal ischemic injury, which results in destruction of the involved representations and disruption of functional connectivity relationships. Behavioral recovery correlates with representation remapping and functional connectivity normalization, suggesting functional organization is critical for recovery and a potentially valuable therapeutic target. However, the cellular and molecular mechanisms that drive this systems-level plasticity are unknown, making it difficult to approach therapeutic modulation of functional brain organization. Using cortical neuroimaging in mice, this dissertation explores the role of specific genes in sensory deprivation induced functional brain map plasticity during development and after focal ischemic injury. In the three contained chapters, I demonstrate the following: 1) Arc, an excitatory neuron synaptic-plasticity gene, is required for representation remapping and behavioral recovery after focal cortical ischemia. Further, perilesional sensory deprivation can direct remapping and improve behavioral recovery. 2) Early visual experience modulates functional connectivity within and outside of the visual cortex through an Arc-dependent mechanism. 3) Electrically coupled inhibitory interneuron networks limit spontaneous activity syncrhony between distant cortical regions. This work starts to define the molecular basis for plasticity in functional brain organization and may help develop approaches for therapeutic modulation of functional brain organization

Doctor of Philosophy

dissertationAlcohol use disorders (AUDs) have had a devastating impact on the health and lives of those who struggle with AUDs. Given the impact of AUDs on human health, the neural mechanisms that underlie ethanol-seeking behaviors are a topic of intense interest. In this dissertation, I investigated the neural mechanisms of ethanol-seeking. Motivation for seeking ethanol can be characterized by learning about both the rewarding and aversive properties of ethanol. Indeed, increased drinking would be observed if an animal was more motivated for ethanol's rewarding effects. Furthermore, similar increases in ethanol consumption would be accompanied by an attenuation in learning about ethanol's aversive effects. In this dissertation, I explore the neural mechanisms of reward and aversion that may contribute to increased ethanol-seeking behavior. First, to investigate how mechanisms of reward contribute to ethanolseeking, I implemented the techniques necessary to record phasic dopamine (DA) signaling during ethanol-seeking (Chapter 2). Phasic dopamine release is distinguished by the subsecond release and reuptake of the neurotransmitter. Recent work has found that phasic DA release in the nucleus accumbens may be linked to motivation and performance of reward-seeking behavior but few studies have investigated phasic dopamine release during operant ethanol selfadministration. In Chapter 3, I describe phasic DA release being evoked by cues iv predictive of ethanol availability. Furthermore, the magnitude of the DA was found to be predictive of shorter lever press latencies. Finally, phasic DA release was evoked during the performance of an ethanol-rewarded lever press. The dopamine recorded during ethanol-seeking is consistent with the hypothesis that dopamine may mediate both the motivation for ethanol and performance of ethanol-seeking behavior. Second, to investigate the mechanisms of aversive learning about ethanol, I focused on a brain region long associated with aversion, the lateral habenula (LHb). Recent work identified the LHb in learning about aversion to cocaine, thereby suggesting it may have a role in learning about the aversive effects of ethanol. In Chapter 4, I describe that lesions to the LHb caused an increase in home cage ethanol consumption. Furthermore, when an aversive injection of ethanol was paired to a novel tastant, the consumption of the novel tastant improved more rapidly than in intact animals. The above results implicate the LHb in learning about ethanol's aversive effects. Future studies must be performed to establish which LHb afferents mediate aversion to ethanol

Campus & alumni news

Boston University Medicine was published by the Boston University Medical Campus, and presented stories on events and topics of interest to members of the BU Medical Campus community. It followed the discontinued publication Centerscope as Boston University Medicine from 1991-2005, and was continued as Campus & Alumni News from 2006-2013 before returning to the title Boston University Medicine from 2014-present

On-a-chip microdischarge thruster arrays inspired by photonic device technology for plasma television

This study shows that the practical scaling of a hollow cathode thruster device to MEMS level should be possible albeit with significant divergence from traditional design. The main divergence is the need to operate at discharge pressures between 1-3bar to maintain emitter diameter pressure products of similar values to conventional hollow cathode devices. Without operating at these pressures emitter cavity dimensions become prohibitively large for maintenance of the hollow cathode effect and without which discharge voltage would be in the hundreds of volts as with conventional microdischarge devices. In addition this requires sufficiently constrictive orifice diameters in the 10µm – 50µm range for single cathodes or <5µm larger arrays. Operation at this pressure results in very small Debye lengths (4 -5.2pm) and leads to large reductions in effective work function (0.3 – 0.43eV) via the Schottky effect. Consequently, simple work function lowering compounds such as lanthanum hexaboride (LaB6) can be used to reduce operating temperature without the significant manufacturing complexity of producing porous impregnated thermionic emitters as with macro scale hollow cathodes, while still operating <1200°C at the emitter surface. The literature shows that LaB6 can be deposited using a variety of standard microfabrication techniques

Digital Image Correlation System Design, Verification and Analysis

Two dimensional digital image correlation provides an accurate and effective way to capture strain data on test sections with unusual or oblique geometries. The system requires a camera to record video footage, alignment fixtures and software to convert the footage into strain values. The system works by capturing the video footage of a specific portion of the specimen and comparing the movement of selected pixels. This is all done in the software GOM Correlate and Tracker. This test document outlines the setup, procedure, and validation steps to fulfill this goal. The setup involves a camera, tripod, blue lighting, and laser distance measurers. Then we discuss the steps to take once your video has been captured to postprocess. The process of setup, running a test, and analyzing the video was a system developed from scratch and required continuous improvement. Finally, once our system was verified as a class B extensometer, we were able to obtain real displacement data on a test specimen and correlated it with material data to present a real-world application. The result of this project is a fully functioning and adaptable digital image correlation system that LTA Galactic can utilize for testing purposes. The final presentation will be a full explanation on the system, how it works, the tests we’ve run with it to verify accuracy and the error analysis

Abnormal hematopoietic phenotypes in Pim kinase triple knockout mice

BACKGROUND: Pim (proviral insertion in murine lymphoma) kinases are a small family of constitutively active, highly conservative serine/threonine oncogenic kinases and have 3 members: Pim1, Pim2, and Pim3. Pim kinases are also implicated in the regulation of B- and T- cell responses to cytokines and hematopoietic growth factors. The roles of Pim kinases in the regulation of primitive hematopoietic stem cells (HSCs) are largely unknown. METHODS: In the current study, Pim1(−/−)2(−/−)3(−/−) triple knockout (TKO) mice were used to determine the role of Pim kinases in hematopoiesis. Peripheral blood hematological parameters were measured in Pim TKO mice and age-matched wild-type (WT) controls. Primary, secondary, and competitive transplantations were performed to assay the long-term repopulating HSCs in Pim TKO mice. In vivo BrdU incorporation assay and ex vivo Ki67 staining and caspase 3 labeling were performed to evaluate the proliferation and apoptosis of HSCs in Pim TKO mice. RESULTS: Compared to age-matched WT controls, Pim TKO mice had lower peripheral blood platelet count and exhibited erythrocyte hypochromic microcytosis. The bone marrow cells from Pim TKO mice demonstrated decreased hematopoietic progenitor colony-forming ability. Importantly, Pim TKO bone marrow cells had significantly impaired capacity in rescuing lethally irradiated mice and reconstituting hematopoiesis in primary, secondary and competitive transplant models. In vivo BrdU incorporation in long-term HSCs was reduced in Pim TKO mice. Finally, cultured HSCs from Pim TKO mice showed reduced proliferation evaluated by Ki67 staining and higher rate of apoptosis via caspase 3 activation. CONCLUSIONS: Pim kinases are not only essential in the hematopoietic lineage cell development, but also important in HSC expansion, self-renewal, and long-term repopulation

Oncology Center

Efforts by the Hollings Cancer Center to earn a designation as a National Cancer Center are outlined

Deep Chandra Observations of Abell 2199: the Interplay between Merger-Induced Gas Motions and Nuclear Outbursts in a Cool Core Cluster

We present new Chandra observations of Abell 2199 that show evidence of gas sloshing due to a minor merger, as well as impacts of the radio source, 3C 338, hosted by the central galaxy, NGC 6166, on the intracluster gas. The new data are consistent with previous evidence of a Mach 1.46 shock 100" from the cluster center, although there is still no convincing evidence for the expected temperature jump. Other interpretations of this feature are possible, but none is fully satisfactory. Large scale asymmetries, including enhanced X-ray emission 200" southwest of the cluster center and a plume of low entropy, enriched gas reaching 50" to the north of the center, are signatures of gas sloshing induced by core passage of a merging subcluster about 400 Myr ago. An association between the unusual radio ridge and low entropy gas are consistent with this feature being the remnant of a former radio jet that was swept away from the AGN by gas sloshing. A large discrepancy between the energy required to produce the 100" shock and the enthalpy of the outer radio lobes of 3C 338 suggests that the lobes were formed by a more recent, less powerful radio outburst. Lack of evidence for shocks in the central 10" indicates that the power of the jet now is some two orders of magnitude smaller than when the 100" shock was formed.Comment: 17 pages, 20 figures, accepted for publication in Ap