Georgetown Neuroscientists — In Their Own Words

November 17, 2010

Researchers describe their scientific presentations for neuroscience 2010

Researchers from Georgetown University Medical Center’s departments of neuroscience, pharmacology, physiology, biochemistry, molecular and cellular biology, and the interdisciplinary program of neuroscience will present more than 50 research abstracts at the 40th Annual Meeting of the Society for Neuroscience Nov. 13th through the 17th in San Diego.

Modulation of temporal relationships between default mode and task-positive networks by the dopamine transporter genotype during working memory and the resting state

Session: Imaging Human Memory Function

Abstract/Poster: 603.21/KKK65

Date/Time/Location: Tuesday, Nov. 16, 2010 / 8:00 ““ 9:00 am PT / Halls B-H

“My research investigates how a gene regulating the neurotransmitter dopamine affects communication between brain regions during a memory task. I show that one set of brain regions associated with “mind wandering” tends to communicate with memory-performing regions too strongly in one genotype group (the “10/10″ group), but not the other (the “9/10″ group), suggesting that these “10/10″ subjects may be less focused on the task. This research has strong implications for Attention Deficit Hyperactivity Disorder (ADHD), as ADHD patients tend to show a similarly increased communication with “mind-wandering” areas, and also tend to have the “10/10″ genotype. This suggests that this one endophenotype of ADHD, which is associated with mind-wandering, may be partly explained by genes.”

-Evan Gordon, PhD candidate, Interdisciplinary Program in Neuroscience

Investigating the time course of visual categorization with rapid adaptation event-related potentials

Session: Visual Learning and Categorization

Abstract/Poster: 279.9/RR20.

Date/Time/Location: Sunday, Nov. 14, 2010 / 1:00 – 2:00 pm PT / Halls B-H

“Visual object categorization is a fundamental cognitive ability requiring the combination of visual shape and shape-independent symbolic information. Using electroencephalography allowing high temporal resolution observation of neural activity in healthy human subjects, we observed signals associated with shape-selective processing before one fifth of a second following stimulus onset, originating from occipitotemporal brain regions. In contrast, signals associated with category-specific, shape-independent information appeared only later than one fifth of a second following stimulus onset, localized to frontal brain regions. This temporal and spatial dissociation of shape- and category-specific attributes of visual objects contributes to our understanding of the neural processing disrupted in neurological disorders including semantic dementia and the sequelae of stroke.”

Clara Scholl, PhD candidate, Interdisciplinary Program in Neuroscience

Crossmodal suppression of auditory evoked responses in early blind subjects

Session: Sensory Disorders: Visual and Auditory Responses to Damage and Disease

Abstract/Poster: 765.5/V1

Date/Time/Location: Wednesday, Nov 17, 2010 / 8:00 – 9:00 am PT / Halls B-H

“Living in a continuously changing environment, we are permanently exposed to a great variety of stimuli that activate all our senses and influence our behavior. Therefore most inputs irrelevant to our current goals and needs should be suppressed while processing of the important information facilitated. In the present study, we recorded EEG in early blind and sighted control volunteers. The subjects performed a tactile task with three memory loads. Distracting auditory stimuli were presented monotonously throughout the entire experimental block. In both groups, evoked responses to tactile stimuli were progressively accelerated while responses to auditory distracters progressively delayed by memory load. However, amplitudes of the responses varied across memory conditions in a different way in the groups of early blind and sighted volunteers. Thus we found evidences for facilitation of task-relevant tactile and suppression of distracting auditory information processing in both groups. However, mechanisms underlying facilitation and suppression differed between sighted and early blind individuals.”

Iriwa Anurova, PhD, Post-doctoral research fellow, Department of Physiology and Biophysics

Limbic and auditory contributions to tinnitus

Session: Auditory Processing: Perception, Action, and Behavior

Abstract/Poster: 170.23/GG7

Date/Time/Location: Sunday, Nov. 14, 2010 / 10:00 ““ 11:00 am PT / Halls B-H

“Experiencing transient ringing in the ears is common, but for many this buzzing sound, called “tinnitus”, is a constant presence. Our data indicate that dysfunction in the limbic system, a part of the brain regulating emotion and behavior, may explain why tinnitus is transient for some, but develops into a chronic disorder in others. We argue that limbic structures do not work effectively with the auditory brain to “turn off” the unwanted buzzing in people with chronic tinnitus.”

Amber Leaver, PhD, Post-doctoral research fellow, Department of Physiology and Biophysics

Acoustic-phonetic processing and temporal complexity in the auditory ventral stream: A meta-analysis

Session: Acoustic-phonetic processing and temporal complexity in the auditory ventral stream: A meta-analysis

Abstract/Poster: 275.24/PP4

Date/Time/Location: Sunday, Nov. 14, 2010 / 4:00 ““ 5:00 pm PT / Halls B-H

“We performed a meta-analysis of published results from functional brain imaging studies of speech perception for their consistency in anatomical localization. Robust results were found for multiple speech phenomena in the brain’s left superior temporal gyrus (STG), which is part of the temporal lobe. When we looked at effects of brain response to elemental speech sounds relative to full words, we found that robust effects for elemental speech sounds were in mid STG whereas robust effects for words were in anterior STG. This suggests a spoken word recognition pathway different from the classical neurological model. Better language mapping in the brain will lead to safer and more precise surgeries, for example, for patients with brain tumors or persons with epilepsy.”

Iain DeWitt, PhD candidate, Department of Physiology and Biophysics

Tau and Þ±-Synuclein mutually modulate their post-translational modifications in gene transfer animal models

Session: Tau: Molecular and Cellular Mechanisms of Tauopathy and FTD

Abstract/Poster: 49.9/I38

Date/Time/Location: Saturday, Nov. 13, 2010 / 1:00 ““ 2:00 pm PT / Halls B-H

“It is known that several neurodegenerative diseases involve accumulation of microtubule Tau protein and Þ± -Synuclein within cells leading to Tau tangles (NFTs) and Lewy bodies (LBs), which predominantly contain Synuclein. These diseases share overlapping clinical symptoms such as Parkinsonism, cognitive decline and dementia. Several pathological and biochemical pathways seem to lead to protein aggregation in these diseases. We think that the balance between enzymes called kinases and phosphatases is a driving force in the interaction between these pathogenic proteins. Tau disregulation is the main culprit in a group of diseases called tauopathies, where the protein accumulates leading to dementia, motor disorders, depression, mood changes and in some cases weakness and stiffness. Tau is also associated with memory impairment in AD, while Synculein is corelated with motor disorders in PD.

Recently, Tau was suggested to be the second most important risk factor for PD after Synuclein, and both proteins seem to accumulate in the the cells in a wide spectrum of neruodegenerative diseases. We observed that endogenous Tau became hyper-phosphorylated when Synuclein was lentivirally expressed and vice versa, suggesting a link between these two proteins. We examined the function of enzymes called kinases, which phosphorylate proteins (by adding phosphate ions), and phosphatases, which de-phosphorylate (detach phosphate ions) proteins and found an imbalance between enzyme activities that maintain the stochoimetry of phosphorylated to hyper-phosphoryalted proteins within a healthy physiological range. The increase in the level of hyper-phosphorylated proteins led to aggregation, suggesting that phosphorylation increases the propensity of these proteins to accumulate into pathogenic inclusions within neurons. Aggregation was also correlated with increased cell death and degeneration of neurons when either protein was expressed to trigger the phosphorylation of the other. These data address pathologically how development of one neurodegenerative disease may increase the risks of others.”

Sonya B. Dumanis, PhD candidate, Department of Neuroscience

Spinal cord contusion injury stimulates endogenous SOX2 expressing cells in adult mice

Session: Spinal Cord Injury: Cellular and Molecular Mechanisms: Glia

Abstract/Poster: 357.4/U5

Date/Time/Location: Monday, Nov 15, 2010 / 11:00 – 12:00 pm PT / Halls B-H

“SOX2 (sex determining region Y-box 2) is a transcription factor that regulates self-renewal and potency of embryonic and neural stem cells. In the adult spinal cord after injury, there was an apparent increase of SOX2 expressing cells in areas where central canal was visible and in peripheral residual spinal cord tissue. In addition, the persistent increase of SOX2 expressing cells even chronically at 4 weeks after SCI suggests the presence of an endogenous multipotential stem cell pool in the injured spinal cord that may be considered a potential therapeutic target.”

Hyun Joon Lee, PhD, Post-doctoral research fellow, Department of Neuroscience

Characterization of synuclein-directed proinflammatory events

Session: Metabolism and Toxicity of Alpha-Synuclein III

Abstract/Poster: 458.13/N5

Date/Time/Location: Monday, Nov. 15, 2010 / 1:00 ““ 2:00 pm PT / Halls B-H

“The research presented in this abstract is motivated by an overarching goal to open a novel avenue for Parkinson’s disease (PD) therapies. PD is an age-related neurodegenerative disorder, characterized by the loss of dopamine neurons. Disease progression also includes the accumulation of a protein know as alpha-synuclein as well as neuroinflammation, which evidence suggests contributes to neuron loss. The studies herein are aimed at investigating the relationship between alpha-synuclein and inflammation. By understanding the role alpha-synuclein plays in PD inflammation we will be able to design novel therapeutics.”

Dawn Joseph, PhD candidate, Interdisciplinary Program in Neuroscience

Multiple stressors enhance alpha-synuclein-induced toxicity

Session: Metabolism and Toxicity of Alpha-Synuclein I

Abstract/Poster: 53.22/O2

Date/Time/Location: Saturday, Nov. 13, 2010 / 2:00 ““ 3:00 pm PT / Halls B-H

“Parkinson’s disease is a devastating neurodegenerative disease that results in the typical clinical symptoms of tremor, rigidity and slowness of movement. Unfortunately, the cause of sporadic Parkinson’s disease is not known. We and others have proposed that multiple events converge to result in Parkinson’s disease. In our study we examined the combined effect of various cell stressors relevant to the specific cells that succumb to Parkinson’s disease and show that both genetic and environmental factors are important in cell vulnerability and death. These studies will aid in understanding the underlying mechanisms of disease and the development of novel therapies.”

Li Rebekah Feng, PhD candidate, Interdisciplinary Program in Neuroscience

Gene deletions A-ephrins are associated with behavioral stereotypy, abnormal cell sorting in the mouse striatum, and a dissociated response to amphetamine and cocaine.

Session: Motor System Development

Abstract/Poster: 32.4/D10.

Date/Time/Location: Saturday, Nov. 13, 2010 / 4:00 – 5:00 pm PT / Halls B-H

“The striatum of the basal ganglia integrates inputs from motor, sensory, and associative cortex as well as midbrain dopamine regions, and it is critical for motor functioning. Abnormalities in striatal networks have been implicated in a variety of developmental neurological disorders such as Tourette syndrome, Obsessive Compulsive Disorder, and Attention Deficit Hyperactivity Disorder. Recent studies in the Kromer laboratory have implicated the Eph receptor tyrosine kinase family, and their corresponding ephrin ligands, as a major cell-cell signaling system that participates in regulating striatal cell sorting and network formation. Mice with various gene deletions of ephrins-A2, -A3, and/or -A5 exhibit abnormal behaviors such as environmental neglect, oral stereotypies, and compulsive facial grooming rituals. Accordingly, they may consitute an animal model for developmental neurological disorders. The present data further characterizes spontaneous motor behaviors in these mice as well as differences in motor responses to dopaminergic drugs in order to evaluate how disrupting Eph/ephrin signaling during striatal development alters the proper regulation of dopamine synaptic function.”

Rachel Wurzman, MS, PhD candidate, Interdisciplinary Program in Neuroscience

GGF2 and FGF2, growth factors that stimulate endogenous precursor cell proliferation, improve functional recovery after spinal cord injury

Session: Spinal Cord Injury: Cellular and Molecular Mechanisms: Glia

Abstract/Poster: 357.5/U6

Date/Time/Location: Monday, Nov. 15, 2010 / 8:00 -9:00 am PT / Halls B-H

“Demyelination and abnormal remyelination of axons are major pathological consequences of chronic spinal cord injury (SCI). The adult spinal cord contains a pool of endogenous glial precursor cells which spontaneously respond to SCI with increased proliferation. The current project attempts to enhance the proliferation of these cells and improve long-term functional recovery by treating SCI mice with growth factors including basic fibroblast growth factor (FGF2) and glial growth factor 2 (GGF2).”

Matthew Whittaker, PhD, Post-doctoral research fellow, Department of Neuroscience

Effects of methylphenidate on functional network connectivity differ by DAT1 in children with ADHD

Session: Cognitive Development: Down Syndrome

Abstract/Poster: 402.12/LLL49.

Date/Time/Location: Monday, Nov. 15, 2010 / 11:00 ““ 12:00pm PT / Halls B-H

“I investigated the effects of the stimulant medication commonly prescribed to ADHD patients, methylphenidate, on brain network functional connectivity in children with ADHD. I found that methylphenidate, which increases dopamine signaling by blocking striatal dopamine transporters (DAT), increased functional connectivity within the brain’s default-mode (“resting state”) network, consistent with similar research. Additionally, methylphenidate was found to reduce cross-network interference in carriers of the DAT1 10/10 genotype, but not in carriers of the DAT1 9/10 genotype. These results suggest that methylphenidate strengthens default mode network functional connectivity, and depending on DAT1 genotype, modulates cross-network interference.”

Lauren Michelle Pepe, PhD candidate, Interdisciplinary Program in Neuroscience

Role of local BDNF synthesis in spine morphogenesis

Session: Development: Activity-Dependent Remodeling of Synapses

Abstract/Poster: 234.20/D4

Date/Time/Location: Sunday, Nov. 14, 2010 / 4:00 ““ 5:00 pm PT / Halls B-H

“Alterations in the number and morphology of dendritic spines (small protrusions along neuronal branches that help transmit signals between neurons) are associated with a number of neurological diseases, including mental retardation, epilepsy, and neurodegenerative diseases such as Alzheimer’s disease. The goal of this research project is to understand how BDNF, a key protein involved in cell survival and maintenance, may regulate the development and maturation of dendritic spines. These studies will provide significant insight into processes fundamental for brain development and synaptic plasticity, as well as offer insight into the causes of some neurological diseases.”

Lauren Orefice, PhD candidate, Interdepartmental Program in Neuroscience

Pharmacological modulation of network activity in an in vitro epilepsy model studied with a perforated multi-electrode array

Session: Epilepsy: Networks

Abstract/Poster: 150.14/I27

Date/Time/Location: Sunday, Nov. 14, 2010 / 9:00 ““ 10:00 am PT / Halls B-H

“Our project involves recording electrical signals from an in vitro model of epilepsy through which we are able to study seizure genesis and propagation in a neuronal structure and make inferences about human epilepsy. We use a novel recording device, which is a perforated multi-electrode array, that allows us to record in high spatial and temporal resolutions signals from our neuronal tissue. We have found that inhibitory and excitatory neurotransmission influence seizure propagation in differing ways and we plan to study these transmitter systems in further detail to possibly find new therapeutics for epilepsy.”

Alfredo Gonzalez-Sulser, PhD candidate, Interdisciplinary Program in Neuroscience

Effects of nicotine on neuronal nicotinic receptors expressed in rat primary cultured neurons

Session: Nicotinic Acetylcholine Receptors: Regulation and Signaling

Abstract/Poster: 38.18/F32

Date/Time/Location: Saturday, Nov. 13, 2010 / 2:00 pm ““ 3:00 pm PT / Halls B-H

“What we investigate here are the effects of chronic nicotine treatment on neuronal nicotinic receptors expressed in primary cultured neurons isolated from several regions of rat brain. Particularly, we are interested in studying the mechanism of up-regulation (increase of nicotinic receptor density) that nicotine promotes in the smoker brain. This process is believed to be crucial in smoking addiction.”

Ermelinda Lomazzo, PhD candidate, Department of Pharmacology

GABAA receptor Þ²3 subunits are essential in striatal MSN tonic current

Session: GABA Receptors: Physiology II

Abstract/Poster: 443.7/F15

Date/Time/Location: Monday, Nov. 15, 2010 / 3:00 ““ 4:00 pm PT / Halls B-H

“Medium spiny neuron (MSN) output of the striatum is largely thought to control movement, and imbalances are thought to underlie the movement disorders associated with Parkinson’s disease. Our previous research has shown that certain extrasynaptic GABAA receptors alter MSN excitability. By genetically manipulating these receptors in mice, we show that beta3 GABAA subunit containing receptors play an important role in MSN output, and may provide a potential role in therapeutics for resetting striatal output in Parkinson’s disease.”

Megan Janssen, PhD, Post-doctoral research fellow, Department of Physiology and Biophysics

Effects of robotic training on velocity dependent overground locomotor measures following SCI in rats

Session: Spinal Cord Injury: Posture and Locomotion

Abstract/Poster: 259.16/W9

Date/Time/Location: Sunday, Nov. 14, 2010 / 4:00 ““ 5:00 pm PT / Halls B-H

“Measures such as step length, and cycle time, are commonly used by researchers to assess locomotion. However, locomotor measures are strongly connected to overground velocity (when walking slowly you take short slow steps, and when walking fast you take long quick steps). This becomes problematic when investigating the locomotion of rodents with neurological injuries, which tend to walk much slower than healthy animals. In this study we took a different approach, and investigated the velocity dependence of locomotor measures, not the measures themselves, allowing us to accurately compare animals traveling at different velocities. Our studies show that daily robotic treadmill training has the ability to change the overground locomotor measures of rats following a spinal cord injury, not just change their walking speed.”

Nathan Neckel, PhD, Post-doctoral research fellow, Department of Neuroscience

Comparative up-regulation of neuronal nicotinic receptors by nicotine, carbachol, and choline

Session: Nicotinic Acetylcholine Receptors: Regulation and Signaling

Abstract/Poster: 38.17/F31

Date/Time/Location: Saturday, Nov. 13, 2010 / 1:00 ““ 2:00 pm PT / Halls B-H

“Nicotine is known to increase the number of brain derived neuronal nicotinic acetylcholine receptors (nAChRs). This unique characteristic of the nicotinic receptor has many implications, including nicotine addiction and therapies for neurodegenerative disease. In Vitro, we demonstrated that carbachol, a nAChR agonist like nicotine, up-regulates nAChRs with a higher efficacy than nicotine. Our current studies seek to understand the mechanisms involved in carbachol mediated up-regulation of nAChRs and how these mechanisms might differ than nicotine mediated up-regulation.”

Gregory Patrick Hussmann, PhD candidate, Department of Pharmacology

Parkin reduces intraneuronal beta-amyloid levels, neuronal loss and gliosis in 3xTg AD animal models

Session: Alzheimer’s Disease: Anti-Abeta and Related Treatments

Abstract/Poster: 650.20/H52

Date/Time/Location: Tuesday, Nov. 16, 2010 / 4:00 ““ 5:00 pm PT / Halls B-H

“Alzheimer’s disease is characterized by extracellular deposition of amyloid-beta, which clumps to form plaques. AD is also characterized by accumulation of Tau protein, which forms tangles. Parkin is associated with juvenile onset Parkinson’s disease. It is a protein that cleans toxic particles, which accumulate in the cell. We tested parkin in a transgenic mouse, which expresses the human genes that cause AD. We found that parkin cleared intracellular toxic amyloid proteins and prevented the protein from clumping outside the cell. Meaning that clearance of intracellular component of amyloid will result in attenuation of deposition of the protein outside the cell to form plaques. The clearance of amyloid with parkin also resulted in a decrease in brain inflammation indicating that protein aggregation causes an inflammatory response in the brain and parkin clearance of amyloid eliminates protein aggregates, inside the cell, leading to less inflammation. Amyloid deposition was associated with Tau accumulation but clearance of amyloid led to a decrease in Tau protein pathology, which leads to collapse of the skeleton of the cell and causes cell death. The good effects of parkin cleaning of protein disposal in the cell also lead to protection from degenerative death, observed in AD, indicating a cross-talk between different proteins that have been implicated in the genesis of different neurodegenerative diseases, including AD, PD and other forms of dementia and Parkinsonian disorders.”

Preeti Khandelwal, Post-doctoral research fellow, Department of Neuroscience

Parkin targets common pathways to attenuate the pathologic effects of AÞ²1-42, Þ±-Synuclein and Tau in gene transfer animal models

Session: Old Age Markers of Pathology

Abstract/Poster: 349.17/K1

Date/Time/Location: Monday, Nov. 15, 2010 / 8:00 ““ 9:00 am PT / Halls B-H

“Neurodegenerative diseases (ND) involve multiple pathogenic proteins, including Þ±-Synuclein and Tau, which aggregate in intracellular inclusions, and AÞ²1-42 which aggregates in intracellular and extracellular deposits. The Parkinson-associated protein parkin tags unwanted proteins and cellular debris and drags them for degradation or recycling. Parkin can also degrade proteins by wrapping them in vesicles or pockets that contain digestive enzymes to degrade them. In this work we found that parkin can degrade toxic proteins preventing their aggregation and its subsequent effects. The degradation or cleaning of toxic protein also eliminates activation of enzymes, which lead to phosphorylation (addition of phosphate ions) to modify protein structure and impair its function so it accumulates and becomes toxic. Parkin employs different mechanisms, including silencing enzyme activities and cleaning the cell from toxic proteins to reduce their levels. MRI scans show that parkin can reverse the effects of toxic proteins on brain damage.”

Charbel Moussa, PhD, Research Assistant Professor, Department of Neuroscience

Ethanol exposure enhances the sodium/calcium exchanger currents in inferior colliculus neurons

Session: Alcohol: Neural Mechanisms

Abstract/Poster: 473.4/II20

Date/Time/Location: Monday, Nov 15, 2010 / 4:00 – 5:00 pm PT / Halls B-H

“We have obtained evidence that the flow of calcium ions into brain cells via voltage-gated calcium channels play an important role in the generation of neuronal hyperexcitability that leads to alcohol withdrawal seizures. Another possible route for Ca2+ entry is via the sodium/calcium exchanger (NCX), a bidirectional transporter that couples the influx/efflux of Ca2+ to the efflux/influx of Na+ to regulate the levels of intracellular Ca2+. Ethanol is known to inhibit voltage-gated calcium channels; however, its effect on the sodium/calcium exchanger is unknown. Using single brain cells, we find that acute ethanol application enhances by ~2-fold outward (Na+exit/Ca2+entry) NCX currents. No change was observed in the magnitude of inward (Na+entry/Ca2+exit) NCX currents following ethanol exposure. These findings suggest that immediate effects of NCX activation by ethanol would be Ca2+ loading and accumulation of Na+ in the cytosol, resulting in depolarization of neurons that might lead to hyperexcitability. For the first time, this study shows an excitatory effect of acute ethanol application on the reverse mode of NCX activity in the CNS.”

Prosper N’Gouemo, PhD, Assistant Professor , Department of Pediatrics

Eph/ephrin signaling directs dendritic elaboration in the developing neocortex

Session: Dendrite Growth and Branching Abstract/Poster: 640.7 Date/Time/Location: Tuesday, Nov 16, 2010 / 3:00 – 4:00 pm PT / Halls B-H

“In some neurodevelopmental disorders, shifts in neuronal form have been described in parts of the cortex, yet little is known about some of the basic mechanisms responsible for normal cortical neuronal maturation. This poster examines the roles for a family of signaling molecules, the Eph receptors and ephrin ligands, in directing the initial outgrowth of dendritic arbors of cortical neurons. Understanding how Ephs and ephrins guide the development of cortical neurons could lead to new insights into abnormal states.”

Meredith Clifford, PhD candidate, Interdisciplinary Program in Neuroscience

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