History‎ > ‎2015‎ > ‎Neuroscience Research Day 2015‎ > ‎

Abstracts 2015

Oral Presentations

Session 1 (10:00 - 11:00 AM)

  • Dr. Hyung Nam: "Neuropharmacology of Alcoholism and Psychiatric Disorders"
  • Peace Ibole: "Newly Discovered Nicotinic Receptor and Its Roles in Amyloid Beta 1-42 Pathology in Alzheimer’s Disease"
  • Merve Kasap: "Role of Sodium Leak Current Channel in Involuntary Movement Disorders in C. Elegans"

Session 2 (1:00 - 2:00 PM)

  • Dr. Elizabeth Disbrow: "The Interaction of Cognitive and Motor Dysfunction in Parkinson's Disease"
  • Courtney Keller: "The Effects of the Combination of Metyrapone and Oxazepam on Central Corticosterone and Conditioned Emotional Memories"
  • Kevin Holly: "Automated Analysis of Stretch-Attend Posture in Rodent Behavioral Experiments"


Poster Presentations (2:30 - 3:50 PM)

Category: Graduate and Medical Students

(1). Cortical Oscillatory Dysfunction During Movement Initiation in Parkinson’s Disease

Benjamin J Barker1, EM Dressler2, K Russo3, E Franz4, R Turner5, M Ventura2,6, L Hinkley7, KA Sigvardt8, V Wheelock8, EA Disbrow1

1Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA; 2Center for Neuroscience, UC Davis, Davis CA; 3Department of Psychology, UC Berkeley, Berkeley CA;4Action Brain and Cognition Laboratory, Department of Psychology, and fMRI,

University of Otago, Dunedin, New Zealand; 5Department of Neurobiology and Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA; 6Department of Psychology, UC Davis, Davis CA; 7Department of Radiology, UC San Francisco, San Francisco CA; 8Department of Neurology, UC Davis, Sacramento CA;

Parkinsonian executive dysfunction affects subjects’ ability to adapt behaviors in response to new environmental situations. The pathophysiology of executive dysfunction in Parkinson’s Disease (PD) is not fully understood, but there is growing evidence that abnormal cortical oscillatory action may underlie Parkinsonian impairment of motor and cognitive function. Previously, magentoencephalography (MEG) has revealed a diffuse slowing of oscillatory activity at rest in PD patients. Our objective was to identify the oscillatory cortical activity during movement initiation in healthy subjects, and to elucidate precise changes in this activity in association with PD. A whole-head biomagnetometer with 275 first-order axial gradiometers was used to record neuromagnetic activity in 18 controls and 18 PD patients matched for age and premorbid IQ. Oscillatory activity was recorded while subjects responded with a button press to either matched (control) or unmatched (initiation) visual stimuli. These visual stimuli consisted of a cue arrow (left or right) followed by a target arrow(s). For matched trials the left or right arrow was redisplayed, for unmatched (initiation) a bidirectional arrow was displayed. Whole-brain reconstructions of oscillatory activity were co-registered with each subject’s structural MRI. Activity was observed in Brodmann’s areas (BA) 4 (M1), BA 6 (premotor cortex), BA 7 (posterior parietal cortex), BA 24 (anterior cingulate), and BA 9/10 (anterior/dorsolateral prefrontal cortex). The results showed peak latency differences between the control group and Parkinson’s group during movement initiation. The Parkinson’s group latency was slower in left BA 6 in the gamma band, left BA 4 in the beta band, and left BA 9/10 in the alpha band. Amplitude comparisons between Parkinson’s initiation and control initiation showed a greater decrease in power with PD subjects in left BA 9/10 in the beta band, contralateral BA 6 in the alpha band, contralateral BA7 in the beta band, and bilateral BA 4 in the beta band. BA 24 did not show an amplitude change between Parkinson’s initiation and control initiation. A reduced response was observed in the motor cortex in the PD group, with a concomitant increase in power change amplitude in PD BA 9/10 and BA 6 compared to controls during initiation conditions. Our results supported previously published hypotheses of slowed oscillatory activity associated with PD. Furthermore we observed slowed oscillatory activity during event-related movement initiation in PD patients.


(2). Pharmacological Modulation of Catatonic/Avolitional States in C. elegans

Julie M. Dagenhardt¹, A. Trinh3, E. J. Aamodt2, and D. S. Dwyer1,3

1Department of Pharmacology, Toxicology, and Neuroscience, 2Department of Biochemistry, 3Department of Psychiatry, Louisiana State University Health Sciences center, Shreveport, LA

Catatonia and avolition are prevalent in patients with schizophrenia, and are difficult to treat. Accidently, we noticed a catatonic/avolitional state, characterized by a lack of voluntary movement, in specific mutant strains of C. elegans. In particular, the daf-2 strain shows this state when exposed to food deprivation and dimethyl sulfoxide (DMSO) at 25°C.  daf-2 is a temperature-sensitive loss-of-function mutation in the insulin/IGF-1 receptor.  A second mutant strain, unc-64, displays a similar avolitional phenotype and has a loss-of-function mutation in syntaxin.  We hypothesized that it should be possible to correct this state with the right drug. To test this idea, we induced catatonia/avolition by exposing the animals to the combination of elevated temperature (25°C), food deprivation, and DMSO in the absence (control) or presence of drug.   We then counted the number of animals moving more than two head-lengths at various time points.  Many drugs that were tested in the assay were negative; however, we found that certain second-generation antipsychotic drugs showed some positive effects.  Since these drugs block both dopamine and serotonin receptors, we then evaluated receptor-selective agents for their effects in our assay. Serotonergic antagonists, such as cyproheptadine and ritanserin, restored the animals' movement.  2-Aminoethoxydiphenyl borate (2-APB), tamoxifen, and lithium were tested, but did not increase spontaneous movement.  Levamisole worsened the animals' condition, which suggested that excessive acetylcholine may play a role. We then tested acetylcholine receptor blockers hexamethonium and decamethonium, which both partially restored the animals' movement.  Together, the data suggest that the catatonic/avolitional state is induced by excessive serotonergic and cholinergic tone in particular neural circuits.  We hope that further studies on these strains may help us learn how to treat catatonia and avolitional states in man.

 

(3). Respiratory Abnormalities in KCNA1-Null Mouse Model of Sudden Unexpected Death in Epilepsy

Hemangini A Dhaibar

Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, Louisiana


(4). Calcium Imaging of Nicotinic Acetylcholine Receptors (nAChR) Incubated with Amyloid Beta 1-42 (αβ1-42)

Phillip T. Doughty, Teresa A. Murray

Biomedical Engineering, Louisiana Tech University, Ruston, LA

Neurotransmitter receptors modulate the transmission of electrochemical signals between cells through the activation of ion channels. A specific type of neurotransmitter receptor activates upon binding nicotine or acetylcholine and is called a nicotinic acetylcholine receptor (nAChR). Previous studies have implicated nAChR in Alzheimer’s disease (AD), specifically in their role in internalizing beta amyloid peptide 1-42 (Aβ1-42). While healthy cells produce the first forty amino acids in the beta amyloid peptide chain, cells associated with Alzheimer’s disease have been found to produce a chain of the first forty-two amino acids, which then tends to aggregate outside the cell membrane and has been implicated in cell death. Others have recently shown that Aβ1-42, which is normally released outside the cell, can accumulate inside cells in AD. With the knowledge that the pore in an ion channel is too narrow to allow particles larger than a single ion to enter a cell by that route, subsequent research showed that when the receptor is endocytosed, Aβ1-42 enters the cell with the receptor. Ligand sensitivity, channel activation, and other functions differ depending on the composition of the five subunits that form the receptor. There are several different types of homologous subunits that can be incorporated into these receptors. This study examines the internalization of calcium ions (Ca2+) through affected ion channels using calcium imaging techniques and how incubation with physiologically relevant concentrations of Aβ1-42 changes this activity. This study focuses on cells expressing the α7β2.4 concatemer, which is a novel combination of receptor subunits.

 

(5). The Role of Astrocytes in the Mammalian Brain Following Moderate Diffuse Traumatic Brain Injury

Chelsea A. Dressel, Vladislav Voziyanov, Ben Kemp, Kevin Holly, and Teresa A. Murray

Biomedical Engineering, Louisiana Tech University, Ruston, LA

Astrocytes, which are neuroglial cells in the central nervous system, play an important role in supporting neurons and maintaining brain homeostasis. Following traumatic brain injury (TBI), it is well recognized that inflammation is a contributing factor in the pathological response. Pro-inflammatory cytokines are released by activated microglia which can in turn contribute to the activation of astrocytes in the brain. Astrocyte activation can be characterized by an increase in glial fibrillary acidic protein (GFAP) and increased proliferation. In order to examine the effects of TBI, mice were bred to express green fluorescent protein (GFP) under the GFAP promoter. Mice were implanted with gradient index (GRIN) lenses and a region of the cortex was longitudinally imaged using multiphoton microscopy. In order to deliver a diffuse moderate TBI, mice were injured using a fluid percussion device.  In vivo images were acquired prior to injury in order to obtain baseline images. Following injury, images were collected weekly for four weeks. The mean GFP intensities at each time point are compared in order to better define the role of astrocytes in inflammation via the time course of GFAP expression in the mammalian brain following a moderate traumatic brain injury.

 

(6). Dimensionally Stable Boron-Doped Ultrananocrystalline Diamond Microelectrodes - Towards Chronic Dopamine Detection 

Gaurab Dutta1, Chao Tan1 and Prabhu U Arumugam1

1Institute of Micro manufacturing, Louisiana Tech University, Ruston, Louisiana

Over the years major goal of neuroscience has been establishing brain- behavior relationship through the progress in advance neurochemical monitoring. Within that scope neurotransmitter dopamine plays an important part controlling and predicting positive stimuli for reward in brain regions that regulates movement of neuronal signal. Normal levels of dopamine in the brain allow the usual freedom of movement, whereas excess dopamine in the brain often creates rewarding feelings and sometimes leads to Schizophrenia, Parkinson disease, psychosis and cocaine addiction. Recent advancement in material science paves way for highly stable electrodes and bio-transducer interfaces for enhancement in electrochemical detection of dopamine. Among them boron doped ultrananocrystalline diamond (BDUNCD) exhibits excellent electronic, chemical, dimensional and biological properties. A gaining reputation as a reliable and robust electrode material, BDUNCD is expected to provide better resistance to surface fouling. Here, we report BDUNCD exhibiting a good sensitivity and high spatial-temporal resolution for dopamine detection at micrometer size electrodes. BDUNCD shows a sound dimensional stability for in vitro dopamine detection at extended periods of time with minimal surface oxidation. Only a 18 % decrease in peak current was observed with very minimal changes in kinetics even after subjecting the electrode surface to high anodic potentials (up to +1.4V) for 40 h. We also report surface reactivation strategies using electrochemical pretreatments that is vital to use BDUNCD in chronic brain chemical monitoring. The results are important in understanding the fouling mechanism in BDUNCD.


(7). Automated Analysis of Stretch-Attend Posture in Rodent Behavioral Experiments

Kevin S. Holly1, Casey O. Orndorff2, and Teresa A. Murray1

1Department of Biomedical Engineering, 2Department of Mathematics and Statistics, Louisiana Tech University, Ruston, LA

Rodent behavioral analysis is often used to access the effects of pharmaceuticals, implantations, or surgical procedures in preclinical research. With limited funding in some research labs, there is a need for open source software that detects stretch-attend posture (SAP) in rodents. SAP, which is generally associated with anxiety, occurs when the rodent lowers its back and elongates its body. Evaluation with human scorers is time-consuming and susceptible to error due to fatigue.  An open source image detecting software using MATLAB is being developed to detect SAP with a flexible yet user friendly GUI. The software allows the users to analyze multi-tiff video files of rodents from an overhead view. After the user enters a threshold input with the optional assistance of a threshold preview GUI, the input images are converted into binary images. The rodent’s tail is removed and an ellipse is formed around the body of the mouse. Using the eccentricity value of the ellipse (the ratio of the distance between the foci and its major axis length) and the speed of the rodent, the SAP is detected. The program provides plots displaying SAP detection as well as the corresponding speed and eccentricity values with the option of saving the data in Excel files. The SAP program was assessed with ten 5 min videos of male Swiss mice moving around in an open field box. The computer scoring was compared to the majority voting consensus of 5 human scorers. An eccentricity greater than 0.90 appears to be a good indicator of SAP when the speed of the mouse is less than 12 cm/s. The current version of the software is 90.37% accurate with a sensitivity and specificity of 79.53% and 91.74%, respectively. The software provides consistent results whereas the human scorers varied amongst each other.


(Oral only). Newly Discovered Nicotinic Receptor and Its Roles in Amyloid Beta 1-42 Pathology in Alzheimer’s Disease

Peace Ibole, Himgauri Naik, and Teresa A. Murray.

Center for Biomedical Research and Rehabilitation Sciences, Louisiana Tech University, Ruston, LA

We investigated endocytosis of oligomeric amyloid beta peptide Aβ1-42 via the nicotinic acetylcholine receptor (nAChR). These receptors are comprised of 5 homologous protein subunits. It has been shown previously that Aβ1-42 is internalized with a homomeric nAChR composed of five α7 subunits (α7-nAChR). We hypothesized that a recently discovered heteromeric nicotinic receptor composed of α7 and β2 subunits (α7β2-nAChR) would not internalize as much Aβ1-42 as the α7-nAChR. Indeed, we found that cells stably expressing α7-nAChR had higher levels of Aβ1-42 than cells stably expressing α7β2-nAChR when incubated with Aβ1-42. We also hypothesized that Aβ1-42 would be more toxic to cells expressing α7-nAChR then cells expressing α7β2-nAChR. We used receptor concatemers with known stoichiometry and position including the homomeric α7-nAChR and two heteromeric α7β2-nAChR, one with a single β2 subunit and one with two β2 subunits.  Preliminary live/dead cell assays results show that Aβ1-42 is toxic to the cells containing any of the nAChRs, but we have determined that the participation of the β2 subunit requires a more sensitive experiment.

 

(8). AAV9 Enables Wide-Scale Gene Transfer and Disease Modeling in Adult Rats

KL Jackson, RD Dayton, RL Klein

Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA.

Wide-scale gene transfer to the CNS of rats was previously achieved with intravenous gene transfer to neonatal rats using the adeno-associated virus (AAV) vector system. However, gene transfer to adult rats would be more relevant for adult onset diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration and would also facilitate pre-gene transfer measurements and post-symptomatic interventions. We compared several serotypes of AAV (1, 8, 9, rh10) for green fluorescent protein (GFP) gene transfer in young adult rats administered via the tail vein at equivalent vector doses per kg. AAV9 resulted in significantly stronger expression in the spinal cord and the cerebellum than the other serotypes tested. Gene transfer was more efficient in neonates than adults, but there did not appear to be any difference between genders. AAV9 was used to express the ALS-related protein transactive response DNA-binding protein, 43 kDa (TDP-43). TDP-43 induced severe motor paralysis over the course of a few weeks in a tightly vector dose-dependent manner. Interestingly, the amount of vector needed to induce these symptoms is lower than what is used to visualize GFP. The model entails very consistent small fold overexpression in the spinal cord, i.e. less than two-fold. With this preclinical model, we are attempting both small molecule and gene therapy strategies.

 

(9). Role of Sodium Leak Current Channel in Involuntary Movement Disorders in C. Elegans

Merve Kasap1, Eric Aamodt2, Donard S. Dwyer1, 3

1Department of Pharmacology, Toxicology and Neuroscience, 2Department of Biochemistry,  3Department of Psychiatry, Louisiana State University Health Sciences Center, Shreveport, LA

The human sodium leak current channel (NALCN) is implicated in many genetic forms of the movement disorders such as dystonia and dyskinesia.  Mutations in NALCN cause similar abnormalities in mice, Drosophila and C. elegans.  Reduced NALCN expression in Drosophila altered locomotive behavior and circadian rhythms although the flies were viable and fertile.  Also, they displayed a narrow abdomen phenotype with ‘hesitant walking’ and had altered sensitivities to general anesthetics such as halothane.  Loss-of-function mutation in C. elegans NALCN caused animals to move extremely slowly and when touched on the tail they showed a fainting or freezing response similar to frozen gait in Parkinson’s disease patients.  Gain-of-function mutation in NALCN caused an extremely active phenotype; worms showed excess coiling, turns and reversals similar to dystonia and dyskinesia.  We think that mutations in NACLN disrupt the depolarization-repolarization balance by changing the relative concentrations of sodium, calcium and potassium inside the cell.  Previously, we showed that it is possible to correct movement of NALCN loss-of-function animals with nicotine and K+ channel blockers.  Therefore, we hypothesized that we should be able to correct movement in gain-of-function (gf) mutant animals [unc-77 (e625) allele] with a similar strategy.  In order to evaluate the movements of the worms, we observed spontaneous movement, startle response and foraging (food seeking) behavior.  Our studies with potassium channel activators on gf animals remain inconclusive except 2-aminoethoxydiphenyl borate (2-APB).  2-APB is a pharmacological agent with various actions such as such as inhibiting inositol trisphosphate receptors, transient receptor potential channels, and gap junctions; and modifying store-operated calcium channels function.  Beside 2-APB, we discovered several pharmacological agents such as nimodipine, flunarizine and ethoxzolamide that improve or correct the movement of gf animals in the foraging assay.  These drugs potentially share a common mechanism of action by regulating calcium flux. We hope to discover specific pharmacological agents that target the NALCN. Drugs that can correct behavioral deficits caused by NALCN mutations may be useful for the treatment of human movement disorders.

 

(Oral Only). The Effects of the Combination of Metyrapone and Oxazepam on Central Corticosterone and Conditioned Emotional Memories

Courtney M Keller, Glenn F Guerin, Nicholas E Goeders.

Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA

Cocaine activates the hypothalamic-pituitary-adrenal (HPA) axis, and we have previously demonstrated that a combination of drugs (i.e., metyrapone (Met) and oxazepam (Ox)) known to attenuate HPA-axis activity effectively decreases cocaine taking and seeking in rats as well as humans.  However, these behavioral effects are not matched by changes in plasma corticosterone (CORT), indicating that a different mechanism of action must be involved in the effects of Met-Ox.  In addition to activating the HPA axis, cocaine increases local CORT concentrations in discrete brain regions, including the medial prefrontal cortex (MPC).  Therefore, we hypothesized that Met-Ox attenuates cocaine taking and seeking by decreasing cocaine-induced increases in CORT in the MPC.  Microdialysis studies in the MPC revealed that cocaine increases CORT, while administration of Met-Ox prevents these cocaine-induced increases in CORT. Interestingly, different effects were observed in the nucleus accumbens where Met-Ox significantly reduced CORT when compared to cocaine alone, even though cocaine did not significantly increase CORT when compared to vehicle treatment.  Therefore, the combination Met-Ox may be attenuating drug taking and seeking by specifically decreasing CORT in the MPC. While the exact function of CORT in the brain has not been fully explored, several studies suggest that the hormone may affect learning and memory.  Therefore, we tested the effects of Met-Ox in the conditioned emotional response (CER) paradigm.  With CER, rats are trained to associate previously neutral cues (i.e., the presentation of a flashing light and tone) with the delivery of electric footshock.  During the presentation of the conditioned stimuli, rats treated with vehicle showed the expected suppression of lever pressing.  Met-Ox treated rats, however, continued to respond during the presentation of the conditioned stimuli, and this effect was dose related.  Thus, these experiments revealed that Met-Ox blocks conditioned emotional memories, which may play a role in relapse.

 

(10). Depression and Brain Connectivity in Parkinson’s Disease

Howard E Morgan1, Chris Ledbetter2, Hyung Nam3, Chris Higginson4, Cristalyn Reynolds5, Elizabeth Disbrow5

1School of Medicine, 2Department of Neurosurgery, 3Department of Pharmacology, Toxicology, and Neuroscience, 5Department of Neurology, Louisiana State University Health Sciences center, Shreveport, LA; 4Deptartment of Psychology, Loyola. 

Depression is a common non-motor symptom of Parkinson’s Disease (PD); however, the pathophysiology is understudied.  To test the hypothesis that in people with PD brain connectivity is reduced in regions associated with depression, resting state fMRI was performed on participants in 2010 using a 3T Siemens TIM Trio MR system to collect T1- weighted MP-RAGE and echo planar functional T2*- BOLD images.  Image preprocessing and analysis was performed in SPM 8, and first-level functional connectivity analysis was performed in CONN toolbox.  Second-level analyses determining connectivity was done in AFNI using 3dMean (cluster threshold of 200 voxels and pearson’s correlation threshold of 0.250).  Eighteen PD patients and 17 age-matched controls were recruited from Movement Disorders Clinic at University of California Davis Medical Center, with the inclusion criteria:  diagnosis of PD, right dominant PD, age of 55-75, and responsive to levodopa.  Exclusion criteria:  contraindication to MRI, H&Y >3.0, severe tremor, motor fluctuations, Dyskinesia, dementia, EDS.  The main outcome measure for this study was connectivity (Pearson correlation of signal intensity over time for a given region) between the medial prefrontal cortex (MPFC) and dorsal anterior cingulate cortex (dACC) seeds in voxels.  For the MPFC seed, the control group displayed more connectivity than PD:  both had bilateral posterior cingulate cortex and anterior superior frontal gyri positively correlated, but only control had bilateral supramarginal gyri positively and bilateral inferior parietal lobules negatively correlated.  The right and left dACC showed similar connectivity in PD and control groups – including superior, middle, inferior frontal gyri; insula; caudate nuclei – but there was still more volume connected in the controls (total voxels in LdACC control = 32145, RdACC control = 32145) compared to PD (total voxels in LdACC PD = 18028, RdACC PD = 19125).  In general, connectivity was decreased in PD patients in depression related regions, suggesting a substrate for Parkinsonian depression.

 

(11). Processing Speed Deficits have Far Reaching Consequences in PD

Hoang M. Nguyen1, Brianna Hall2, Christopher I. Higginson3, Karen A. Sigvardt4, Lin Zhang4, Norika Malhado-Chang4, Elizabeth A. Disbrow1, 5, 6

1Department of Pharmacology, Toxicology, and Neuroscience, 2School of Medicine, Louisiana State University Health Sciences Center, Shreveport, LA; 3Department of Psychology, Loyola University, Maryland; 4Department of Neurology, UC Davis, Sacramento, CA; 5Overton Brooks VA; 6Department of Neurology, Louisiana State University Health Sciences Center, Shreveport LA

Processing speed is a dopamine dependent measure of cognitive proficiency that has been shown to increase with age.  Parkinson’s disease (PD) is a dopaminergic neurodegenerative disorder that is associated with aging, possibly putting people with PD at higher risk for processing speed deficiency.  Thus, we hypothesize that processing speed is increased in those with PD without dementia compared to controls.  We studied a group of 68 participants with PD (35 males, 33 females) and 50 controls (26 males, 24 females) between the ages of 55 and 75.  Groups were matched for age, years of education, and premorbid IQ.  Subjects with PD were medicated and in relatively early stages of the disease. Subjects underwent a battery of neuropsychological tests, including measures of processing speed, attention, memory, cognitive flexibility, activities of daily living, and quality of life, as well as motor performance.  Processing speed was evaluated using the Symbol Digit Modalities Test.  Between groups comparisons were made using Multivariate Analysis of Variance (MANOVA), and age, daytime sleepiness and motor performance (functional Dexterity Test) were used as covariates in the analysis as possible confounding factors.  Processing speed was significantly decreased in the PD group (Mean(SD) 44.3 (11.9) items completed in 90 sec.) compared to controls (Mean(SD) 52.4 (8.2) items completed in 90 sec.; F(4, 113)=12.78, p<0.0001).  Additionally, maximum likelihood factor analysis revealed two factors in PD: cognitive and motor.  The items that loaded heavily on the cognitive pattern were measures of trail-making, switching, inhibition, and processing speed.  Those that loaded heavily on the motor pattern were manual dexterity, mobility, and processing speed.   Factor loadings are listed in table 1.

     Manual Dexterity    Mobility Processing Speed Inhibition SwitchCategory Switch Trailmaking 
 Factor 1 -.040.056 -.685 .780 -.726 .577 
 Factor 2.485 .343 -.465 .109 .252 .153 

Interestingly, increased processing speed was also associated with increased difficulty with activities of daily living (UPDRS II; R= -.426, p=0.001) and instrumental activities of daily living (R= -.653, p<0.0001) as well as decreased self-report quality of life (R= -.279, p=0.024).   Our results indicate that processing speed is negatively affected in PD.  This deficit has far reaching consequences, contributing to motor and cognitive deficits associated with the disease as well as every-day activities and quality of life. 

 

(12). Hypo NMDAR-neurogranin (Nrgn) Signaling Regulates Schizophrenic Behaviors through Cortico-striatal Circuitry

John Sullivan1, Ashlie N. Reker1, Lailun Nahar1, Daylen Griffen1, Madison Davis1, Hyung W. Nam1

Department of Pharmacology, Toxicology, and Neuroscience. Louisiana State University Health Science Center, Shreveport, LA.

Schizophrenia affects approximately 51 million people worldwide, and presents a severe cost to the individual and society. Both clinical and preclinical research have contributed to the current understanding of the molecular mechanisms of glutamate; however, the brain glutamate function and its connectivity in relation to the pathophysiology of schizophrenia are not well studied. The focus of this study was to contribute to the understanding of hypo NMDAR-Neurogranin (Nrgn), in relation to the symptomatology of schizophrenia in mice. A variant of Nrgn gene has been detected in human schizophrenic patients, and is therefore a target of interest in current research. To test schizophrenic symptoms, we utilized viral mediated gene expression and optogenetics, and measured pre-pulse inhibition (PPI) and social interaction in mice. We identified that Nrgn up-regulation in the mPFC strengthens PPI response, whereas optogenetics stimulation results in no change. Social withdrawal was observed in mice with decreased Nrgn expression in the NAc, and was also showed to be restored by over expression of Nrgn. Furthermore, this result of increased sociability implies that Nrgn plays an important role in glutamate receptor-mediated signaling via its depolarization mechanism in the NAc. Overall, the NMDAR-Nrgn regulation has been shown to display region specific differences in the mPFC and the NAc, indicating that the schizophrenic behaviors and molecular mechanism in those regions are different. Moreover, optogenetics findings can further the development of neural networks between brain circuitry and intracellular glutamate signaling. This study can help contribute to the process of finding ways to ameliorate the symptoms of schizophrenia and suggest therapeutic treatments for patients.


(13). Inflammatory Cytokines Associated with Neurovascular Disorders Alter Neurolymphatic Marker Expression in Brain Endothelial Cells and in Microparticles

J. Winny Yun, Emily V. Stevenson, J. Steven Alexander.

LSUHSC-Shreveport Molecular and Cellular Physiology, Shreveport, LA

Inflammatory cytokines promote cerebrovascular stress in several neurodegenerative diseases including multiple sclerosis (MS) and Alzheimer’s disease (AD) and may provoke endothelial disturbances, which contribute to blood-brain barrier breakdown and intensification of disease. Despite its high metabolic rate and the sensitivity of neurons to waste products of metabolism, the brain has been classically described as lacking a conventional ‘lymphatic’ system. However, non-conventional ‘lymphatic’ channels and lymphatic-specific proteins have been recently identified in human brain tissue as well as in serum samples and the expression of these proteins has been reported to be altered in MS (Chaitanya et al., J Neuroinflammation. 2013 Oct 14;10:125). These findings indicate the possibility that the presence of circulating ‘neurolymphatic’ biomarkers (LYVE-1, FOXC2, VEGFR-3, Podoplanin, Prox-1) may originally derive from brain endothelial cells which can undergo lymphatic specification in response to inflammatory stimuli. The present study suggests that altered neurolymphatic marker expression observed in forms of MS may represent partitioning of these biomarkers within caveloae-rich microparticles, which may segregate signaling modules related to neurovascular disease. 


(14). Pharmacogenetic Interactions in Two Mouse Models of Sudden Unexpected Death in Epilepsy

Stephanie Villalba, Nicky Gautier, and Edward Glasscock

Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA


(15). In vivo Integrated Imaging Support System

Vlad Voziyanov and Teresa A. Murray

Center for Biomedical Engineering and Rehabilitation Sciences, Louisiana Tech University, Ruston, LA

In order to image live animals, a system is required to keep them positioned under the microscope while keeping them anesthetized and warm. Most available heating systems are thick and uneven, limiting the number of microscopes they can be used with. Most available stereotaxic frames are bulky and have difficulty aligning mice across imaging sessions unlike the more compact head plates. Keeping the heating pad separate from the positioning system increased the likelihood that shifting the heating pad would separate the head plate from the skull due to increased shear stress on the head plate. The In Vivo Integrated Imaging Support System is a water-based heated plate with a head plate securing system attached to the heated plate. The system includes a nose cone with an elastomer shroud for anesthesia. Our integrated system is more compact than a comparable system with a traditional heated pad and head restraint, allowing it to be used with more microscope systems. After assembly, hot water was run through the heated plate and the temperature recorded. It was found that the temperature in the channels was on average two degrees lower than the temperature of the water in the reservoir. We used the system for over 40 imaging sessions, during which mice were under anesthesia for up to 2 hours using the nose cone system for isoflurane. In conclusion, the integrated system worked as intended, keeping the mouse warm at a constant temperature as well as well anesthetized for the duration of each imaging session. 


Category: Post-doctoral Fellows and Medical Residents

 

(16). Unilateral Adie Pupil –An Isolated Clinical Finding in Early Neurosyphilis 

Syed W. Abbas1 MD, Omar Hussein1 MD, and Stephen L. Jaffe1 MD      

1Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, Louisiana

Objective: To report a patient with unilateral dilated pupil, slowly constricting and redilating with tonic constriction, more responsive to accommodation than light, or Adie pupil as an isolated clinical finding in early neurosyphilis. Background: Neurosyphilis is an important non-emergent cause of pupillary defects with ocular involvement in 40-50% of cases. Argyll Robertson pupil (small, unresponsive to light, but constricting on accommodation) and bilateral Adie pupil are the most common pupillary defects seen in Neurosyphilis. We are reporting an unusual clinical presentation of a patient with a unilateral Adie pupil, most likely due to treponemal infection of the ciliary ganglion and/or short ciliary nerves, as an isolated clinical finding in early Neurosyphilis. Methods: Case report. Results: A young female was transferred to our neurology service from an outside hospital emergency department because of a syncopal episode and newly diagnosed dilated left eye pupil. Patient also noticed that her left eye pupil was larger than right eye and this was a new change for her. She admitted to having unprotected sex. Neurological examination was without knee/ankle hyporeflexia, tending to exclude Holmes-Adie syndrome. Ophthalmological examination showed visual acuity 20/20 OD and OS, full extra ocular movements, and full visual fields.  Right pupil with brisk response to light and accommodation, 4 to 2 mm; left Adie pupil, slow constriction to accommodation better than light, 8-6 mm; but brisk 8-3 mm response with dilute pilocarpine (Cannon’s denervation hypersensitivity). An acute unilateral Adie pupil was diagnosed. Magnetic Resonance Imaging (MRI) of the brain was unrevealing and MR angiogram showed attenuated left middle cerebral artery temporal branches raising the question of vasospasm. Serum non treponemal RPR titer was 1:128. Lumbar puncture (LP) showed Opening pressure of 33cm of water, Cerebrospinal fluid (CSF) nucleated cell count 162, with 97% lymphocytes. CSF VDRL titer was 1:8(high). We also found treponemal specific antigen FTA-abs reactive. Patient was started on IV Penicillin G for 10 days and then weekly IM benzathine penicillin for 3 weeks. Serial LPs, serologic, and ophthalmologic examinations were recommended at 3 and 6 months. CONCLUSION: A newly diagnosed anisocoria requires urgent clinical attention to rule out surgically correctable intracranial lesions, however, a unilateral dilated Adie’s pupil may be an isolated finding in Neurosyphilis. Keywords: Adie’s pupil, neurosyphilis, cycloplegia


(17). Intermittent Bilateral Deep Brain Stimulation of Nucleus Accumbens Shell Reduces IV Methamphetamine Self-Administration in Wistar Rats

Vinita Batra PhD, Glenn F Guerin*, Nicholas E Goeders PhD*, and Jessica Wilden MD

Department of Neurosurgery and *Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA

INTRODUCTION: There is increasing interest in neuromodulation for addiction. Methamphetamine abuse is a global health epidemic with no proven treatment.  We previously found that unilateral deep brain stimulation (DBS) of the nucleus accumbens shell (AcbSh) in Wistar rats transiently and unreliably decreased IV methamphetamine self-administration for 15 minutes.  In this subsequent experiment, we delivered bilateral AcbSh DBS to evaluate its effect.

METHODS: Rats implanted with IV catheters and bilateral AcbSh electrodes underwent daily 2-hour sessions in two-lever (active/IV methamphetamine and inactive/no reward) operant chambers to establish methamphetamine self-administration.  After stable responding was achieved, 3 hours of treatment with DBS was administered (Sham/0 µA n=4 and Active/200 µA n=4) in a separate environment immediately prior to the daily operant sessions for 5 consecutive days.  Following each DBS treatment, subjects were disconnected from the stimulation apparatus and moved into the operant chambers to examine the effects of remote neuromodulation on methamphetamine use.

RESULTS: There was a significant decrease in total 2-hour methamphetamine intake in rats receiving active DBS versus sham with an average reduction of 65% (P<0.05).  Methamphetamine administration returned to baseline levels following the cessation of DBS therapy.

CONCLUSIONS: Limited bilateral AcbSh DBS delivered outside of the drug use environment decreased IV methamphetamine self-administration to a much greater degree than unilateral DBS. The AcbSh is a neuroanatomical substrate for psychostimulant reinforcement and may be a target for intermittent neuromodulatory therapies that could be administered during periods of sobriety. 


(18). Acute Post Infectious Cerebellitis as Possible Autoimmune Process Targeting the Cerebellar Cells rather Than Manifestation of Viral Neuro-invasion: 2 Case Reports

Omar Hussein, Raghav Aachi, Rosario Riel-Romero

Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA

Acute post infectious cerebellitis is a condition characterized by cerebellar signs and symptoms following a systemic viral infection. Few case reports have documented the manifestations of cerebellar dysfunction as the sole presentation of viral infection. Etiology of this condition remains unrecognized and due to the rarity of the cases, no large studies have been conducted. It has been hypothesized that etiology could be either autoimmune versus direct neuro-invasion. A few cases reported normal CSF analysis and normal brain MRI in these patients.

We report 2 cases of cerebellar dysfunction in pediatric patients that occurred post viral infection, specifically EBV infection, with subtle initial symptoms of either pharyngitis or colitis. Serum testing indicated acute viral infection, whereas CSF analysis showed no pleocytosis or any other signs of inflammation or infection. Furthermore, one of the cases was tested for EBV PCR in the CSF and it did not detect any EBV copies. MRI of the brain was unremarkable in both cases indicating no signs of edema or enhancement. Clinically, At least one case spontaneously improved over few weeks to months without any residual symptoms or signs. The other case was lost to follow up and may imply that the patient had recovered as follow up was not deemed necessary.

These findings reflect a non-inflammatory response in the CNS despite signs of active systemic infection. The term Acute Post Infectious cerebellitis then is a misnomer as it indicates inflammation as an etiology, but rather it is just cellular dysfunction which could be secondary to antibodies produced due to the acute infection causing dysfunction of some cellular components, but not responsible for eliciting acute inflammatory response in the CNS. Also, the fact that the cerebellar dysfunction symptoms occurred few weeks after the initial systemic symptoms, coupled with the response to steroid therapy reported in some of the cases, support our autoimmune hypothesis rather than direct viral infection.

While other viruses, specifically Varicella, has been described quite often in association with cerebellar dysfunction, Ebstein-Barr virus has been reported only in a handful of case reports.

Our 2 patients underscore the importance of considering EBV infection as a contributory factor in patients who present with acute cerebellar dysfunction. 


(19). Scn2a-null heterozygosity improves survival and modifies neurocardiac interaction in the Kcna1-null mouse model of SUDEP

Vikas Mishra1, Nicky Gautier1, Bharat K. Karumuri2, Rui Liu2, Ioannis Vlachos2, Leonidas D. Iasemidis2 and Edward Glasscock1

1Department of Cellular Biology & Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA; 2Biomedical Engineering, Louisiana Tech University, Ruston, LA

 

(20). Decreased Neurogranin in the Nucleus Accumbens Promotes the Reward Motivation and Reinforcement for Ethanol Seeking  

Ashlie N. Reker1, John M. Sullivan III1, Alfredo Oliveros2, David J. Hinton2,3, Doo-Sup Choi2,3, Hyung W. Nam1

1Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Science Center, Shreveport, LA, 2Department of Molecular Pharmacology and Experimental Therapeutics, 3Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, Minnesota.

Striatal glutamate signaling has been implicated in the pathophysiology of neurological disorders and alcoholism. NMDA glutamate receptors play an essential role in both reward motivation and seeking behaviors, but its intracellular target is not well studied. Neurogranin (Ng) is predominantly expressed on the postsynaptic dendrite and is an intracellular target of NMDAR signaling, however, evidence for the role of Ng signaling in alcohol related behaviors have not yet been established.  In the present study, we identified that the dampening of NMDAR-Ng signaling enhances the reward motivation during Pavlovian conditioning and promotes excessive ethanol seeking during operant conditioning, while also increasing sensitivity to ethanol intoxication. We found that the lack of Ng in the nucleus accumbens (NAc) increases intrinsic motivation and insensitivity to aversive effects of reinforcement during ethanol seeking behaviors. Ng -/- mice also show enhanced motivation measured by a progressive ratio schedule (PR) schedule, while Ng +/+ mice showed significant increased response by NAc specific optogenetic stimulation. Finally, we demonstrated that chronic ethanol administration could reduce both the length of axons and mGluR5 expression in the NAc, which promotes excessive ethanol drinking in Ng -/- mice.  Our results indicated that Ng is a key determinant in the postsynaptic intracellular mechanism resulting from NMDAR and is associated with a higher susceptibility of enhanced reward motivation for excessive ethanol drinking.

 

(21). A Case of Progressively Expanding Total Hemimegalencephaly

Jayson D. Rodriguez MD1, Arun A. Kalra MD1,2, Eduardo Gonzalez-Toledo MD-PhD1,3

1Department of Neurology, 2Department of Pediatrics, 3Department of Radiology, Louisiana State University Health Sciences Center, Shreveport, LA.

Hemimegalencephaly (HME) is a rare brain malformation characterized by enlargement of one cerebral hemisphere. Total HME involving ipsilateral cerebellum and brainstem is the least frequent form. The typical clinical triad of total HME includes intractable epilepsy, psychomotor delay and hemiparesis. We present a case of total HME with unique constitution of brain malformations and progressively expanding size that is rarely reported in literature. A two year old white male was transferred to our institution for higher level of care from an outside facility where he presented with seizures and had a right frontal mass on CT scan. Past history included cerebral palsy, prominent developmental delay, left-hemiparesis, shunted right hydrocephalus and seizures controlled on levetiracetam, which was tapered off seven months ago. Present seizures were focal motor with left-sided Todd’s paralysis. On detailed history, he was having unrecognized partial complex seizures all along.  Global developmental delay was more prominent in the motor area. On examination, he had prominent hypotonia and no signs of increased intracranial pressure. Levetiracetam was restarted with no further clinical seizures. EEG revealed disorganized background on the right hemisphere with multiple epileptogenic foci giving rise to four electroencephalographic seizure events ranging from three to twelve seconds. Based on this, levetiracetam dose was increased. Current MRI was compared to the previous MRIs showing the following findings. First MRI at one week age confirmed prenatal ultrasound finding of right-sided hydrocephalus, but showed prominent right ventriculomegaly with midline shift and compression of the rest of the intracranial structures. MRI at two months of age, after shunt revision, showed markedly decreased size of the right ventricle. Both cerebral hemispheres were about equal size but right cerebellum was prominently enlarged and right frontal cerebrum was misshapen.  The current MRI shows that the right cerebral hemisphere has grown tremendously in size squeezing the left hemisphere again. The enlarged right cerebellum now shows abnormal folia. In addition, the right hemisphere showed a large right frontal/perisylvian pachygyria, occipital polymicrogyria, and prominent cleft between fusiform and parahippocampal gyrus. MR spectroscopy findings of the bright right frontal white matter confirmed this to be Taylor type focal cortical dysplasia. He was referred to Neurosurgery for evaluation and possible hemispherectomy. Normally, cerebral dysgenesis does not continue to grow in size which makes this a strange entity.

 

(22). Functional expression of brain Kv1.1 potassium channels in mouse heart

Man Si1, Nicky Gautier1, Kathryn Hamilton1, and Edward Glasscock1

1Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences center, Shreveport, LA

 

Category: Faculty

(23). Exploring The Behavioral Pharmacology Of Polydrug Abuse: Methamphetamine And Benzodiazepines

Christopher D. Schmoutz1, Allyson L. Spence1, Savannah R. Porter1, Sarah M. Harold1, Courtney N. Jamison1, Guanguan Li2, James M. Cook2, Glenn F. Guerin1, Nicholas E. Goeders1

1Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA; 2Department of Chemistry, University of Wisconsin Milwaukee, WI.

Recent drug discovery research has elucidated the subtype-dependent effects of the activation of certain GABAA receptors and consequently, the receptor binding profile of a benzodiazepine agonist (BZD) determines its physiological, neurochemical and behavioral effects. Employing subtype-selective ligands may enhance the therapeutic effects of BZDs (e.g., anxiolysis) while limiting their undesirable effects (e.g., sedation). Two binding sites have been characterized in rodent brain tissue: a “central” BZD binding site associated with the GABAA receptor and a “peripheral” BZD binding site associated with the translocator protein of 18kDa (TSPO). One benzodiazepine derivative (oxazepam) has demonstrated significant efficacy in decreasing methamphetamine-associated behaviors, especially when compared to alprazolam, a BZD known to bind predominantly to GABAA receptors and not to the TSPO. These differences between BZDs are not as apparent in the context of cocaine-reinforced behaviors. This suggests that activation of TSPO may be more important than GABAA receptor activation in the actions of BZDs on methamphetamine-related behaviors. To test this hypothesis, we have performed an investigation of the behavioral pharmacology and in vitro receptor binding of Ro5-4864, a novel BZD derivative and selective TSPO ligand. Pretreatment with Ro5-4864 (5-60 mg/kg, IP) decreased ongoing methamphetamine self-administration behaviors during daily 2-hour behavioral sessions, especially in female rats. These results support our hypothesis of the efficacy of selective TSPO-related BZD derivatives and suggest that gender may be a significant factor in modulating their neurotherapeutic potential.

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