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The Transient Receptor Potential Vanilloid-1 Channel and Neuronal Survival in Degenerative DiseaseWard, Nicholas John 23 July 2014 (has links)
Neuronal responses to stress are an important component of neurodegenerative disease and may represent targets for therapeutic intervention. In normal and pathogenic physiological conditions, members of the transient receptor potential (TRP) family of cation channels have been implicated in transducing stress-related stimuli. Studies detailed in this document characterize the response of the vanilloid-1 TRP channel (TRPV1) to stress from elevated intraocular pressure (IOP) in a mouse model of glaucomatous optic neuropathy. Knockout of TRPV1 (<i>Trpv1</i>-/-) resulted in accelerated degeneration of retinal ganglion cells (RGCs) with elevated IOP. Compared to C57 controls, <i>Trpv1</i>-/- mice exhibited more extensive pathology in terms of axonal transport deficits, loss of RGC axons within the optic nerve, and loss of RGC somas in the retina. This accelerated pathology indicates that TRPV1 may mediate important survival mechanisms in response to IOP-induced stress of RGCs. Soon after IOP elevation, TRPV1 protein levels transiently increase within a layer of the retina associated with RGC dendrites and synapses. Likewise, TRPV1 localization near RGC synaptic active zones increases with IOP-induced stress, indicating a potential influence of TRPV1 on synaptic activity. Morphological studies of RGC dendrites demonstrated that TRPV1 does influence dendritic complexity, indicating a potential role for TRPV1 at synaptic sites in dendrites. The data indicate that TRPV1 may help RGCs survive in response to stress by influencing activity at RGC synapses.
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A Role for Astrocytes in Dopamine-Glutamate Interactions of the Prefrontal CortexVollbrecht, Peter John 17 April 2014 (has links)
Both dopamine and glutamate are critically involved in cognitive processes such as working memory. Evidence has demonstrated that manipulation of either neurotransmitter can lead to alterations in the other. Astrocytes, which express dopamine receptors, are essential elements in the termination of glutamatergic signaling: the astrocytic glutamate transporter GLT-1 is responsible for >90% of cortical glutamate uptake. The effect of dopamine denervation on glutamate transporters, and other glutamate-related proteins in the prefrontal cortex (PFC) , is unknown. In an effort to determine if astrocytes are a locus of cortical dopamine-glutamate interactions, we examined the effects of chronic dopamine denervation on PFC protein and mRNA levels of glutamate transporters and glutamate-related proteins. PFC dopamine denervation elicited a marked increase in GLT-1 and mGluR2/3 protein levels, but had no effect on levels of other glutamate transporters or glutamate-related proteins. Increases in GLT-1 and mGluR2/3 were dependent on the extent of dopamine depletion with moderate depletion resulting in increased protein levels, while severe dopamine depletion failed to elicit an increase in GLT-1 or mGluR2/3. Astrocyte number and activation were not affected by dopamine depletion. High affinity glutamate transport was positively correlated with the extent of dopamine depletion. Increases in GLT-1 and mGluR2/3 may act to homeostatically regulate increases in extracellular glutamate levels and attenuate symptoms associated with prefrontal cortical dysfunction in disorders such as schizophrenia.
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Rare variants affecting regulation of serotonin and dopamine transport contribute to the genetic liability of autismCampbell, Nicholas George 30 April 2014 (has links)
Autism spectrum disorder (ASD) is a neuropsychiatric condition with a range of deficits in social reciprocity and communication, and patterns of rigid-compulsive behaviors. ASD prevalence is estimated at approximately 1 in 100 individuals, with substantial evidence for a largely genetic etiology of complex architecture. The work described here is based on the principle that genes involved in the etiology of ASD will converge onto shared biological systems, and those systems will inform investigation into the pathogenesis of ASD. The purpose of this work was to test the hypothesis that genes encoding monoamine regulation networks harbor genetic variants associated with ASD. In part this was driven by the phenomenon of hyperserotonemia in a third of ASD cases. Genes in monoamine networks were thus analyzed for presence of ASD associated variation, and downstream functional studies of two such proteins, the adenosine A3 receptor (a regulator of the serotonin transporter) as well as the dopamine transporter, were revealed novel abnormalities. In conclusion, the results are highly supportive that both a genetic and functional liability exists within the broad context of monoamine dysfunction and ASD.
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Fourier Optical Imaging of Discrete Stimuli in Primate Somatosensory CortexWinberry, Jeremy Edward 27 March 2014 (has links)
Optical imaging of intrinsic signals (OIS) has improved our understanding of the functional organization of the cerebral cortex. However, the technique places time constraints on experiments due to the averaging needed to overcome cardiovascular noise. A novel OIS method, using continuous image acquisition of a periodically presented stimulus, followed by a Fourier decomposition, promises to reduce experiment time while separating the stimulated response from the cardiovascular noise. Discrete, periodic finger stimulation and Fourier OIS were used to generate a functional map of finger somatotopy in squirrel monkey SI cortex. Phase delay correction was successfully performed through both stimulus reversal/subtraction and subtraction of a single, discrete stimulus. Magnitude borders between digits were described, and a harmonic analysis showed that they are caused by overlapping response from the adjacent finger representation. Digit selectivity analysis demonstrated a selectivity gradient within digit representations in both cortical areas 3b and 1. Significance maps were generated by calculating the signal-to-noise ratio (SNR) for each pixel. SNR maps required more stimulation repetitions than magnitude maps, but demonstrated higher sensitivity for regions with low activity and less overall blood vessel artifact. Finally, a comparison to episodic OIS and electrophysiological receptive field mapping showed that Fourier OIS maps are comparable to those standards.
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Linking molecular, electrical, and behavioral rhythms in the brains biological clockJones, Jeffrey Robert 17 March 2015 (has links)
Understanding the relationship between gene networks, neurons, and circuits that determine behavior is a fundamental problem in neuroscience. The brains biological clock the suprachiasmatic nucleus (SCN) is an excellent model system in which to study this crucial problem. SCN neurons possess daily molecular transcriptional/translational feedback loops and exhibit rhythms in spontaneous action potential frequency. The synchronized output of the SCN neural network ultimately dictates circadian behavior and physiology. A key unsolved question in circadian neurobiology is how these rhythms interact to form a coherent pacemaker. To address this question, I combined electrophysiology, real-time imaging of gene expression, SCN-specific optogenetic manipulation of neuronal firing, and monitoring of locomotor activity to elucidate the links between the molecular and electrical rhythms that comprise the brains biological clock and their circadian behavioral output. I found that optogenetic induction or suppression of firing rate within SCN neurons is sufficient to reset the phase and alter the period of the molecular clockworks, that this resetting requires action potentials and network communication, and that in vivo optogenetic stimulation of the SCN entrains locomotor activity rhythms. Additionally, the expression of the clock gene Period1 is necessary for the coordination of molecular and electrical rhythms in SCN neurons. Thus, I conclude that there is a bidirectional relationship between circadian rhythms in gene expression and electrical activity in SCN neurons such that firing rate is both an output of and an input onto the molecular clock.
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Neural Correlates of Anticipation in Children at High Risk for AnxietyClauss, Jacqueline Alexandra 03 December 2014 (has links)
Inhibited temperament is a biological risk factor for the development of social anxiety disorder. In adolescents and young adults, inhibited temperament has been associated with increased amygdala reactivity and alterations in prefrontal cortex regulation. Brain activation in children with an inhibited temperament who have yet to develop anxiety disorders has not been examined. In this study of young children, we identified neural vulnerabilities in the prefrontal cortex activation associated with preparing to view social stimuli. Further, we found that inhibited children had stronger connections within a limbic-visual processing network when preparing to view social stimuli. This is the first study to identify underlying neural vulnerabilities associated with inhibited temperament and to show that young children with this phenotype already have critical alterations in brain activation.
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Under Attack: Nervous System Patterns of RNA Editing in Response to Reovirus InfectionHood, Jennifer Lyn 05 December 2014 (has links)
The innate immune response serves as a defense against infection, but it can also have negative consequences, particularly when it affects the central nervous system (CNS). Interferon is a key mediator of the innate immune response, and is responsible for the induction of a number of interferon-stimulated genes (ISGs). Transcripts encoding ADAR1, a double-stranded RNA-specific adenosine deaminase involved in the adenosine-to-inosine (A-to-I) editing of mammalian RNAs, are alternatively spliced in response to interferon, resulting in induction of an interferon- inducible protein isoform (p150) of ADAR1 that is up-regulated in both cell culture and in vivo model systems in response to pathogen or interferon stimulation. In contrast to other tissues, p150 is expressed at extremely low levels in the brain and it is unclear what role, if any, this isoform plays in the innate immune response of the CNS. ADAR1s involvement in editing RNA substrates critical for CNS function led us to in- vestigate the expression of ADAR1 isoforms in response to viral infection of the brain and to explore possible alterations in A-to-I editing profiles for CNS-specific ADAR targets. We used a neurotropic strain of reovirus to infect neonatal mice and exploit the endogenous interferon system. Subsequently, we characterized ADAR1 isoform expression in discrete brain regions using multiple, complementary methods of analysis.

We also used a multiplexed, high-throughput sequencing strategy to quantify A-to-I editing profiles in the same brain regions. While intracranial injection of reovirus resulted in a widespread increase in the expression of ADAR1 (p150) in the CNS and peripheral organs, significant changes in site-specific A-to-I conversion were quite limited, suggesting the possibility of more complex regulatory mechanisms for p150 editing or non-editing related functions for this interferon-sensitive isoform of ADAR1.
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Mechanistically Distinct Modes of Endocannabinoid Mobilization at Glutamatergic Synapses of the Lateral Division of the Central Amygdala and Its Regulation by Chronic StressRamikie, Teniel Sonya 08 December 2014 (has links)
The lateral division of the central amygdala (CeAL) is a key structure at the limbic-motor interface regulating stress-responses and emotional learning. Endocannabinoid (eCB) signaling is heavily implicated in the regulation of stress-response physiology and emotional learning processes, however, the role of eCBs in the modulation of synaptic efficacy in the CeAL is not well understood. Here we describe the subcellular localization of type 1 cannabinoid receptors (CB1) and the eCB synthetic machinery at glutamatergic synapses in the CeAL and find that CeAL neurons exhibit multiple mechanistically and temporally distinct modes of postsynaptic eCB mobilization. Furthermore, this work demonstrates that following chronic stress exposure, eCB-mediated suppression of CeAL excitatory inputs is enhanced. Collectively, these data identify a prominent role for eCBs in the modulation of excitatory drive to CeAL neurons and provide insight into the mechanisms by which eCB signaling and exogenous cannabinoids could regulate stress-responses and emotional learning.
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The reversal of dopamine transporter function is governed by plasma membrane interactions and disrupted by genetic variationsHamilton, Peter James 08 December 2014 (has links)
Dopaminergic neurotransmission plays an important role in the regulation of cognitive, behavioral, and motor functions. Abnormalities in the dopamine (DA) system have been implicated in neuropsychiatric disorders including drug addiction, schizophrenia, attention deficit hyperactivity disorder, and autism spectrum disorder (ASD). The DA transporter (DAT) is a presynaptic protein that regulates DA neurotransmission by mediating the re-uptake of synaptically released DA. The DAT is a major molecular target of the psychostimulant amphetamine (AMPH), which causes an elevation in extracellular DA by inducing a reversal in DAT function.
Since DA neurotransmission is heavily dictated by DAT function, understanding the regulators of DAT transport may be instrumental in understanding DA-related neuropsychiatric disorders. In this dissertation, I report multiple avenues of research that explore the regulatory events associated with DAT-mediated reverse transport of DA. First, I present that the phospholipid PIP2 directly binds, through electrostatic interactions, to positively charged DAT N-terminal residues. This interaction is required for robust AMPH-induced, DA efflux, yet does not affect the process of DA uptake. I also describe an ASD-associated de novo mutation in the DAT gene. This de novo mutation causes profound abnormalities in DAT function, including a persistent reverse transport of DA. Exposing the mutant DAT to Zn2+ partially reverses the functional deficits observed in the transporter. Lastly, I functionally characterize the effect of two separate gene variations associated with ASD, one in the DAT-interacting protein syntaxin 1 (STX1) and one in the DAT itself. I observe that the STX1 variant is hypo-phosphorylated at a key regulatory residue, resulting in a reduction in the capacity of the DAT to reverse transport DA. In parallel, I observe that the hDAT variant has reduced interactions with STX1, which also results in a reduction in the capacity of the DAT to transport DA in reverse. Collectively, these data outline multiple molecular and structural regulators of the reversal of DAT function and may contribute to a more complete understanding of the etiology of DA-related neuropsychiatric disorders.
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THE NEUROTOXICITY OF TRIMETHYLTIN CHLORIDE (DEPHROTOXICITY, CHOLINERGIC, HIPPOCAMPUS)ROBERTSON, DONALD GLENN. January 1900 (has links)
Thesis (Ph. D.)--University OF MICHIGAN.
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