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      Corticostriatal Dysfunction in Huntington’s Disease: The Basics

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          Abstract

          The main input to the basal ganglia, the corticostriatal pathway, shows some of the earliest signs of neuropathology in Huntington’s disease (HD), an inherited neurodegenerative condition that typically strikes in mid-life with progressively deteriorating cognitive, emotional, and motor symptoms. Although an effective treatment remains elusive, research on transgenic animal models has implicated dysregulation of glutamate (Glu), the excitatory amino acid released by corticostriatal neurons, in HD onset. Abnormalities in the control of Glu transmission at the level of postsynaptic receptors and Glu transport proteins play a critical role in the loss of information flow through downstream circuits that set the stage for the HD behavioral phenotype. Parallel but less-well characterized changes in dopamine (DA), a key modulator of Glu activation, ensure further deficits in neuronal communication throughout the basal ganglia. Continued analysis of corticostriatal Glu transmission and its modulation by DA, including analysis at the neurobehavioral level in transgenic models, is likely to be an effective strategy in the pursuit of HD therapeutics.

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          Most cited references109

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          Diversity of astrocyte functions and phenotypes in neural circuits.

          Astrocytes tile the entire CNS. They are vital for neural circuit function, but have traditionally been viewed as simple, homogenous cells that serve the same essential supportive roles everywhere. Here, we summarize breakthroughs that instead indicate that astrocytes represent a population of complex and functionally diverse cells. Physiological diversity of astrocytes is apparent between different brain circuits and microcircuits, and individual astrocytes display diverse signaling in subcellular compartments. With respect to injury and disease, astrocytes undergo diverse phenotypic changes that may be protective or causative with regard to pathology in a context-dependent manner. These new insights herald the concept that astrocytes represent a diverse population of genetically tractable cells that mediate neural circuit-specific roles in health and disease.
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            Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum.

            Clinical manifestations in diseases affecting the dopamine system include deficits in emotional, cognitive, and motor function. Although the parallel organization of specific corticostriatal pathways is well documented, mechanisms by which dopamine might integrate information across different cortical/basal ganglia circuits are less well understood. We analyzed a collection of retrograde and anterograde tracing studies to understand how the striatonigrostriatal (SNS) subcircuit directs information flow between ventromedial (limbic), central (associative), and dorsolateral (motor) striatal regions. When viewed as a whole, the ventromedial striatum projects to a wide range of the dopamine cells and receives a relatively small dopamine input. In contrast, the dorsolateral striatum (DLS) receives input from a broad expanse of dopamine cells and has a confined input to the substantia nigra (SN). The central striatum (CS) receives input from and projects to a relatively wide range of the SN. The SNS projection from each striatal region contains three substantia nigra components: a dorsal group of nigrostriatal projecting cells, a central region containing both nigrostriatal projecting cells and its reciprocal striatonigral terminal fields, and a ventral region that receives a specific striatonigral projection but does not contain its reciprocal nigrostriatal projection. Examination of results from multiple tracing experiments simultaneously demonstrates an interface between different striatal regions via the midbrain dopamine cells that forms an ascending spiral between regions. The shell influences the core, the core influences the central striatum, and the central striatum influences the dorsolateral striatum. This anatomical arrangement creates a hierarchy of information flow and provides an anatomical basis for the limbic/cognitive/motor interface via the ventral midbrain.
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              D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons.

              Dopamine shapes a wide variety of psychomotor functions. This is mainly accomplished by modulating cortical and thalamic glutamatergic signals impinging upon principal medium spiny neurons (MSNs) of the striatum. Several lines of evidence suggest that dopamine D1 receptor signaling enhances dendritic excitability and glutamatergic signaling in striatonigral MSNs, whereas D2 receptor signaling exerts the opposite effect in striatopallidal MSNs. The functional antagonism between these two major striatal dopamine receptors extends to the regulation of synaptic plasticity. Recent studies, using transgenic mice in which cells express D1 and D2 receptors, have uncovered unappreciated differences between MSNs that shape glutamatergic signaling and the influence of DA on synaptic plasticity. These studies have also shown that long-term alterations in dopamine signaling produce profound and cell-type-specific reshaping of corticostriatal connectivity and function.
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                Author and article information

                Contributors
                Journal
                Front Hum Neurosci
                Front Hum Neurosci
                Front. Hum. Neurosci.
                Frontiers in Human Neuroscience
                Frontiers Media S.A.
                1662-5161
                28 June 2016
                2016
                : 10
                : 317
                Affiliations
                [1]Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana University Bloomington, IN, USA
                Author notes

                Edited by: Daniela S. Andres, Swiss Federal Institute of Technology (ETH) and University of Zurich (UZH), Switzerland

                Reviewed by: Carlos Cepeda, David Geffen School of Medicine at the University of California, Los Angeles, USA; Eugene A. Kiyatkin, National Institute on Drug Abuse, USA

                *Correspondence: Kendra D. Bunner kdbunner@ 123456indiana.edu ; George V. Rebec rebec@ 123456indiana.edu
                Article
                10.3389/fnhum.2016.00317
                4924423
                27445757
                717e5592-b88c-4b3a-8209-cfd501094027
                Copyright © 2016 Bunner and Rebec.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 21 April 2016
                : 13 June 2016
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 138, Pages: 12, Words: 10951
                Funding
                Funded by: CHDI Foundation 10.13039/100005725
                Award ID: A-7449
                Categories
                Neuroscience
                Review

                Neurosciences
                glutamate,dopamine,cortiostriatal circuitry,electrophysiology,huntington’s disease
                Neurosciences
                glutamate, dopamine, cortiostriatal circuitry, electrophysiology, huntington’s disease

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