scholarly journals Proteomic Analysis of the Spinophilin Interactome in Rodent Striatum Following Psychostimulant Sensitization

Proteomes ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 53 ◽  
Author(s):  
Darryl Watkins ◽  
Jason True ◽  
Amber Mosley ◽  
Anthony Baucum
Keyword(s):  
Drugs Of Abuse ◽  
Specific Activity ◽  
Cell Types ◽  
Medium Spiny Neurons ◽  
Indirect Pathway ◽  
Motor Programs ◽  
Post Translational Modifications ◽  
Spiny Neurons ◽  
Dopamine Signaling ◽  
Specific Regulation

Glutamatergic projections from the cortex and dopaminergic projections from the substantia nigra or ventral tegmental area synapse on dendritic spines of specific GABAergic medium spiny neurons (MSNs) in the striatum. Direct pathway MSNs (dMSNs) are positively coupled to protein kinase A (PKA) signaling and activation of these neurons enhance specific motor programs whereas indirect pathway MSNs (iMSNs) are negatively coupled to PKA and inhibit competing motor programs. An imbalance in the activity of these two programs is observed following increased dopamine signaling associated with exposure to psychostimulant drugs of abuse. Alterations in MSN signaling are mediated by changes in MSN protein post-translational modifications, including phosphorylation. Whereas direct changes in specific kinases, such as PKA, regulate different effects observed in the two MSN populations, alterations in the specific activity of serine/threonine phosphatases, such as protein phosphatase 1 (PP1) are less well known. This lack of knowledge is due, in part, to unknown, cell-specific changes in PP1 targeting proteins. Spinophilin is the major PP1-targeting protein in striatal postsynaptic densities. Using proteomics and immunoblotting approaches along with a novel transgenic mouse expressing hemagglutainin (HA)-tagged spinophilin in dMSNs and iMSNs, we have uncovered cell-specific regulation of the spinophilin interactome following a sensitizing regimen of amphetamine. These data suggest regulation of spinophilin interactions in specific MSN cell types and may give novel insight into putative cell-specific, phosphatase-dependent signaling pathways associated with psychostimulants.

scholarly journals Transcriptional Diversity of Medium Spiny Neurons in the Primate Striatum

2020 ◽  
Author(s):  
Jing He ◽  
Michael Kleyman ◽  
Jianjiao Chen ◽  
Aydin Alikaya ◽  
Kathryn M. Rothenhoefer ◽  
...  
Keyword(s):  
Dorsal Striatum ◽  
Cell Types ◽  
Specific Information ◽  
Medium Spiny Neurons ◽  
Striatal Neurons ◽  
Cell Type ◽  
Indirect Pathway ◽  
Spiny Neurons ◽  
Single Nucleus ◽  
Cell Type Specific

AbstractThe striatum is the neural interface between dopamine reward signals and cortico-basal ganglia circuits responsible for value assignments, decisions, and actions. Medium spiny neurons (MSNs) make up the vast majority of striatal neurons and are traditionally classified as two distinct types: direct- and indirect-pathway MSNs. The direct- and indirect-pathway model has been useful for understanding some aspects of striatal functions, but it accounts for neither the anatomical heterogeneity, nor the functional diversity of the striatum. Here, we use single nucleus RNA-sequencing and Fluorescent In-Situ Hybridization to explore MSN diversity in the Rhesus macaque striatum. We identified MSN subtypes that correspond to the major subdivisions of the striatum. These include dorsal striatum subtypes associated with striosome and matrix compartments, as well as ventral striatum subtypes associated with the shell of the nucleus accumbens. We also describe a cell type that is anatomically restricted to “Neurochemically Unique Domains in the Accumbens and Putamen (NUDAPs)”. Together, these results help to advance nonhuman primate studies into the genomics era. The identified cell types provide a comprehensive blueprint for investigating cell type-specific information processing, and the differentially expressed genes lay a foundation for achieving cell type-specific transgenesis in the primate striatum.

scholarly journals Differential Protein Expression in Striatal D1- and D2-Dopamine Receptor-Expressing Medium Spiny Neurons

Proteomes ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 27
Author(s):  
M. Shahid Mansuri ◽  
Gang Peng ◽  
Rashaun S. Wilson ◽  
TuKiet T. Lam ◽  
Hongyu Zhao ◽  
...  
Keyword(s):  
Drugs Of Abuse ◽  
Affinity Purification ◽  
Neuronal Cell ◽  
Principal Component ◽  
Cell Types ◽  
Differentially Expressed ◽  
Cellular Heterogeneity ◽  
Specific Cell ◽  
Medium Spiny Neurons ◽  
Spiny Neurons

Many neurological disorders and diseases including drug addiction are associated with specific neuronal cell types in the brain. The striatum, a region that plays a critically important role in the development of addictive drug-related behavior, provides a good example of the cellular heterogeneity challenges associated with analyses of specific neuronal cell types. Such studies are needed to identify the adaptive changes in neuroproteomic signaling that occur in response to diseases such as addiction. The striatum contains two major cell types, D1 and D2 type dopaminoceptive medium spiny neurons (MSNs), whose cell bodies and processes are intermingled throughout this region. Since little is known about the proteomes of these two neuronal cell populations, we have begun to address this challenge by using fluorescence-activated nuclear sorting (FANS) to isolate nuclei-containing fractions from striatum from D1 and D2 “Translating Ribosome Affinity Purification” (TRAP) mice. This approach enabled us to devise and implement a robust and reproducible workflow for preparing samples from specific MSN cell types for mass spectrometry analyses. These analyses quantified at least 685 proteins in each of four biological replicates of 50 K sorted nuclei from two D1 mice/replicate and from each of four biological replicates of 50 K sorted nuclei from two D2 mice/replicate. Proteome analyses identified 87 proteins that were differentially expressed in D1 versus D2 MSN nuclei and principal component analysis (PCA) of these proteins separated the 8 biological replicates into specific cell types. Central network analysis of the 87 differentially expressed proteins identified Hnrnpd and Hnmpa2b1 in D1 and Cct2 and Cct7 in D2 as potential central interactors. This workflow can now be used to improve our understanding of many neurological diseases including characterizing the short and long-term impact of drugs of abuse on the proteomes of these two dopaminoceptive neuronal populations.

scholarly journals Sex-specific involvement of indirect-pathway medium spiny neurons in behavioral alteration of 16p11.2 hemi-deletion mouse model

IBRO Reports ◽  
2019 ◽  
Vol 6 ◽  
pp. S494
Author(s):  
Jaekyoon Kim ◽  
Christopher Angelakos ◽  
Joseph Linch ◽  
Sarah Ferri ◽  
Ted Abel
Keyword(s):  
Mouse Model ◽  
Medium Spiny Neurons ◽  
Indirect Pathway ◽  
Behavioral Alteration ◽  
Spiny Neurons

scholarly journals Levodopa-Induced Dyskinesia Is Related to Indirect Pathway Medium Spiny Neuron Excitotoxicity: A Hypothesis Based on an Unexpected Finding

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Svetlana A. Ivanova ◽  
Anton J. M. Loonen
Keyword(s):  
Oxidative Stress ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Age Of Onset ◽  
Medium Spiny Neuron ◽  
Synaptic Membrane ◽  
Medium Spiny Neurons ◽  
Unexpected Finding ◽  
Indirect Pathway ◽  
Spiny Neurons

A serendipitous pharmacogenetic finding links the vulnerability to developing levodopa-induced dyskinesia to the age of onset of Huntington’s disease. Huntington’s disease is caused by a polyglutamate expansion of the protein huntingtin. Aberrant huntingtin is less capable of binding to a member of membrane-associated guanylate kinase family (MAGUKs): postsynaptic density- (PSD-) 95. This leaves more PSD-95 available to stabilize NR2B subunit carrying NMDA receptors in the synaptic membrane. This results in increased excitotoxicity for which particularly striatal medium spiny neurons from the indirect extrapyramidal pathway are sensitive. In Parkinson’s disease the sensitivity for excitotoxicity is related to increased oxidative stress due to genetically determined abnormal metabolism of dopamine or related products. This probably also increases the sensitivity of medium spiny neurons for exogenous levodopa. Particularly the combination of increased oxidative stress due to aberrant dopamine metabolism, increased vulnerability to NMDA induced excitotoxicity, and the particular sensitivity of indirect pathway medium spiny neurons for this excitotoxicity may explain the observed increased prevalence of levodopa-induced dyskinesia.

scholarly journals Binge Alcohol Drinking Alters Synaptic Processing of Executive and Emotional Information in Core Nucleus Accumbens Medium Spiny Neurons

2021 ◽  
Vol 15 ◽  
Author(s):  
Jenya Kolpakova ◽  
Vincent van der Vinne ◽  
Pablo Giménez-Gómez ◽  
Timmy Le ◽  
In-Jee You ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Alcohol Drinking ◽  
Drugs Of Abuse ◽  
Alcohol Exposure ◽  
Medium Spiny Neurons ◽  
Dependent Manner ◽  
Emotional Information ◽  
Core Nucleus ◽  
Spiny Neurons

The nucleus accumbens (NAc) is a forebrain region mediating the positive-reinforcing properties of drugs of abuse, including alcohol. It receives glutamatergic projections from multiple forebrain and limbic regions such as the prefrontal cortex (PFCx) and basolateral amygdala (BLA), respectively. However, it is unknown how NAc medium spiny neurons (MSNs) integrate PFCx and BLA inputs, and how this integration is affected by alcohol exposure. Because progress has been hampered by the inability to independently stimulate different pathways, we implemented a dual wavelength optogenetic approach to selectively and independently stimulate PFCx and BLA NAc inputs within the same brain slice. This approach functionally demonstrates that PFCx and BLA inputs synapse onto the same MSNs where they reciprocally inhibit each other pre-synaptically in a strict time-dependent manner. In alcohol-naïve mice, this temporal gating of BLA-inputs by PFCx afferents is stronger than the reverse, revealing that MSNs prioritize high-order executive processes information from the PFCx. Importantly, binge alcohol drinking alters this reciprocal inhibition by unilaterally strengthening BLA inhibition of PFCx inputs. In line with this observation, we demonstrate that in vivo optogenetic stimulation of the BLA, but not PFCx, blocks binge alcohol drinking escalation in mice. Overall, our results identify NAc MSNs as a key integrator of executive and emotional information and show that this integration is dysregulated during binge alcohol drinking.

scholarly journals Selective D2 and D3 receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens

2018 ◽  
Author(s):  
Daniel F. Manvich ◽  
Alyssa K. Petko ◽  
Rachel C. Branco ◽  
Stephanie L. Foster ◽  
Kirsten A. Porter-Stransky ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Drugs Of Abuse ◽  
Ex Vivo ◽  
Medium Spiny Neurons ◽  
D3 Receptor ◽  
Receptor Antagonists ◽  
Fast Scan Cyclic Voltammetry ◽  
Spiny Neurons ◽  
Cocaine Responses ◽  
Da Release

AbstractBackgroundThe D3 receptor (D3R) has emerged as a promising pharmacotherapeutic target for the treatment of several diseases including schizophrenia, Parkinson’s disease, and substance use disorders. However, studies investigating the modulatory impact of D3R antagonism on dopamine neurotransmission or the effects drugs of abuse have produced mixed results, in part because D3R-targeted compounds often also interact with D2 receptors (D2R). The purpose of this study was to compare the consequences of selective D2R or D3R antagonism on the behavioral effects of cocaine in mice, and to identify the neurobiological mechanisms underlying their modulatory effects.MethodsWe characterized the effects of selective D2R or D3R antagonism in mice on 1) basal and cocaine-induced locomotor activity, 2) presynaptic dopamine release and clearance in the nucleus accumbens using ex vivo fast scan cyclic voltammetry, and 3) dopamine-mediated signaling in D1-expressing and D2-expressing medium spiny neurons using ex vivo electrophysiology.ResultsPretreatment with the selective D2R antagonist L-741,626 attenuated, while pretreatment with the selective D3R antagonist PG01037 enhanced, the locomotor-activating effects of acute and repeated cocaine administration. While both antagonists potentiated cocaine-induced increases in presynaptic DA release, D3R blockade uniquely facilitated DA-mediated excitation of D1-expressing medium spiny neurons in the nucleus accumbens.ConclusionsSelective D3R antagonism potentiates the behavioral-stimulant effects of cocaine in mice, an effect that is in direct opposition to that produced by selective D2R antagonism or nonselective D2-like receptor antagonists, likely by facilitating D1-mediated excitation in the nucleus accumbens. These findings provide important insights into the neuropharmacological actions of D3R antagonists on mesolimbic dopamine neurotransmission.

Unique Properties of R-Type Calcium Currents in Neocortical and Neostriatal Neurons

2000 ◽  
Vol 84 (5) ◽  
pp. 2225-2236 ◽  
Author(s):  
Robert C. Foehring ◽  
Paul G. Mermelstein ◽  
Wen-Jie Song ◽  
Sasha Ulrich ◽  
D. James Surmeier
Keyword(s):  
Pyramidal Neurons ◽  
Cell Types ◽  
Calcium Currents ◽  
Medium Spiny Neurons ◽  
Cell Type ◽  
Channel Current ◽  
Spiny Neurons ◽  
Deactivation Kinetics ◽  
Whole Cell Recordings ◽  
Neocortical Pyramidal Neurons

Whole cell recordings from acutely dissociated neocortical pyramidal neurons and striatal medium spiny neurons exhibited a calcium-channel current resistant to known blockers of L-, N-, and P/Q-type Ca2+ channels. These R-type currents were characterized as high-voltage–activated (HVA) by their rapid deactivation kinetics, half-activation and half-inactivation voltages, and sensitivity to depolarized holding potentials. In both cell types, the R-type current activated at potentials relatively negative to other HVA currents in the same cell type and inactivated rapidly compared with the other HVA currents. The main difference between cell types was that R-type currents in neocortical pyramidal neurons inactivated at more negative potentials than R-type currents in medium spiny neurons. Ni2+ sensitivity was not diagnostic for R-type currents in either cell type. Single-cell RT-PCR revealed that both cell types expressed the α1E mRNA, consistent with this subunit being associated with the R-type current.

scholarly journals Transitions between sleep and feeding states in rat ventral striatum neurons

2012 ◽  
Vol 108 (6) ◽  
pp. 1739-1751 ◽  
Author(s):  
Luis A. Tellez ◽  
Isaac O. Perez ◽  
Sidney A. Simon ◽  
Ranier Gutierrez
Keyword(s):  
Neural Networks ◽  
Ventral Striatum ◽  
Cell Types ◽  
Projection Neurons ◽  
Inhibitory Interneurons ◽  
Medium Spiny Neurons ◽  
Spiny Neurons ◽  
Fast Spiking ◽  
First Time

Neurons in the nucleus accumbens (NAc) have been shown to participate in several behavioral states, including feeding and sleep. However, it is not known if the same neuron participates in both states and, if so, how similar are the responses. In addition, since the NAc contains several cell types, it is not known if each type participates in the transitions associated with feeding and sleep. Such knowledge is important for understanding the interaction between two different neural networks. For these reasons we recorded ensembles of NAc neurons while individual rats volitionally transitioned between the following states: awake and goal directed, feeding, quiet-awake, and sleeping. We found that during both feeding and sleep states, the same neurons could increase their activity (be activated) or decrease their activity (be inactivated) by feeding and/or during sleep, thus indicating that the vast majority of NAc neurons integrate sleep and feeding signals arising from spatially distinct neural networks. In contrast, a smaller population was modulated by only one of the states. For the majority of neurons in either state, we found that when one population was excited, the other was inhibited, suggesting that they act as a local circuit. Classification of neurons into putative interneurons [fast-spiking interneurons (pFSI) and choline acetyltransferase interneurons (pChAT)] and projection medium spiny neurons (pMSN) showed that all three types are modulated by transitions to and from feeding and sleep states. These results show, for the first time, that in the NAc, those putative inhibitory interneurons respond similarly to pMSN projection neurons and demonstrate interactions between NAc networks involved in sleep and feeding.

New insights into the mechanism of drug-induced dyskinesia

CNS Spectrums ◽  
2012 ◽  
Vol 18 (1) ◽  
pp. 15-20 ◽  
Author(s):  
Anton J. M. Loonen ◽  
Svetlana A. Ivanova
Keyword(s):  
Antipsychotic Drugs ◽  
Term Treatment ◽  
Medium Spiny Neurons ◽  
Indirect Pathway ◽  
Drug Induced ◽  
Disease Research ◽  
Spiny Neurons ◽  
Long Term Treatment ◽  
Cortical Circuit

Dyskinesia is an extrapyramidal movement disorder characterized by involuntary, repetitive, irregular motions that affect the mouth and face and/or the limbs and trunk. Tardive dyskinesia (TD) is a well-known complication of long-term treatment with antipsychotic drugs. Dyskinesia is also induced with levodopa, a treatment for Parkinson's disease, and it occurs spontaneously as a symptom of Huntington's disease. Research on the pathogenesis of TD has focused on a dysfunction of either the dopaminergic or serotonergic system. However, recent evidence has suggested that we should focus on the possible damage of GABAergic medium spiny neurons (MSNs). MSNs are the first station in the cortico-striato-thalamo-cortical circuit that regulates the amplitude and velocity of movements. Two pathways can be distinguished in this circuit: a direct pathway, which increases movements (hyperkinesia), and an indirect pathway, which decreases movements (hypokinesia). Both pathways are activated by glutamatergic corticostriatal neurons. Here, we discuss some evidence that supports the hypothesis that indirect pathway MSNs are damaged in dyskinesia.

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