scholarly journals Synapse-specific opioid modulation of thalamo-cortico-striatal circuits

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
William T Birdsong ◽  
Bart C Jongbloets ◽  
Kim A Engeln ◽  
Dong Wang ◽  
Grégory Scherrer ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Pyramidal Neurons ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
Delta Opioid Receptor ◽  
Medium Spiny Neurons ◽  
Spiny Neurons ◽  
Opioid Drugs ◽  
Circuit Components ◽  
Relative Selectivity

The medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of MSNs by MThal inputs. These results suggest that opioid effects on pain and reward may be shaped by the relative selectivity of opioid drugs to the specific circuit components.

scholarly journals Synapse-specific Opioid Modulation of Thalamo-cortico-striatal Circuits

2019 ◽  
Author(s):  
William T. Birdsong ◽  
Bart C. Jongbloets ◽  
Kim A. Engeln ◽  
Dong Wang ◽  
Gregory Scherrer ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Pyramidal Neurons ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
Delta Opioid Receptor ◽  
Medium Spiny Neurons ◽  
Spiny Neurons ◽  
Opioid Drugs ◽  
Circuit Components ◽  
Relative Selectivity

AbstractThe medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of MSNs by MThal inputs. These results suggest that opioid effects on pain and reward may be shaped by the relative selectivity of opioid drugs to the specific circuit components.

scholarly journals Ethanol Disinhibits Dorsolateral Striatal Medium Spiny Neurons Through Activation of A Presynaptic Delta Opioid Receptor

2015 ◽  
Vol 41 (7) ◽  
pp. 1831-1840 ◽  
Author(s):  
Mary H Patton ◽  
Bradley M Roberts ◽  
David M Lovinger ◽  
Brian N Mathur
Keyword(s):  
Opioid Receptor ◽  
Delta Opioid Receptor ◽  
Medium Spiny Neurons ◽  
Spiny Neurons

Altered Neuronal Circuitry

2014 ◽  
Author(s):  
Michael S. Levine ◽  
Elizabeth A. Wang ◽  
Jane Y. Chen ◽  
Carlos Cepeda ◽  
Véronique M. André
Keyword(s):  
Mouse Models ◽  
Pyramidal Neurons ◽  
Therapeutic Interventions ◽  
Disease Stage ◽  
Medium Spiny Neurons ◽  
Behavioral Alterations ◽  
Spiny Neurons ◽  
Cortical Pyramidal Neurons ◽  
Late Stages ◽  
Dopamine Modulation

In mouse models of Huntington’s disease (HD), synaptic alterations in the cerebral cortex and striatum are present before overt behavioral symptoms and cell death. Similarly, in HD patients, it is now widely accepted that early deficits can occur in the absence of neural atrophy or overt motor symptoms. In addition, hyperkinetic movements seen in early stages are followed by hypokinesis in the late stages, indicating that different processes may be affected. In mouse models, such behavioral alterations parallel complex biphasic changes in glutamate-mediated excitatory, γ‎-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission and dopamine modulation in medium spiny neurons of the striatum as well as in cortical pyramidal neurons. The progressive electrophysiologic changes in synaptic communication that occur with disease stage in the cortical and basal ganglia circuits of HD mouse models strongly indicate that therapeutic interventions and strategies in human HD must be targeted to different mechanisms in each stage and to specific subclasses of neurons.

scholarly journals Rhes protein transits from neuron to neuron and facilitates mutant huntingtin spreading in the brain.

2021 ◽  
Author(s):  
Uri Nimrod Ramirez Jarquin ◽  
Manish Sharma ◽  
Neelam Shahani ◽  
Yunqing Li ◽  
Siddaraju Boregowda ◽  
...  
Keyword(s):  
Protein Transport ◽  
Brain Slices ◽  
Brain Regions ◽  
Medium Spiny Neurons ◽  
Striatal Neurons ◽  
Spiny Neurons ◽  
Tunneling Nanotube ◽  
Intact Brain ◽  
Cortical Regions ◽  
The Brain

Rhes (RASD2) is a thyroid hormone-induced gene that regulates striatal motor activity and promotes neurodegeneration in Huntington disease (HD) and tauopathy. Previously, we showed that Rhes moves between cultured striatal neurons and transports the HD protein, polyglutamine-expanded huntingtin (mHTT) via tunneling nanotube (TNT)-like membranous protrusions. However, similar intercellular Rhes transport has not yet been demonstrated in the intact brain. Here, we report that Rhes induces TNT-like protrusions in the striatal medium spiny neurons (MSNs) and transported between dopamine-1 receptor (D1R)-MSNs and D2R-MSNs of intact striatum and organotypic brain slices. Notably, mHTT is robustly transported within the striatum and from the striatum to the cortical areas in the brain, and Rhes deletion diminishes such transport. Moreover, we also found transport of Rhes to the cortical regions following restricted expression in the MSNs of the striatum. Thus, Rhes is a first striatum-enriched protein demonstrated to move and transport mHTT between neurons and brain regions, providing new insights on interneuronal protein transport in the brain.

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 Restoration of KCC2 Membrane Localization in Striatal Dopamine D2 Receptor-Expressing Medium Spiny Neurons Rescues Locomotor Deficits in HIV Tat-Transgenic Mice

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110220
Author(s):  
Aaron J. Barbour ◽  
Sara R. Nass ◽  
Yun K. Hahn ◽  
Kurt F. Hauser ◽  
Pamela E. Knapp
Keyword(s):  
Transgenic Mice ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Brain Regions ◽  
D1 Receptor ◽  
Membrane Localization ◽  
Hippocampal Damage ◽  
Medium Spiny Neurons ◽  
Dopamine D2 ◽  
Spiny Neurons

People infected with HIV (PWH) are highly susceptible to striatal and hippocampal damage. Motor and memory impairments are common among these patients, likely as behavioral manifestations of damage to these brain regions. GABAergic dysfunction from HIV infection and viral proteins such as transactivator of transcription (Tat) have been well documented. We recently demonstrated that the neuron specific Cl− extruder, K+ Cl− cotransporter 2 (KCC2), is diminished after exposure to HIV proteins, including Tat, resulting in disrupted GABAAR-mediated hyperpolarization and inhibition. Here, we utilized doxycycline (DOX)-inducible, GFAP-driven HIV-1 Tat transgenic mice to further explore this phenomenon. After two weeks of Tat expression, we found no changes in hippocampal KCC2 levels, but a significant decrease in the striatum that was associated with hyperlocomotion in the open field assay. We were able to restore KCC2 activity and baseline locomotion with the KCC2 enhancer, CLP290. Additionally, we found that CLP290, whose mechanism of action has yet to be described, acts to restore phosphorylation of serine 940 resulting in increased KCC2 membrane localization. We also examined neuronal subpopulation contributions to the noted effects and found significant differences. Dopamine D2 receptor-expressing medium spiny neurons (MSNs) were selectively vulnerable to Tat-induced KCC2 loss, with no changes observed in dopamine D1 receptor-expressing MSNs. These results suggest that disinhibition/diminished hyperpolarization of dopamine D2 receptor-expressing MSNs can manifest as increased locomotion in this context. They further suggest that KCC2 activity might be a therapeutic target to alleviate motor disturbances related to HIV.

scholarly journals Mushroom spine dynamics in medium spiny neurons of dorsal striatum associated with memory of moderate and intense training

2016 ◽  
Vol 113 (42) ◽  
pp. E6516-E6525 ◽  
Author(s):  
Paola C. Bello-Medina ◽  
Gonzalo Flores ◽  
Gina L. Quirarte ◽  
James L. McGaugh ◽  
Roberto A. Prado Alcalá
Keyword(s):  
Memory Consolidation ◽  
Dorsal Striatum ◽  
Inhibitory Avoidance ◽  
Brain Structures ◽  
Brain Regions ◽  
Medium Spiny Neurons ◽  
Spine Density ◽  
Spiny Neurons ◽  
Intense Training ◽  
Transfer Of Information

A growing body of evidence indicates that treatments that typically impair memory consolidation become ineffective when animals are given intense training. This effect has been obtained by treatments interfering with the neural activity of several brain structures, including the dorsal striatum. The mechanisms that mediate this phenomenon are unknown. One possibility is that intense training promotes the transfer of information derived from the enhanced training to a wider neuronal network. We now report that inhibitory avoidance (IA) induces mushroom spinogenesis in the medium spiny neurons (MSNs) of the dorsal striatum in rats, which is dependent upon the intensity of the foot-shock used for training; that is, the effect is seen only when high-intensity foot-shock is used in training. We also found that the relative density of thin spines was reduced. These changes were evident at 6 h after training and persisted for at least 24 h afterward. Importantly, foot-shock alone did not increase spinogenesis. Spine density in MSNs in the accumbens was also increased, but the increase did not correlate with the associative process involved in IA; rather, it resulted from the administration of the aversive stimulation alone. These findings suggest that mushroom spines of MSNs of the dorsal striatum receive afferent information that is involved in the integrative activity necessary for memory consolidation, and that intense training facilitates transfer of information from the dorsal striatum to other brain regions through augmented spinogenesis.

scholarly journals A Systematic Review of Transcriptional Dysregulation in Huntington’s Disease Studied by RNA Sequencing

2021 ◽  
Vol 12 ◽  
Author(s):  
Bimala Malla ◽  
Xuanzong Guo ◽  
Gökçe Senger ◽  
Zoi Chasapopoulou ◽  
Ferah Yildirim
Keyword(s):  
Gene Expression ◽  
Systematic Review ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Rna Sequencing ◽  
Brain Regions ◽  
Medium Spiny Neurons ◽  
Rna Seq ◽  
Transcriptional Dysregulation ◽  
Spiny Neurons

Huntington’s disease (HD) is a chronic neurodegenerative disorder caused by an expansion of polyglutamine repeats in exon 1 of the Huntingtin gene. Transcriptional dysregulation accompanied by epigenetic alterations is an early and central disease mechanism in HD yet, the exact mechanisms and regulators, and their associated gene expression programs remain incompletely understood. This systematic review investigates genome-wide transcriptional studies that were conducted using RNA sequencing (RNA-seq) technology in HD patients and models. The review protocol was registered at the Open Science Framework (OSF). The biomedical literature and gene expression databases, PubMed and NCBI BioProject, Array Express, European Nucleotide Archive (ENA), European Genome-Phenome Archive (EGA), respectively, were searched using the defined terms specified in the protocol following the PRISMA guidelines. We conducted a complete literature and database search to retrieve all RNA-seq-based gene expression studies in HD published until August 2020, retrieving 288 articles and 237 datasets from PubMed and the databases, respectively. A total of 27 studies meeting the eligibility criteria were included in this review. Collectively, comparative analysis of the datasets revealed frequent genes that are consistently dysregulated in HD. In postmortem brains from HD patients, DNAJB1, HSPA1B and HSPB1 genes were commonly upregulated across all brain regions and cell types except for medium spiny neurons (MSNs) at symptomatic disease stage, and HSPH1 and SAT1 genes were altered in expression in all symptomatic brain datasets, indicating early and sustained changes in the expression of genes related to heat shock response as well as response to misfolded proteins. Specifically in indirect pathway medium spiny neurons (iMSNs), mitochondria related genes were among the top uniquely dysregulated genes. Interestingly, blood from HD patients showed commonly differentially expressed genes with a number of brain regions and cells, with the highest number of overlapping genes with MSNs and BA9 region at symptomatic stage. We also found the differential expression and predicted altered activity of a set of transcription factors and epigenetic regulators, including BCL6, EGR1, FOSL2 and CREBBP, HDAC1, KDM4C, respectively, which may underlie the observed transcriptional changes in HD. Altogether, our work provides a complete overview of the transcriptional studies in HD, and by data synthesis, reveals a number of common and unique gene expression and regulatory changes across different cell and tissue types in HD. These changes could elucidate new insights into molecular mechanisms of differential vulnerability in HD.Systematic Review Registration:https://osf.io/pm3wq

scholarly journals Delta Opioid Receptor Agonist KNT-127 Facilitates Neuroexcitability in the Mouse Infralimbic Cortex via mTOR Pathway to Exert an Antidepressant Effect

2021 ◽  
Author(s):  
Toshinori Yoshioka ◽  
Daisuke Yamada ◽  
Keita Iio ◽  
Hiroshi Nagase ◽  
Akiyoshi Saitoh
Keyword(s):  
Opioid Receptor ◽  
Brain Regions ◽  
Delta Opioid Receptor ◽  
Antidepressant Effect ◽  
Potential Candidate ◽  
Gamma Aminobutyric Acid ◽  
Infralimbic Cortex ◽  
Pi3k Inhibitor Ly294002 ◽  
Postsynaptic Currents ◽  
Phosphorylation Level

Background and Purpose Growing evidence demonstrates that the delta opioid receptor (DOP) is an attractive candidate for novel antidepressants with the potential to exhibit rapid action with few adverse effects. However, the underlying detailed functional mechanism remains elusive. Previously, we reported that the selective DOP agonist, KNT-127, produced robust antidepressant-like effects in the mice forced swimming test (FST). Thus, we attempted to identify the cellular mechanism underlying this effect. Experimental Approach Male ICR mice (4–6 weeks) were used in all experiments. The FST was conducted as a screening model for antidepressants. The phosphorylation level of proteins in specific brain regions was quantified using Western blotting. Glutamate/gamma-aminobutyric acid-dependent postsynaptic currents were detected using whole-cell voltage-clamp recordings. Key Results The selective mTOR inhibitor, rapamycin, and the PI3K inhibitor, LY294002, blocked the antidepressant-like effects of KNT-127 in the FST. KNT-127 increased the phosphorylation level of mTOR signal-related proteins, Akt and p70S6K, in the medial prefrontal cortex. The bilateral microinfusion of KNT-127 in the infralimbic cortex decreased immobility in the FST. The frequency of miniature excitatory postsynaptic currents in the infralimbic cortex increased and that of miniature inhibitory postsynaptic currents decreased with the perfusion of KNT-127, which was blocked by pretreatment with rapamycin. Conclusions and Implications KNT-127 displays antidepressant-like actions through the direct facilitation of neuronal excitability in the mice infralimbic cortex, which is implicated in the PI3K-Akt-mTOR-p70S6K signaling pathway. These results could indicate the first steps in elucidating the complete mechanical functions of DOPs as a potential candidate for novel antidepressants.

scholarly journals Morphology of Human Nucleus Accumbens Neurons Based on the Immunohistochemical Expression of Gad67

2016 ◽  
Vol 17 (4) ◽  
pp. 297-302
Author(s):  
Maja Sazdanovic ◽  
Slobodanka Mitrovic ◽  
Milos Todorovic ◽  
Maja Vulovic ◽  
Dejan Jeremic ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Pyramidal Neurons ◽  
Immunohistochemical Analysis ◽  
Medium Spiny Neurons ◽  
Immunohistochemical Expression ◽  
Spiny Neurons ◽  
Different Types ◽  
Human Brains

Abstract The nucleus accumbens is a part of the ventral striatum along with the caudate nucleus and putamen. The role of the human nucleus accumbens in drug addiction and other psychiatric disorders is of great importance. The aim of this study was to characterize medium spiny neurons in the nucleus accumbens according to the immunohistochemical expression of GAD67. This study was conducted on twenty human brains of both sexes between the ages of 20 and 75. The expression of GAD67 was assessed immunohistochemically, and the characterization of the neurons was based on the shape and size of the soma and the number of impregnated primary dendrites. We showed that neurons of the human nucleus accumbens expressed GAD67 in the neuron soma and in the primary dendrites. An analysis of the cell body morphology revealed the following four different types of neurons: fusiform neurons, fusiform neurons with lateral dendrites, pyramidal neurons and multipolar neurons. An immunohistochemical analysis showed a strong GAD67 expression in GABAergic medium spiny neurons, which could be classifi ed into four different types, and these neurons morphologically correlated with those described by the Golgi study.

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