Computational Investigation of Role of Active Conductances in Information Processing in Striatal Medium Spiny Neurons

2009 ◽  
pp. 891-894 ◽  
Author(s):  
V. Parab ◽  
R. Manchanda
Keyword(s):  
Information Processing ◽  
Medium Spiny Neurons ◽  
Computational Investigation ◽  
Spiny Neurons

scholarly journals Putative role of pharmacogenetics to elucidate the mechanism of tardive dyskinesia in schizophrenia

2019 ◽  
Vol 20 (17) ◽  
pp. 1199-1223 ◽  
Author(s):  
Anton JM Loonen ◽  
Bob Wilffert ◽  
Svetlana A Ivanova
Keyword(s):  
Oxidative Stress ◽  
Tardive Dyskinesia ◽  
Genetic Variants ◽  
Long Term Potentiation ◽  
Specific Gene ◽  
Medium Spiny Neurons ◽  
Spiny Neurons ◽  
Long Term Treatment

Identifying biomarkers which can be used as a diagnostic tool is a major objective of pharmacogenetic studies. Most mental and many neurological disorders have a compiled multifaceted nature, which may be the reason why this endeavor has hitherto not been very successful. This is also true for tardive dyskinesia (TD), an involuntary movement complication of long-term treatment with antipsychotic drugs. The observed associations of specific gene variants with the prevalence and severity of a disorder can also be applied to try to elucidate the pathogenesis of the condition. In this paper, this strategy is used by combining pharmacogenetic knowledge with theories on the possible role of a dysfunction of specific cellular elements of neostriatal parts of the (dorsal) extrapyramidal circuits: various glutamatergic terminals, medium spiny neurons, striatal interneurons and ascending monoaminergic fibers. A peculiar finding is that genetic variants which would be expected to increase the neostriatal dopamine concentration are not associated with the prevalence and severity of TD. Moreover, modifying the sensitivity to glutamatergic long-term potentiation (and excitotoxicity) shows a relationship with levodopa-induced dyskinesia, but not with TD. Contrasting this, TD is associated with genetic variants that modify vulnerability to oxidative stress. Reducing the oxidative stress burden of medium spiny neurons may also be the mechanism behind the protective influence of 5-HT2 receptor antagonists. It is probably worthwhile to discriminate between neostriatal matrix and striosomal compartments when studying the mechanism of TD and between orofacial and limb-truncal components in epidemiological studies.

scholarly journals Cocaine effects on mouse incentive-learning and human addiction are linked to α2 subunit-containing GABAA receptors

2010 ◽  
Vol 107 (5) ◽  
pp. 2289-2294 ◽  
Author(s):  
Claire I. Dixon ◽  
Hannah V. Morris ◽  
Gerome Breen ◽  
Sylvane Desrivieres ◽  
Sarah Jugurnauth ◽  
...  
Keyword(s):  
Behavioral Sensitization ◽  
Binding Pocket ◽  
Receptor Subtype ◽  
Medium Spiny Neurons ◽  
Gabaergic Neurotransmission ◽  
Spiny Neurons ◽  
Benzodiazepine Binding ◽  
Necessary And Sufficient ◽  
The Brain

Because GABAA receptors containing α2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltage-clamp recordings from NAcc medium spiny neurons of mice with α2 gene deletion showed reduced synaptic GABAA receptor-mediated responses. Behaviorally, the deletion abolished cocaine’s ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of α2-GABAA receptors (α2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 15-4513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In α2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of α2−GABAA receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction, we found specific markers and haplotypes of the GABRA2 gene to be associated with human cocaine addiction.

scholarly journals Dysregulated Information Processing by Medium Spiny Neurons in Striatum of Freely Behaving Mouse Models of Huntington's Disease

2008 ◽  
Vol 100 (4) ◽  
pp. 2205-2216 ◽  
Author(s):  
Benjamin R. Miller ◽  
Adam G. Walker ◽  
Anand S. Shah ◽  
Scott J. Barton ◽  
George V. Rebec
Keyword(s):  
Information Processing ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Population Level ◽  
Medium Spiny Neurons ◽  
Processing Scheme ◽  
Background Strain ◽  
Spiny Neurons ◽  
Freely Behaving

Huntington's disease (HD) is an autosomal dominant condition that compromises behavioral output. Dysfunction of medium spiny neurons (MSNs), which are the sole output system of the striatum, is thought to underlie HD pathophysiology. What is not known is how HD alters MSN information processing during behavior, which likely drives the HD behavioral phenotype. We recorded from populations of MSNs in two freely behaving and symptomatic HD mouse models: R6/2 transgenics are based on a C57BL/6J*CBA/J background and show robust behavioral symptoms, whereas knock-in (KI) mice have a 129sv background and express relatively mild behavioral signs. At the single-unit level, we found that the MSN firing rate was elevated in R6/2 but not in KI mice compared with their respective wild-type (WT) controls. In contrast, burst activity, which corresponds to periods of high-frequency firing, was altered in both HD models compared with WT. At the population level, we found that correlated firing between pairs of MSNs was a prominent feature in WT that was reduced in both HD models. Similarly, coincident bursts, which are bursts between pairs of neurons that overlap in time and occur more often in pairs of MSNs that exhibit correlated firing, were decreased in HD mice. Our results indicate an important role in both bursting and correlated burst firing for information processing in MSNs. Dysregulation of this processing scheme, moreover, is a key component of HD pathophysiology regardless of the severity of HD symptoms, genetic construct, and background strain of the mouse models.

scholarly journals Distinct role of nucleus accumbens D2-MSN projections to ventral pallidum in different phases of motivated behavior

2020 ◽  
Author(s):  
Carina Soares-Cunha ◽  
Raquel Correia ◽  
Ana Verónica Domingues ◽  
Bárbara Coimbra ◽  
Nivaldo AP de Vasconcelos ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Behavioral Effect ◽  
Ventral Pallidum ◽  
Medium Spiny Neurons ◽  
Motivated Behavior ◽  
Spiny Neurons ◽  
Reward Delivery ◽  
Instrumental Task ◽  
Motivated Behaviors

AbstractThe nucleus accumbens (NAc) is a key region in motivated behaviors. NAc medium spiny neurons (MSNs) are divided into those expressing dopamine receptor D1 or D2. Classically, D1- and D2-MSNs have been described as having opposing roles in reinforcement but recent evidence suggests a more complex role for D2-MSNs.Here we show that optogenetic modulation of D2-MSN to ventral pallidum (VP) projections during different stages of motivated behavior has contrasting effects in motivation. Activation of D2-MSN-VP projections during a reward-predicting cue results in increased motivational drive, whereas activation at reward delivery results in decreased motivation; optical inhibition has the opposite behavioral effect. In addition, in a free choice instrumental task, animals prefer the lever that originates one pellet in opposition to pellet plus D2-MSN-VP optogenetic activation, and vice versa for optogenetic inhibition.In summary, D2-MSN-VP projections play different (and even opposing) roles in distinct phases of motivated behavior.

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