Genetic Selection for Alcohol Preference in Mice Alters Dorsal Striatum Neurotransmission

Fritz, Brandon M.; Muñoz, Braulio; Atwood, Brady K.

doi:10.1111/acer.14187

Cited by 9 publications

(19 citation statements)

References 51 publications

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“…Brain slices were collected for electrophysiology as previously described 31 , 32 . Mice were deeply anesthetized via isoflurane and euthanized via decapitation.…”

Section: Methodsmentioning

confidence: 99%

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Input-selective adenosine A1 receptor-mediated synaptic depression of excitatory transmission in dorsal striatum

Fritz

Yin

Atwood

2021

Sci Rep

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The medial (DMS) and lateral (DLS) dorsal striatum differentially drive goal-directed and habitual/compulsive behaviors, respectively, and are implicated in a variety of neuropsychiatric disorders. These subregions receive distinct inputs from cortical and thalamic regions which uniquely determine dorsal striatal activity and function. Adenosine A1 receptors (A1Rs) are prolific within striatum and regulate excitatory glutamate transmission. Thus, A1Rs may have regionally-specific effects on neuroadaptive processes which may ultimately influence striatally-mediated behaviors. The occurrence of A1R-driven plasticity at specific excitatory inputs to dorsal striatum is currently unknown. To better understand how A1Rs may influence these behaviors, we first sought to understand how A1Rs modulate these distinct inputs. We evaluated A1R-mediated inhibition of cortico- and thalamostriatal transmission using in vitro whole-cell, patch clamp slice electrophysiology recordings in medium spiny neurons from both the DLS and DMS of C57BL/6J mice in conjunction with optogenetic approaches. In addition, conditional A1R KO mice lacking A1Rs at specific striatal inputs to DMS and DLS were generated to directly determine the role of these presynaptic A1Rs on the measured electrophysiological responses. Activation of presynaptic A1Rs produced significant and prolonged synaptic depression (A1R-SD) of excitatory transmission in the both the DLS and DMS of male and female animals. Our findings indicate that A1R-SD at corticostriatal and thalamostriatal inputs to DLS can be additive and that A1R-SD in DMS occurs primarily at thalamostriatal inputs. These findings advance the field’s understanding of the functional roles of A1Rs in striatum and implicate their potential contribution to neuropsychiatric diseases.

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“…Brain slices were collected for electrophysiology as previously described 31 , 32 . Mice were deeply anesthetized via isoflurane and euthanized via decapitation.…”

Section: Methodsmentioning

confidence: 99%

“…Our general slice electrophysiology protocol followed our previously described methodology 31 , 32 . Whole-cell voltage clamp recordings were made using a Multiclamp 700B amplifier and Digidata 1550B (Molecular Devices, San Jose, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Input-selective adenosine A1 receptor-mediated synaptic depression of excitatory transmission in dorsal striatum

Fritz

Yin

Atwood

2021

Sci Rep

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“…All experiments were performed similar to our previous studies with some experiment-specific modifications 5,25,47,48 . These methods are described in brief below.…”

Section: Methodsmentioning

confidence: 99%

Synapse-specific expression of mu opioid receptor long-term depression in the dorsomedial striatum

Muñoz

Haggerty

Atwood

2020

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The dorsal striatum is a brain region involved in action control, with dorsomedial striatum (DMS) mediating goal-directed actions and dorsolateral striatum (DLS) mediating habitual actions. Presynaptic long-term synaptic depression (LTD) plasticity at glutamatergic inputs to dorsal striatum mediates many dorsal striatum-dependent behaviors and disruption of LTD influences action control. Our previous work identified mu opioid receptors (MORs) as mediators of synapse-specific forms of synaptic depression at a number of different DLS synapses. We demonstrated that anterior insular cortex inputs are the sole inputs that express alcohol-sensitive MOR-mediated LTD (mOP-LTD) in DLS. Here, we explore mOP-LTD in DMS using mouse brain slice electrophysiology. We found that contrary to DLS, DMS mOP-LTD is induced by activation of MORs at inputs from both anterior cingulate and medial prefrontal cortices as well as at basolateral amygdala inputs and striatal cholinergic interneuron synapses on to DMS medium spiny neurons, suggesting that MOR synaptic plasticity in DMS is less synapse-specific than in DLS. Furthermore, only mOP-LTD at cortical inputs was sensitive to alcohol's deleterious effects. These results suggest that alcohol-induced neuroadaptations are differentially expressed in a synapse-specific manner and could be playing a role in alterations of goal-directed and habitual behaviors. Alcohol exposure, both acute and chronic, leads to changes in brain function from the genetic level through to changes in cellular function and network alterations 1-4. A common outcome of alcohol-induced cellular adaptations are changes in synaptic plasticity that likely underlie altered neurocircuit function 5,6. One component of alcohol use disorder is a transition from flexible goal-directed alcohol use to more habitual or compulsive use and this is paralleled by a transition in the activity between the dorsomedial (DMS) and the dorsolateral striatum (DLS) subregions of the dorsal striatum 7,8. The dorsal striatum is the input nucleus of the basal ganglia and is a key region involve in goal-directed learning and habit formation, where the DMS has a primary role in the control of outcome-driven behavior and learning and the DLS is important for stimulus-driven behavior and learning 7-12. As alcohol use shifts from being outcome-driven to becoming more stimulus-driven and compulsive in nature during alcohol use disorder development, the balance of action control moves from DMS to DLS 7,8,13. The specialized roles in action control of these two dorsal striatal subregions suggest that the neural circuitry of these two areas are differentially affected by ethanol during the development of alcohol use disorders 14-16. GABAergic medium spiny neurons (MSNs) are the striatal output neurons and comprise 95% of dorsal striatal neurons 17. MSNs receive glutamatergic inputs from cortex, thalamus, basolateral amygdala, and cholinergic interneurons (CINs) 18-20. Despite the similarities in neuronal composition and synapse types, the unique inne...

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“…Therefore, understanding differences in basal functioning between the DS of HAP and LAP mice is likely relevant to a number of the alcohol-related phenotypes observed in these animals. Our laboratory recently examined the electrophysiological properties of DS GABAergic medium spiny neurons (MSNs), which account for ~ 95% of the cells in the this region (Tepper et al, 2007), of alcohol-naïve HAP and LAP mice (Fritz et al, 2019). MSNs in the DS were significantly more excitable in Note: Abbreviation: MCC, maximal clique centrality; AR, abundance ratio.…”

Section: Discussionmentioning

confidence: 99%

“…Although sex effects on alcohol drinking exist in HAP and LAP mice, these sex effects are present in rodents, in general, suggesting sex is not specifically related to the divergent alcohol consumption and related phenotypes associated with HAP and LAP mice (Oberlin et al, 2011). Furthermore, our prior work assessing DS neurotransmission demonstrated relatively consistent effects across sexes for each line (Fritz et al, 2019). Volcano plots revealing distributions for the RNA-sequencing, proteomic, and phosphoproteomic analysis can be found in Figure S2.…”

Section: Overview Of Analysesmentioning

confidence: 96%

A multi‐omic analysis of the dorsal striatum in an animal model of divergent genetic risk for alcohol use disorder

Grecco

Haggerty

Doud

et al. 2020

Journal of Neurochemistry

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The development of selectively bred high and low alcohol-preferring mice (HAP and LAP, respectively) has allowed for an assessment of the polygenetic risk for pathological alcohol consumption and phenotypes associated with alcohol use disorder (AUD). Accumulating evidence indicates that the dorsal striatum (DS) is a central node in the neurocircuitry underlying addictive processes. Therefore, knowledge of differential gene, protein, and phosphorylated protein expression in the DS of HAP and LAP mice may foster new insights into how aberrant DS functioning may contribute to AUD-related phenotypes. To begin to elucidate these basal differences, a complementary and integrated analysis of DS tissue from alcohol-naïve male and female HAP and LAP mice was performed using RNA sequencing, quantitative proteomics, and phosphoproteomics. These datasets were subjected to a thorough analysis of gene ontology, pathway enrichment, and hub gene assessment. Analyses identified 2,108, 390, and 521 significant differentially expressed genes, proteins, and phosphopeptides, respectively between the two lines. Network analyses revealed an enrichment in the differential expression of genes, proteins, and phosphorylated proteins connected to cellular organization, cytoskeletal protein binding, and pathways involved in synaptic transmission and functioning. These findings suggest that the selective breeding to generate HAP and LAP mice may lead to a rearrangement of synaptic architecture which could alter DS neurotransmission and plasticity differentially between mouse lines.These rich datasets will serve as an excellent resource to inform future studies on how inherited differences in gene, protein, and phosphorylated protein expression contribute to AUD-related phenotypes.

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Genetic Selection for Alcohol Preference in Mice Alters Dorsal Striatum Neurotransmission

Cited by 9 publications

References 51 publications

Input-selective adenosine A1 receptor-mediated synaptic depression of excitatory transmission in dorsal striatum

Input-selective adenosine A1 receptor-mediated synaptic depression of excitatory transmission in dorsal striatum

Synapse-specific expression of mu opioid receptor long-term depression in the dorsomedial striatum

A multi‐omic analysis of the dorsal striatum in an animal model of divergent genetic risk for alcohol use disorder

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