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

Abstract

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...

Prenatal Opioid Exposure Enhances Responsiveness to Future Drug Reward and Alters Sensitivity to Pain: A Review of Preclinical Models and Contributing Mechanisms

“…Similar hypothesis-generating insights may develop from the large literature base studying the effects of rewarding substances on the brain of mature animals. For instance, multiple drugs of abuse disrupt LTD in the striatum of mature rodents which contributes to addiction related-behaviors ( Xia et al, 2006 ; Kasanetz et al, 2010 ; Nazzaro et al, 2012 ; DePoy et al, 2013 ; Atwood et al, 2014 ; Abburi et al, 2016 ; Muñoz et al, 2018 , 2020 ). Future studies may consider investigating disrupted striatal plasticity among other common neuroadaptations in mature animals of chronic drug exposure as potential mechanisms for the enhanced reward phenotype in models of POE.…”

Spatiotemporal Up-Regulation of Mu Opioid Receptor 1 in Striatum of Mouse Model of Huntington’s Disease Differentially Affecting Caudal and Striosomal Regions

“…Thus our work, albeit in a mouse model of HD, suggests that, as in Parkinson’s disease, changes in MOR1 expression levels could occur as a consequence of dopamine dysregulation. Besides, MOR1s are expressed not only in striatal projection neurons but also in axon terminals in the striatum originating in the neocortex and the thalamus (Birdsong et al, 2019 ; Muñoz et al, 2020 ). Therefore, MOR1 up-regulation might occur in these presynaptic terminals to suppress excessive excitation of these presynaptic neurons.…”

HCN1 channels mediate mu opioid receptor long-term depression at insular cortex inputs to the dorsal striatum

“…The opioid system is expressed throughout the brain(Le Merrer, Becker, Befort, & Kieffer, 2009) and promotes synaptic plasticity in many brain regions(Bao et al, 2007; Dacher & Nugent, 2011a, 2011b; Drake, Chavkin, & Milner, 2007; Iremonger & Bains, 2009), including the dorsal striatum (DS)(Atwood, Kupferschmidt, & Lovinger, 2014; Hawes, Salinas, Lovinger, & Blackwell, 2017; Lovinger, 2010; Munoz, Fritz, Yin, & Atwood, 2018; Muñoz, Haggerty, & Atwood, 2020). The DS is the primary input nucleus of the basal ganglia and can be subdivided in two structures: the dorsomedial striatum (DMS), which controls goal-directed learning, and the dorsolateral striatum (DLS), which regulates habit formation(Burton, Nakamura, & Roesch, 2015; Corbit & Janak, 2016; Hilário & Costa, 2008; Lovinger, 2010; O’Tousa & Grahame, 2014).…”

“…Our previous work established that mu opioid receptor (MOR) activation induces long-term synaptic depression (MOR-LTD) or short-term depression (MOR-STD) of glutamate release in both the DLS and DMS(Atwood, Kupferschmidt, et al, 2014; Munoz et al, 2018; Muñoz et al, 2020). We demonstrated that MOR-mediated synaptic inhibition is expressed at multiple DS synapses (cortical, thalamic, amygdala and cholinergic), but only a subset of corticostriatal synapses expressed MOR-LTD(Atwood, Kupferschmidt, et al, 2014) that was disrupted by prior in vivo ethanol exposure(Munoz et al, 2018; Muñoz et al, 2020).…”