Basal ganglia role in learning rewarded actions and executing previously learned choices: Healthy and diseased states

The basal ganglia (BG) is a collection of nuclei located deep beneath the cerebral cortex that is involved in learning and selection of rewarded actions. Here, we analyzed BG mechanisms that enable these functions. We implemented a rate model of a BG-thalamo-cortical loop and simulated its performance in a standard action selection task. We have shown that potentiation of corticostriatal synapses enables learning of a rewarded option. However, these synapses became redundant later as direct connections between prefrontal and premotor cortices (PFC-PMC) were potentiated by Hebbian learning. After we switched the reward to the previously unrewarded option (reversal), the BG was again responsible for switching to the new option. Due to the potentiated direct cortical connections, the system was biased to the previously rewarded choice, and establishing the new choice required a greater number of trials. Guided by physiological research, we then modified our model to reproduce pathological states of mild Parkinson's and Huntington's diseases. We found that in the Parkinsonian state PMC activity levels become extremely variable, which is caused by oscillations arising in the BG-thalamo-cortical loop. The model reproduced severe impairment of learning and predicted that this is caused by these oscillations as well as a reduced reward prediction signal. In the Huntington state, the potentiation of the PFC-PMC connections produced better learning, but altered BG output disrupted expression of the rewarded choices. This resulted in random switching between rewarded and unrewarded choices resembling an exploratory phase that never ended. Along with other computational studies, our results further reconcile the apparent contradiction between the critical involvement of the BG in execution of previously learned actions and yet no impairment of these actions after BG output is ablated by lesions or deep brain stimulation. We predict that the cortico-BG-thalamo-cortical loop conforms to previously learned choice in healthy conditions, but impedes those choices in disease states

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

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

Genetic Selection for Alcohol Preference in Mice Alters Dorsal Striatum Neurotransmission

Background Although it is widely acknowledged that the risk of developing an alcohol use disorder (AUD) is strongly influenced by genetic factors, very little is known about how this genetic predisposition may alter neurotransmission in a way that promotes AUD susceptibility. The dorsal striatum has garnered increased attention as a brain region of interest in AUD development given its significant roles in goal‐directed and habitual behavior. Methods In the present work, dorsal striatal neurotransmission parameters were measured in preclinical mouse models of high and low AUD risk. We performed brain slice whole‐cell patch clamp electrophysiological recordings from medium spiny neurons (MSNs) in the dorsomedial (DMS) and dorsolateral (DLS) striatum of naïve adult male and female selectively bred high‐ and low‐alcohol–preferring lines of mice (HAP and LAP). Results We found that MSNs of HAP mice were significantly more excitable than those of LAP mice, specifically in the DLS. Additionally, the frequencies of spontaneous glutamate‐ and GABA‐mediated currents were both elevated in HAP mice relative to LAP mice in both dorsal striatal subregions, whereas amplitude differences were more variable between lines and subregions. AMPAR/NMDAR current ratios were significantly lower in HAP mice in both DLS and DMS. Conclusions Collectively, these results suggest that genetic predisposition for high or low alcohol consumption produces significantly different basal functional states within both DLS and DMS which may be important factors in the behavioral phenotypes of HAP and LAP mice

Adeno-Associated Viral Vectors in Neuroscience Research

Adeno-associated viral vectors (AAVs) are increasingly useful preclinical tools in neuroscience research studies for interrogating cellular and neurocircuit functions and mapping brain connectivity. Clinically, AAVs are showing increasing promise as viable candidates for treating multiple neurological diseases. Here, we briefly review the utility of AAVs in mapping neurocircuits, manipulating neuronal function and gene expression, and activity labeling in preclinical research studies as well as AAV-based gene therapies for diseases of the nervous system. This review highlights the vast potential that AAVs have for transformative research and therapeutics in the neurosciences

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

The opioid crisis has resulted in an unprecedented number of neonates born with prenatal opioid exposure (POE); however, the long-term effects of POE on offspring behavior and neurodevelopment remain relatively unknown. The advantages and disadvantages of the various preclinical POE models developed over the last several decades are discussed in the context of clinical and translational relevance. Although considerable and important variability exists among preclinical models of POE, the examination of these preclinical models has revealed that opioid exposure during the prenatal period contributes to maladaptive behavioral development as offspring mature including an altered responsiveness to rewarding drugs and increased pain response. The present review summarizes key findings demonstrating the impact of POE on offspring drug self-administration (SA), drug consumption, the reinforcing properties of drugs, drug tolerance, and other reward-related behaviors such as hypersensitivity to pain. Potential underlying molecular mechanisms which may contribute to this enhanced addictive phenotype in POE offspring are further discussed with special attention given to key brain regions associated with reward including the striatum, prefrontal cortex (PFC), ventral tegmental area (VTA), hippocampus, and amygdala. Improvements in preclinical models and further areas of study are also identified which may advance the translational value of findings and help address the growing problem of POE in clinical populations

A High-fat, High-sugar ‘Western’ Diet Alters Dorsal Striatal Glutamate, Opioid, and Dopamine Transmission in Mice

Understanding neuroadaptations involved in obesity is critical for developing new approaches to treatment. Diet-induced neuroadaptations within the dorsal striatum have the capacity to drive excessive food seeking and consumption. Five-week-old C57BL/6J mice consumed a high-fat, high-sugar ‘western diet’ (WD) or a control ‘standard diet’ (SD) for 16 weeks. Weight gain, glucose tolerance, and insulin tolerance were measured to confirm an obese-like state. Following these 16 weeks, electrophysiological recordings were made from medium spiny neurons (MSNs) in the medial (DMS) and lateral (DLS) portions of dorsal striatum to evaluate diet effects on neuronal excitability and synaptic plasticity. In addition, fast-scan cyclic voltammetry evaluated dopamine transmission in these areas. WD mice gained significantly more weight and consumed more calories than SD mice and demonstrated impaired glucose tolerance. Electrophysiology data revealed that MSNs from WD mice demonstrated increased AMPA-to-NMDA receptor current ratio and prolonged spontaneous glutamate-mediated currents, specifically in the DLS. Evoked dopamine release was also significantly greater and reuptake slower in both subregions of WD striatum. Finally, dorsal striatal MSNs from WD mice were significantly less likely to demonstrate mu-opioid receptor-mediated synaptic plasticity. Neuronal excitability and GABAergic transmission were unaffected by diet in either striatal subregion. Our results demonstrate that a high-fat, high-sugar diet alters facets of glutamate, dopamine, and opioid signaling within the dorsal striatum, with some subregion specificity. These alterations within a brain area known to play a role in food motivation/consumption and habitual behavior are highly relevant for the clinical condition of obesity and its treatment

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

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

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

Variants in the microglial receptor TREM2 confer risk for multiple neurodegenerative diseases. However, it remains unknown how this receptor functions on microglia to modulate these diverse neuropathologies. To understand the role of TREM2 on microglia more generally, we investigated changes in microglial function in Trem2−/− mice. We found that loss of TREM2 impairs normal neurodevelopment, resulting in reduced synapse number across the cortex and hippocampus in 1-month-old mice. This reduction in synapse number was not due directly to alterations in interactions between microglia and synapses. Rather, TREM2 was required for microglia to limit synaptic engulfment by astrocytes during development. While these changes were largely normalized later in adulthood, high fat diet administration was sufficient to reinitiate TREM2-dependent modulation of synapse loss. Together, this identifies a novel role for microglia in instructing synaptic pruning by astrocytes to broadly regulate appropriate synaptic refinement, and suggests novel candidate mechanisms for how TREM2 and microglia could influence synaptic loss in brain injury and disease

Mu opioid receptors on vGluT2‐expressing glutamatergic neurons modulate opioid reward

The role of Mu opioid receptor (MOR)-mediated regulation of GABA transmission in opioid reward is well established. Much less is known about MOR-mediated regulation of glutamate transmission in the brain and how this relates to drug reward. We previously found that MORs inhibit glutamate transmission at synapses that express the Type 2 vesicular glutamate transporter (vGluT2). We created a transgenic mouse that lacks MORs in vGluT2-expressing neurons (MORflox-vGluT2cre) to demonstrate that MORs on the vGluT2 neurons themselves mediate this synaptic inhibition. We then explored the role of MORs in vGluT2-expressing neurons in opioid-related behaviors. In tests of conditioned place preference, MORflox-vGluT2cre mice did not acquire place preference for a low dose of the opioid, oxycodone, but displayed conditioned place aversion at a higher dose, whereas control mice displayed preference for both doses. In an oral consumption assessment, these mice consumed less oxycodone and had reduced preference for oxycodone compared with controls. MORflox-vGluT2cre mice also failed to show oxycodone-induced locomotor stimulation. These mice displayed baseline withdrawal-like responses following the development of oxycodone dependence that were not seen in littermate controls. In addition, withdrawal-like responses in these mice did not increase following treatment with the opioid antagonist, naloxone. However, other MOR-mediated behaviors were unaffected, including oxycodone-induced analgesia. These data reveal that MOR-mediated regulation of glutamate transmission is a critical component of opioid reward

Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer's disease in a mouse model of Aβ amyloidosis

Recently, large-scale human genetics studies identified a rare coding variant in the ABI3 gene that is associated with an increased risk of Alzheimer’s disease (AD). However, pathways by which ABI3 contributes to the pathogenesis of AD are unknown. To address this question, we determined whether loss of ABI3 function affects pathological features of AD in the 5XFAD mouse model. We demonstrate that the deletion of Abi3 locus significantly increases amyloid β (Aβ) accumulation and decreases microglia clustering around the plaques. Furthermore, long-term potentiation is impaired in 5XFAD;Abi3 knockout (“Abi3−/−”) mice. Moreover, we identified marked changes in the proportion of microglia subpopulations in Abi3−/− mice using a single-cell RNA sequencing approach. Mechanistic studies demonstrate that Abi3 knockdown in microglia impairs migration and phagocytosis. Together, our study provides the first in vivo functional evidence that loss of ABI3 function may increase the risk of developing AD by affecting Aβ accumulation and neuroinflammation