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Item ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis(Springer, 2024) Chhabra, Kavaljit H.; Bathina, Siresha; Faniyan, Tumininu S.; Samuel, Dennis J.; Raza, Muhammad Ummear; de Souza Cordeiro, Leticia Maria; Di Prisco, Gonzalo Viana; Atwood, Brady K.; Robles, Jorge; Bainbridge, Lauren; Davis, Autumn; Pharmacology and Toxicology, School of MedicineAims/hypothesis: The brain is a major consumer of glucose as an energy source and regulates systemic glucose as well as energy balance. Although glucose transporters such as GLUT2 and sodium-glucose cotransporter 2 (SGLT2) are known to regulate glucose homeostasis and metabolism, the identity of a receptor that binds glucose to activate glucose signalling pathways in the brain is unknown. In this study, we aimed to discover a glucose receptor in the mouse hypothalamus. Methods: Here we used a high molecular mass glucose-biotin polymer to enrich glucose-bound mouse hypothalamic neurons through cell-based affinity chromatography. We then subjected the enriched neurons to proteomic analyses and identified adhesion G-protein coupled receptor 1 (ADGRL1) as a top candidate for a glucose receptor. We validated glucose-ADGRL1 interactions using CHO cells stably expressing human ADGRL1 and ligand-receptor binding assays. We generated and determined the phenotype of global Adgrl1-knockout mice and hypothalamus-specific Adgrl1-deficient mice. We measured the variables related to glucose and energy homeostasis in these mice. We also generated an Adgrl1Cre mouse model to investigate the role of ADGRL1 in sensing glucose using electrophysiology. Results: Adgrl1 is highly expressed in the ventromedial nucleus of the hypothalamus (VMH) in mice. Lack of Adgrl1 in the VMH in mice caused fasting hyperinsulinaemia, enhanced glucose-stimulated insulin secretion and insulin resistance. In addition, the Adgrl1-deficient mice had impaired feeding responses to glucose and fasting coupled with abnormal glucose sensing and decreased physical activity before development of obesity and hyperglycaemia. In female mice, ovariectomy was necessary to reveal the contribution of ADGRL1 to energy and glucose homeostasis. Conclusions/interpretation: Altogether, our findings demonstrate that ADGRL1 binds glucose and is involved in energy as well as glucose homeostasis in a sex-dependent manner. Targeting ADGRL1 may introduce a new class of drugs for the treatment of type 2 diabetes and obesity.Item Alcohol exposure disrupts mu opioid receptor-mediated long-term depression at insular cortex inputs to dorsolateral striatum(Nature Publishing group, 2018-04-03) Muñoz, Braulio; Fritz, Brandon M.; Yin, Fuqin; Atwood, Brady K.; Psychiatry, School of MedicineDrugs of abuse, including alcohol, ablate the expression of specific forms of long-term synaptic depression (LTD) at glutamatergic synapses in dorsal striatum (DS), a brain region involved in goal-directed and habitual behaviors. This loss of LTD is associated with altered DS-dependent behavior. Given the role of the µ-opioid receptor (MOR) in behavioral responding for alcohol, we explored the impact of alcohol on various forms of MOR-mediated synaptic depression that we find are differentially expressed at specific DS synapses. Corticostriatal MOR-mediated LTD (mOP-LTD) in the dorsolateral striatum occurs exclusively at inputs from anterior insular cortex and is selectively disrupted by in vivo alcohol exposure. Alcohol has no effect on corticostriatal mOP-LTD in dorsomedial striatum, thalamostriatal MOR-mediated short-term depression, or mOP-LTD of cholinergic interneuron-driven glutamate release. Disrupted mOP-LTD at anterior insular cortex–dorsolateral striatum synapses may therefore be a key mechanism of alcohol-induced neuroadaptations involved in the development of alcohol use disorders., µ-opioid receptors (MOR) are known to modulate the reward effects of drugs of abuse, and MOR activation induces long-term depression (LTD) at striatal synapses. Here the authors show that alcohol exposure disrupts MOR-induced LTD only at specific cortical inputs to the striatum.Item Alterations of brain microstructures in a mouse model of prenatal opioid exposure detected by diffusion MRI(Springer Nature, 2022-10-12) Grecco, Gregory G.; Shahid, Syed Salman; Atwood, Brady K.; Wu, Yu‑Chien; Pharmacology and Toxicology, School of MedicineGrowing opioid use among pregnant women is fueling a crisis of infants born with prenatal opioid exposure. A large body of research has been devoted to studying the management of opioid withdrawal during the neonatal period in these infants, but less substantive work has explored the long-term impact of prenatal opioid exposure on neurodevelopment. Using a translationally relevant mouse model of prenatal methadone exposure (PME), the aim of the study is to investigate the cerebral microstructural differences between the mice with PME and prenatal saline exposure (PSE). The brains of eight-week-old male offspring with either PME (n = 15) or PSE (n = 15) were imaged using high resolution in-vivo diffusion magnetic resonance imaging on a 9.4 Tesla small animal scanner. Brain microstructure was characterized using diffusion tensor imaging (DTI) and Bingham neurite orientation dispersion and density imaging (Bingham-NODDI). Voxel-based analysis (VBA) was performed using the calculated microstructural parametric maps. The VBA showed significant (p < 0.05) bilateral alterations in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), orientation dispersion index (ODI) and dispersion anisotropy index (DAI) across several cortical and subcortical regions, compared to PSE. Particularly, in PME offspring, FA, MD and AD were significantly higher in the hippocampus, dorsal amygdala, thalamus, septal nuclei, dorsal striatum and nucleus accumbens. These DTI-based results suggest widespread bilateral microstructural alterations across cortical and subcortical regions in PME offspring. Consistent with the observations in DTI, Bingham-NODDI derived ODI exhibited significant reduction in PME offspring within the hippocampus, dorsal striatum and cortex. NODDI-based results further suggest reduction in dendritic arborization in PME offspring across multiple cortical and subcortical regions. To our best knowledge, this is the first study of prenatal opioid exposure to examine microstructural organization in vivo. Our findings demonstrate perturbed microstructural complexity in cortical and subcortical regions persisting into early adulthood which could interfere with critical neurodevelopmental processes in individuals with prenatal opioid exposure.Item Bassoon contributes to tau-seed propagation and neurotoxicity(Springer Nature, 2022) Martinez, Pablo; Patel, Henika; You, Yanwen; Jury, Nur; Perkins, Abigail; Lee-Gosselin, Audrey; Taylor, Xavier; You, Yingjian; Di Prisco, Gonzalo Viana; Huang, Xiaoqing; Dutta, Sayan; Wijeratne, Aruna B.; Redding-Ochoa, Javier; Shahid, Syed Salman; Codocedo, Juan F.; Min, Sehong; Landreth, Gary E.; Mosley, Amber L.; Wu, Yu-Chien; McKinzie, David L.; Rochet, Jean-Christophe; Zhang, Jie; Atwood, Brady K.; Troncoso, Juan; Lasagna-Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of MedicineTau aggregation is a defining histopathological feature of Alzheimer’s disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer’s disease and progressive supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies.Item Cell-Specific Spinophilin Function Underlying Striatal Motor Adaptations Associated with Amphetamine-Induced Behavioral Sensitization(2022-07) Watkins, Darryl Shumon; Yamamoto, Bryan K.; Atwood, Brady K.; Baucum, Anthony J. II; Hudmon, Andy; Logrip, Marian L.Striatal-mediated pathological disease-states such as Obsessive-Compulsive Disorder (OCD), Parkinson’s Disease (PD), and psychostimulant drug addiction/abuse are coupled with distinct motor movement abnormalities. In addition, these disorders are associated with perturbed synaptic transmission. Proper synaptic transmission is critical for maintaining neuronal communication. Furthermore, in many striatal-dependent disease-states, the principle striatal neurons, medium spiny neurons (MSNs), exhibit differential perturbations in downstream signaling. Signal transduction pathways that are localized to the glutamatergic post-synaptic density (PSD) of GABAergic MSNs regulate protein phosphorylation in a tightly controlled manner. Alterations in the control of this phosphorylation in striatal MSNs are observed in myriad striatal pathological diseasestates and can give rise to perturbations in synaptic transmission. While serine/threonine kinases obtain substrate specificity, in part, by phosphorylating specific consensus sites, serine/threonine phosphatases such as protein phosphatase 1 (PP1) are much more promiscuous. To obtain substrate selectivity, PP1 associates with targeting proteins. The major targeting protein for PP1 in the PSD of striatal dendritic spines is spinophilin. Spinophilin not only binds PP1, but also concurrently interacts with myriad synaptic proteins. Interestingly, dopamine depletion, an animal model of PD, modulates spinophilin protein-protein interactions in the striatum. However, spinophilin function on basal striatal-mediated motor behaviors such as the rotarod or under hyperdopaminergic states such as those observed following psychostimulant-induced behavioral sensitization are less well characterized. To elucidate spinophilin function more specifically, we have generated multiple transgenic animals that allow for cell type-specific loss of spinophilin as well as cell-specific interrogation of spinophilin protein interactions. Here, I report the functional role of spinophilin in regulating striatal mediated motor behaviors and functional changes associated with amphetamine-induced locomotor sensitization. In addition, we define changes in spinophilin protein-protein interactions that may mediate these behavioral changes. Furthermore, global loss of spinophilin abrogates amphetamine-induced sensitization and plays a critical role in striatal motor learning and performance. The data suggest that the striatal spinophilin protein interactome is upregulated in MSNs following psychostimulant administration. In addition, loss of spinophilin changes protein expression in myriad psychostimulant-mediated striatal adaptations. Taken together the data suggests that spinophilin’s protein-protein interactions in the striatum are obligate for appropriate striatal mediated motor function.Item Characterizing Effects of Sphingosine-1-Phosphate Receptor 1 Activation in Subtypes of Central Amygdala Neurons and Effects of Prenatal Methadone Exposure on Motor Cortex Neurons in Mice(2021-04) Mork, Briana E.; Atwood, Brady K.; Sheets, Patrick L.; Cummins, Theodore R.; Fehrenbacher, Jill C.; McKinzie, David L.Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates a wide spectrum of biological processes including apoptosis, immune response and inflammation. S1P receptor (S1PR) ligands have been utilized as an effective immunosuppressant, treatment in multiple sclerosis and studied as a treatment for pain. The primary cellular response to S1P is thought to be elicited through S1PR type 1 (S1PR1). My first goal was to understand how S1PR1 signaling affects neuronal excitability in the central amygdala (CeA), a supraspinal node of the descending pain pathway. The CeA is made up of a heterogenous population of neurons which form complex local and long-range circuits. The central lateral amygdala (CeL) consists of two major populations of inhibitory neurons identified by expression of the peptides somatostatin (Sst) and protein kinase Cδ (PKCδ). Sst neurons have been shown to maintain control over local circuits within the CeL and play a critical role in pain modulation. I utilized transgenic breeding strategies to fluorescently label Sst-expressing CeL neurons for whole-cell electrophysiology in acute brain slice. This strategy allowed me to study the effects of S1PR1 agonist SEW2871 and S1PR1 antagonist NIBR on the cellular physiology of CeL Sst neurons. My findings reveal intrinsically distinct subtypes of CeL Sst neurons that are uniquely affected by S1PR1 activation, which may have implications for how S1P alters supraspinal pain pathways. My second goal was to assess the physiology of motor cortex neurons in mice exposed to prenatal methadone. Methadone is a synthetic μ-opioid agonist used for opioid maintenance therapy and chronic pain management. Methadone treatment for opioid use disorder in pregnant women can result in structural changes within the brain of their offspring causing and developmental delays to their children, including poorer motor performance. Using a mouse model of prenatal methadone exposure (PME), whole-cell electrophysiology, and analyses of cellular morphology, I elucidated the effects of PME on primary motor cortex (M1) output layer 5 (L5) neurons, which encompass the major cortical output pathway for motor control. My findings provide the first evidence that PME disrupts neuronal firing, subthreshold properties, and strength of local inputs onto M1 L5 neurons in prepubescent mice.Item Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer's disease in a mouse model of Aβ amyloidosis(American Association for the Advancement of Science, 2021-11) Karahan, Hande; Smith, Daniel C.; Kim, Byungwook; Dabin, Luke C.; Al-Amin, Md Mamun; Wijeratne, H.R. Sagara; Pennington, Taylor; di Prisco, Gonzalo Viana; McCord, Brianne; Lin, Peter Bor-Chian; Li, Yuxin; Peng, Junmin; Oblak, Adrian L.; Chu, Shaoyou; Atwood, Brady K.; Kim, Jungsu; Medical and Molecular Genetics, School of MedicineRecently, 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.Item Dissecting the Effects of Different Pain Modalities and Oxycodone on Prodynorphin Expressing Neurons in the Mouse Prelimbic Cortex(2022-11) Zhou, Shudi; Atwood, Brady K.; Sheets, Patrick L.; McKinzie, David L.; Truitt, William A.; Jin, XiaomingCurrently, changes to endogenous opioid circuits in various pain modalities, including surgical and neuropathic pain, remain unclear. Dynorphin, which is released by prodynorphin-expressing neurons (Pdyn+ neurons), is the endogenous opioid ligand to kappa opioid receptors (KOR). Moreover, a recent study has shown an increase in prodynorphin (Pdyn) mRNA expression in the prelimbic cortex (PL) in a mouse model of chronic pain. However, alterations in the activity of PL Pdyn-expressing neurons (PLPdyn+ neurons) in postoperative and chronic pain have never been explored. Firstly, I found that the population of PLPdyn+ neurons consists of both pyramidal and inhibitory subtypes. Secondly, I found that one day after surgical incision of the mouse hind paw, the excitability of pyramidal PLPdyn+ neurons was increased in both male and female mice, while the excitability of inhibitory PLPdyn+ neurons was unchanged. However, when postoperative pain behavior subsided, inhibitory PLPdyn+ neurons were hyperexcitable in male mice, while pyramidal PLPdyn+ neurons were hypoexcitable in female mice. Lastly, I dissected electrophysiological changes to PLPdyn+ neurons in the spared nerve injury (SNI) model of chronic neuropathic pain. At both early and late stages of SNI pain development, increased excitability of pyramidal PLPdyn+ neurons was detected in both male and female mice. However, in both male and female mice, the excitability of inhibitory PLPdyn+ neurons decreased 3 days after SNI but was conversely increased when measured 14 days after SNI. My findings suggest that different subtypes of PLPdyn+ neurons manifest distinct alterations in the development of different pain modalities in a sex-specific manner.Item Effects of prenatal opioid exposure on synaptic adaptations and behaviors across development(Elsevier, 2023) Simmons, Sarah C.; Grecco, Greg G.; Atwood, Brady K.; Nugent, Fereshteh S.; Pharmacology and Toxicology, School of MedicineIn this review, we focus on prenatal opioid exposure (POE) given the significant concern for the mental health outcomes of children with parents affected by opioid use disorder (OUD) in the view of the current opioid crisis. We highlight some of the less explored interactions between developmental age and sex on synaptic plasticity and associated behavioral outcomes in preclinical POE research. We begin with an overview of the rich literature on hippocampal related behaviors and plasticity across POE exposure paradigms. We then discuss recent work on reward circuit dysregulation following POE. Additional risk factors such as early life stress (ELS) could further influence synaptic and behavioral outcomes of POE. Therefore, we include an overview on the use of preclinical ELS models where ELS exposure during key critical developmental periods confers considerable vulnerability to addiction and stress psychopathology. Here, we hope to highlight the similarity between POE and ELS on development and maintenance of opioid-induced plasticity and altered opioid-related behaviors where similar enduring plasticity in reward circuits may occur. We conclude the review with some of the limitations that should be considered in future investigations. This article is part of the Special Issue on 'Opioid-induced addiction'.Item Genetic Selection for Alcohol Preference in Mice Alters Dorsal Striatum Neurotransmission(Wiley, 2019-11) Fritz, Brandon M.; Munoz, Braulio; Atwood, Brady K.; Pharmacology and Toxicology, School of MedicineBackground 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.