Browsing by Author "Atwood, Brady"
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Item Adeno-Associated Viral Vectors in Neuroscience Research(Elsevier, 2020-06-12) Haggerty, David L.; Grecco, Gregory G.; Reeves, Kaitlin C.; Atwood, Brady; Pharmacology and Toxicology, School of MedicineAdeno-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.Item Basal ganglia role in learning rewarded actions and executing previously learned choices: Healthy and diseased states(Public Library of Science, 2020-02-10) Mulcahy, Garrett; Atwood, Brady; Kuznetsov, Alexey; Psychiatry, School of MedicineThe 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.Item The Enduring Consequences of Prenatal Opioid Exposure(2022-02) Grecco, Gregory Giovanni; Sheets, Patrick; Atwood, Brady; Yamamoto, Bryan; McKinzie, David; Yoder, KarmenThe opioid crisis has resulted in an unprecedented number of neonates born with prenatal opioid exposure; however, the long-term effects of opioid exposure on offspring behavior and neurodevelopment remain relatively unknown. I developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. PME produced substantial impairments in offspring growth, sensorimotor milestone acquisition, and activity in an open field. Furthermore, these behavioral alterations were associated with significant disruptions in the primary motor cortex (M1). Notably, layer 5 pyramidal neurons of the M1 displayed significantly increased voltage sag which is primarily mediated by HCN1 channels. Interestingly, the α2-adrenergic receptor, a known modulator of HCN1 channels, displayed significantly increased expression in the M1 of PME animals. The locomotor activity in an open field was significantly reduced following in vivo pharmacological activation of the α2-adrenergic receptor with clonidine in PME offspring suggesting this may be therapeutic target for the hyperactivity associated with prenatal exposure to opioids. Previous work has also described an association between prenatal opioid exposure and alterations in opioid reward-related behavior; however, the effect of PME on alcohol reward remains undetermined. Given the widespread accessibility and usage, alcohol represents the most likely addictive substance the growing population of opioid exposed neonates will encounter as they age. I discovered that PME disrupts conditioned preference for alcohol, enhances the locomotor stimulating effects of alcohol, and increases alcohol consumption in a sex-dependent manner. This alcohol-reward phenotype in PME offspring was associated with altered excitatory neurotransmission and disrupted cannabinoid-mediated long-term depression (CB-LTD) in the dorsolateral striatum, an important substrate involved in compulsive drug use. Further work is required to determine the specific inputs at which CB-LTD is disrupted and if restoring this form of plasticity in PME animals prevents the enhanced alcohol addiction phenotype.Item Neuroimaging in Infants with Prenatal Opioid Exposure: Current Evidence, Recent Developments and Targets for Future Research(Elsevier, 2021) Radhakrishnan, Rupa; Grecco, Gregory; Stolze, Kellen; Atwood, Brady; Jennings, Samuel G.; Lien, Izlin Z.; Saykin, Andrew J.; Sadhasivam, Senthilkumar; Radiology and Imaging Sciences, School of MedicinePrenatal opioid exposure (POE) has shown to be a risk factor for adverse long-term cognitive and behavioral outcomes in offspring. However, the neural mechanisms of these outcomes remain poorly understood. While preclinical and human studies suggest that these outcomes may be due to opioid-mediated changes in the fetal and early postnatal brain, other maternal, social, and environmental factors are also shown to play a role. Recent neuroimaging studies reveal brain alterations in children with POE. Early neuroimaging and novel methodology could provide an in vivo mechanistic understanding of opioid mediated alterations in developing brain. However, this is an area of ongoing research. In this review we explore recent imaging developments in POE, with emphasis on the neonatal and infant brain, and highlight some of the challenges of imaging the developing brain in this population. We also highlight evidence from animal models and imaging in older children and youth to understand areas where future research may be targeted in infants with POE.Item The Role of Mediobasal Hypothalamic PACAP in the Control of Body Weight and Metabolism(Oxford University Press, 2021) Bozadjieva-Kramer, Nadejda; Ross, Rachel A.; Johnson, David Q.; Fenselau, Henning; Haggerty, David L.; Atwood, Brady; Lowell, Bradford; Flak, Jonathan N.; Pharmacology and Toxicology, School of MedicineBody energy homeostasis results from balancing energy intake and energy expenditure. Central nervous system administration of pituitary adenylate cyclase activating polypeptide (PACAP) dramatically alters metabolic function, but the physiologic mechanism of this neuropeptide remains poorly defined. PACAP is expressed in the mediobasal hypothalamus (MBH), a brain area essential for energy balance. Ventromedial hypothalamic nucleus (VMN) neurons contain, by far, the largest and most dense population of PACAP in the medial hypothalamus. This region is involved in coordinating the sympathetic nervous system in response to metabolic cues in order to re-establish energy homeostasis. Additionally, the metabolic cue of leptin signaling in the VMN regulates PACAP expression. We hypothesized that PACAP may play a role in the various effector systems of energy homeostasis, and tested its role by using VMN-directed, but MBH encompassing, adeno-associated virus (AAVCre) injections to ablate Adcyap1 (gene coding for PACAP) in mice (Adcyap1MBHKO mice). Adcyap1MBHKO mice rapidly gained body weight and adiposity, becoming hyperinsulinemic and hyperglycemic. Adcyap1MBHKO mice exhibited decreased oxygen consumption (VO2), without changes in activity. These effects appear to be due at least in part to brown adipose tissue (BAT) dysfunction, and we show that PACAP-expressing cells in the MBH can stimulate BAT thermogenesis. While we observed disruption of glucose clearance during hyperinsulinemic/euglycemic clamp studies in obese Adcyap1MBHKO mice, these parameters were normal prior to the onset of obesity. Thus, MBH PACAP plays important roles in the regulation of metabolic rate and energy balance through multiple effector systems on multiple time scales, which highlight the diverse set of functions for PACAP in overall energy homeostasis.Item Spinophilin Cell Type-Specifically Mediates Metabotrophic Glutamate Receptor 5-dependent Excessive Grooming(2022-09) Morris, Cameron W.; Truitt, William; Atwood, Brady; Baucum, Anthony J., II; Ma, Yao-Ying; McKinzie, DavidCompulsive and repetitive behaviors in obsessive-compulsive spectrum disorders (OCSDs) are associated with perturbations in the sensorimotor striatum. Repetitive behaviors are associated with cell type-specific adaptations in striatal direct- and indirect-pathway medium spiny neurons (dMSNs and iMSNs, respectively). Furthermore, preclinical models for understanding OCSDs, such as constitutive knockout of disks large associated protein 3 (SAPAP3), suggest repetitive motor dysfunction, such as excessive grooming, is associated with increased metabotropic glutamate receptor 5 (mGluR5) activity that increases dMSN function relative to iMSNs in the sensorimotor striatum. However, MSN subtype-specific signaling mechanisms that mediate mGluR5-dependent adaptations underlying excessive grooming are not fully understood. Reversible phosphorylation of mGluR5’s C-terminal domain is one mechanism to regulate mGluR5 signaling, however, unlike kinases, promiscuous phosphatases require targeting proteins to shuttle them into contact with their targets. Therefore, phosphatase targeting proteins may be intimately involved in mediating mGluR5-dependent striatal adaptions underlying repetitive behaviors, such as excessive grooming in SAPAP3 deficient mice. Spinophilin, a major striatal postsynaptic phosphatase targeting protein, regulates striatal function, mGluR5 signaling, and forms a protein-protein interaction with SAPAP3 that is increased by mGluR5 co-expression. Therefore, we hypothesized that spinophilin expression in striatal medium spiny neurons mediates mGluR5-dependent excessive grooming. To test this, we used a novel conditional spinophilin mouse line combined with functional, behavioral, and molecular approaches to elucidate spinophilin's MSN subtype-specific contributions to rodent excessive grooming behavior associated with increased mGluR5 function. We found that loss of spinophilin in either MSN subtype abrogated plasticity in the sensorimotor striatum associated with increased mGluR5 function and decreased two models of excessive grooming associated with increased mGluR5 function—SAPAP3 deficient mice and global administration of a mGluR5-specific positive allosteric modulator (VU0360172). Additionally, we found that spinophilin’s protein interaction with mGluR5 correlates with grooming behavior and loss of spinophilin shifts mGluR5 interactions from lipid-raft associated proteins toward postsynaptic density proteins implicated in psychiatric disorders. Collectively, these results identify spinophilin as a novel striatal signaling hub molecule in MSNs that MSN subtype-specifically mediates striatal adaptations associated with repetitive motor dysfunction in psychiatric disorders.Item The Impact of Abstinence from Chronic Alcohol Consumption on the Mouse Striatal Proteome: Sex and Subregion-Specific Differences(2024-10) Duffus, Brittnie-lee Marie; Atwood, Brady; Oblak, Adrian; Mao, Yao-Ying; Baucum, AJ; Fischer, KathrynAlcohol misuse is the third leading preventable cause of death in the world. The World Health Organization currently estimates that 1 in 20 deaths are directly alcohol related. One of the ways in which consuming excessive levels of alcohol can both directly and indirectly affect human mortality and morbidity, is through chronic inflammation. Recently, studies have suggested a link between increased alcohol use and the incidence of neuroinflammatory-related diseases. However, the mechanism in which alcohol potentially influences neuroinflammatory processes is still being uncovered. We implemented an unbiased proteomics exploration of alcohol-induced changes in the striatum, with a specific emphasis on proteins related to inflammation. The striatum is a brain region that is critically involved with the progression of alcohol use disorder. Using mass spectrometry following voluntary alcohol self-administration in mice, we show that distinct protein abundances and signaling pathways in different subregions of the striatum are disrupted by chronic exposure to alcohol compared to water drinking control mice. Further, in mice that were allowed to experience abstinence from alcohol compared to mice that were non-abstinent, the overall proteome and signaling pathways showed additional differences, suggesting that the responses evoked by chronic alcohol exposure are dependent on alcohol use history. To our surprise we did not find that chronic alcohol drinking or abstinence altered protein abundance or pathways associated with inflammation, but rather affected proteins and pathways associated with neurodegeneration and metabolic, cellular organization, protein translation, and molecular transport processes. These outcomes suggest that in this drinking model, alcohol-induced neuroinflammation in the striatum is not a primary outcome controlling altered neurobehavioral function, but these changes are rather mediated by altered striatal neuronal structure and cellular health.Item Vascular amyloid accumulation alters the gabaergic synapse and induces hyperactivity in a model of cerebral amyloid angiopathy(Wiley, 2020-09-10) Cisternas, Pablo; Taylor, Xavier; Perkins, Abigail; Maldonado, Orlando; Allman, Elysabeth; Cordova, Ricardo; Marambio, Yamil; Munoz, Braulio; Pennington, Taylor; Xiang, Shunian; Zhang, Jie; Vidal, Ruben; Atwood, Brady; Lasagna-Reeves, Cristian A.; Anatomy and Cell Biology, School of MedicineCerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. The mechanisms underlying the contribution of CAA to neurodegeneration are not currently understood. Although CAA is highly associated with the accumulation of β‐amyloid (Aβ), other amyloids are known to associate with the vasculature. Alzheimer's disease (AD) is characterized by parenchymal Aβ deposition and intracellular accumulation of tau as neurofibrillary tangles (NFTs), affecting synapses directly, leading to behavioral and physical impairment. CAA increases with age and is present in 70%–97% of individuals with AD. Studies have overwhelmingly focused on the connection between parenchymal amyloid accumulation and synaptotoxicity; thus, the contribution of vascular amyloid is mostly understudied. Here, synaptic alterations induced by vascular amyloid accumulation and their behavioral consequences were characterized using a mouse model of Familial Danish dementia (FDD), a neurodegenerative disease characterized by the accumulation of Danish amyloid (ADan) in the vasculature. The mouse model (Tg‐FDD) displays a hyperactive phenotype that potentially arises from impairment in the GABAergic synapses, as determined by electrophysiological analysis. We demonstrated that the disruption of GABAergic synapse organization causes this impairment and provided evidence that GABAergic synapses are impaired in patients with CAA pathology. Understanding the mechanism that CAA contributes to synaptic dysfunction in AD‐related dementias is of critical importance for developing future therapeutic interventions.