IU Indianapolis ScholarWorks :: Browsing by Author "Grecco, Gregory G."

Browsing by Author "Grecco, Gregory G."

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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 Medicine
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.
Alterations in White Matter Microstructure and Connectivity in Young Adults with Alcohol Use Disorder
(Wiley, 2019) Chumin, Evgeny J.; Grecco, Gregory G.; Dzemidzic, Mario; Cheng, Hu; Finn, Peter; Sporns, Olaf; Newman, Sharlene D.; Yoder, Karmen K.; Radiology and Imaging Sciences, School of Medicine
Background Magnetic resonance imaging (MRI) studies have shown differences in volume and structure in the brains of individuals with alcohol use disorder (AUD). Most research has focused on neuropathological effects of alcohol that appear after years of chronic alcohol misuse. However, few studies have investigated white matter (WM) microstructure and diffusion MRI‐based (DWI) connectivity during early stages of AUD. Therefore, the goal of this work was to investigate WM integrity and structural connectivity in emerging adulthood AUD subjects using both conventional DWI metrics and a novel connectomics approach. Methods Twenty‐two AUD and eighteen controls (CON) underwent anatomical and diffusion MRI. Outcome measures were scalar diffusion metrics and structural network connectomes. Tract Based Spatial Statistics was used to investigate group differences in diffusion measures. Structural connectomes were used as input into a community structure procedure to obtain a co‐classification index matrix (an indicator of community association strength) for each subject. Differences in co‐classification and structural connectivity (indexed by streamline density) were assessed via the Network Based Statistics Toolbox. Results AUD had higher FA values throughout the major WM tracts, but also had lower FA values in WM tracts in the cerebellum and right insula (pTFCE < 0.05). Mean diffusivity was generally lower in the AUD group (pTFCE < 0.05). AUD had lower co‐classification of nodes between ventral attention and default mode networks, and higher co‐classification between nodes of visual, default mode, and somatomotor networks. Additionally, AUD had higher fiber density between an adjacent pair of nodes within the default mode network. Conclusion Our results indicate that emerging adulthood AUD subjects may have differential patterns of FA and distinct differences in structural connectomes compared to CON. These data suggest that such alterations in microstructure and structural connectivity may uniquely characterize early stages of AUD and/or a predisposition for development of AUD.
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 Medicine
Growing 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.
Anterior Cingulate Cortex Metabolites and White Matter Microstructure: A Multimodal Study of Emergent Alcohol Use Disorder
(Springer, 2021) Grecco, Gregory G.; Chumin, Evgeny J.; Dzemidzic, Mario; Cheng, Hu; Finn, Peter; Newman, Sharlene; Dydak, Ulrike; Yoder, Karmen K.; Radiology and Imaging Sciences, School of Medicine
Multimodal imaging is increasingly used to address neuropathology associated with alcohol use disorder (AUD). Few studies have investigated relationships between metabolite concentrations and white matter (WM) integrity; currently, there are no such data in AUD. In this preliminary study, we used complementary neuroimaging techniques, magnetic resonance spectroscopy (MRS), and diffusion weighted imaging (DWI), to study AUD neurophysiology. We tested for relationships between metabolites in the dorsal anterior cingulate cortex (dACC) and adjacent WM microstructure in young adult AUD and control (CON) subjects. Sixteen AUD and fourteen CON underwent whole-brain DWI and MRS of the dACC. Outcomes were dACC metabolites, and diffusion tensor metrics of dACC-adjacent WM. Multiple linear regression terms included WM region, group, and region × group for prediction of dACC metabolites. dACC myo-inositol was positively correlated with axial diffusivity in the left anterior corona radiata (p < 0.0001) in CON but not AUD (group effect: p < 0.001; region × group: p < 0.001; Bonferroni-corrected). In the bilateral anterior corona radiata and right genu of the corpus callosum, glutamate was negatively related to mean diffusivity in AUD, but not CON subjects (all model terms: p < 0.05, uncorrected). In AUD subjects, dACC glutamate was negatively correlated with AUD symptom severity. This is likely the first integrative study of cortical metabolites and WM integrity in young individuals with AUD. Differential relationships between dACC metabolites and adjacent WM tract integrity in AUD could represent early consequences of hazardous drinking, and/or novel biomarkers of early-stage AUD. Additional studies are required to replicate these findings, and to determine the behavioral relevance of these results.
Mu opioid receptors on vGluT2‐expressing glutamatergic neurons modulate opioid reward
(Wiley, 2021-05) Reeves, Kaitlin C.; Kube, Megan J.; Grecco, Gregory G.; Fritz, Brandon M.; Muñoz, Braulio; Yin, Fuqin; Gao, Yong; Haggerty, David L.; Hoffman, Hunter J.; Atwood, Brady K.; Pharmacology and Toxicology, School of Medicine
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.
A Multi-Omic Analysis of the Dorsal Striatum in an Animal Model of Divergent Genetic Risk for Alcohol Use Disorder
(Wiley, 2021) Grecco, Gregory G.; Haggerty, David L.; Doud, Emma H.; Fritz, Brandon M.; Yin, Fuqin; Hoffman, Hunter; Mosley, Amber L.; Simpson, Edward; Liu, Yunlong; Baucum, Anthony J., II.; Atwood, Brady K.; Pharmacology and Toxicology, School of Medicine
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.
The Penrose Effect and its acceleration by the war on drugs: a crisis of untranslated neuroscience and untreated addiction and mental illness
(Springer Nature, 2019-11-28) Grecco, Gregory G.; Andrew Chambers, R.; Psychiatry, School of Medicine
In 1939, British psychiatrist Lionel Penrose described an inverse relationship between mental health treatment infrastructure and criminal incarcerations. This relationship, later termed the ‘Penrose Effect’, has proven remarkably predictive of modern trends which have manifested as reciprocal components, referred to as ‘deinstitutionalization’ and ‘mass incarceration’. In this review, we consider how a third dynamic—the criminalization of addiction via the ‘War on Drugs’, although unanticipated by Penrose, has likely amplified the Penrose Effect over the last 30 years, with devastating social, economic, and healthcare consequences. We discuss how synergy been the Penrose Effect and the War on Drugs has been mediated by, and reflects, a fundamental neurobiological connection between the brain diseases of mental illness and addiction. This neuroscience of dual diagnosis, also not anticipated by Penrose, is still not being adequately translated into improving clinical training, practice, or research, to treat patients across the mental illness-addictions comorbidity spectrum. This failure in translation, and the ongoing fragmentation and collapse of behavioral healthcare, has worsened the epidemic of untreated mental illness and addictions, while driving unsustainable government investment into mass incarceration and high-cost medical care that profits too exclusively on injuries and multi-organ diseases resulting from untreated addictions. Reversing the fragmentation and decline of behavioral healthcare with decisive action to co-integrate mental health and addiction training, care, and research—may be key to ending criminalization of mental illness and addiction, and refocusing the healthcare system on keeping the population healthy at the lowest possible cost.v
Perturbed neurochemical and microstructural organization in a mouse model of prenatal opioid exposure: A multi-modal magnetic resonance study
(Public Library of Science, 2023-07-20) Shahid, Syed Salman; Grecco, Gregory G.; Atwood, Brady K.; Wu, Yu-Chien; Radiology and Imaging Sciences, School of Medicine
Methadone-based treatment for pregnant women with opioid use disorder is quite prevalent in the clinical environment. A number of clinical and animal model-based studies have reported cognitive deficits in infants prenatally exposed to methadone-based opioid treatments. However, the long-term impact of prenatal opioid exposure (POE) on pathophysiological mechanisms that govern neurodevelopmental impairment is not well understood. Using a translationally relevant mouse model of prenatal methadone exposure (PME), the aim of this study is to investigate the role of cerebral biochemistry and its possible association with regional microstructural organization in PME offspring. To understand these effects, 8-week-old male offspring with PME (n = 7) and prenatal saline exposure (PSE) (n = 7) were scanned in vivo on 9.4 Tesla small animal scanner. Single voxel proton magnetic resonance spectroscopy (1H-MRS) was performed in the right dorsal striatum (RDS) region using a short echo time (TE) Stimulated Echo Acquisition Method (STEAM) sequence. Neurometabolite spectra from the RDS was first corrected for tissue T1 relaxation and then absolute quantification was performed using the unsuppressed water spectra. High-resolution in vivo diffusion MRI (dMRI) for region of interest (ROI) based microstructural quantification was also performed using a multi-shell dMRI sequence. Cerebral microstructure was characterized using diffusion tensor imaging (DTI) and Bingham-neurite orientation dispersion and density imaging (Bingham-NODDI). MRS results in the RDS showed significant decrease in N-acetyl aspartate (NAA), taurine (tau), glutathione (GSH), total creatine (tCr) and glutamate (Glu) concentration levels in PME, compared to PSE group. In the same RDS region, mean orientation dispersion index (ODI) and intracellular volume fraction (VFIC) demonstrated positive associations with tCr in PME group. ODI also exhibited significant positive association with Glu levels in PME offspring. Significant reduction in major neurotransmitter metabolites and energy metabolism along with strong association between the neurometabolites and perturbed regional microstructural complexity suggest a possible impaired neuroadaptation trajectory in PME offspring which could be persistent even into late adolescence and early adulthood.
Pharmacokinetic data of synthetic cathinones in female Sprague-Dawley rats
(Elsevier, 2018-10-25) Grecco, Gregory G.; Kisor, David F.; Sprague, Jon E.; Medicine, School of Medicine
The synthetic cathinones methylone, butylone, and pentylone differ from each other through the one carbon lengthening of the α-alkyl chain: methylone (-CH3), butylone (-CH2CH3), and pentylone (-CH2CH2CH3) while 3,4-methylenedioxymethamphetamine (MDMA) differs from methylone by a single oxygen atom. Studies with MDMA, suggests that there may be male and female pharmacokinetic and pharmacodynamic differences. In the present study, we present the plasma pharmacokinetic data relative to a 20 mg/kg, subcutaneous doses of methylone, butylone and pentylone in female Sprague-Dawley rats. Briefly, plasma samples were collected via a jugular vein cannula, purified, and analyzed using a HPLC system. While we have previously reported on the consistent relationship between structure and pharmacokinetics of these synthetic cathinones in male, Sprague-Dawley rats (Grecco and Sprague, 2016), this data set suggests that there is no consistent relationship of chemical structure and pharmacokinetics of methylone, butylone and pentylone in female Sprague-Dawley rats. The findings from the present study further emphasize the need for the inclusion of female subjects in the pharmacokinetic studies of synthetic cathinones as it is very possible male-female differences may exist in rodent models.
Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry
(eLife Sciences, 2021-03-16) Grecco, Gregory G.; Mork, Briana E.; Huang, Jui-Yen; Metzger, Corinne E.; Haggerty, David L.; Reeves, Kaitlin C.; Gao, Yong; Hoffman, Hunter; Katner, Simon N.; Masters, Andrea R.; Morris, Cameron W.; Newell, Erin A.; Engleman, Eric A.; Baucum, Anthony J.; Kim, Jiuen; Yamamoto, Bryan K.; Allen, Matthew R.; Wu, Yu-Chien; Lu, Hui-Chen; Sheets, Patrick L.; Atwood, Brady K.; Pharmacology and Toxicology, School of Medicine
Despite the rising prevalence of methadone treatment in pregnant women with opioid use disorder, the effects of methadone on neurobehavioral development remain unclear. We 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. We investigated the effects of PME on physical development, sensorimotor behavior, and motor neuron properties using a multidisciplinary approach of physical, biochemical, and behavioral assessments along with brain slice electrophysiology and in vivo magnetic resonance imaging. Methadone accumulated in the placenta and fetal brain, but methadone levels in offspring dropped rapidly at birth which was associated with symptoms and behaviors consistent with neonatal opioid withdrawal. PME produced substantial impairments in offspring physical growth, activity in an open field, and sensorimotor milestone acquisition. Furthermore, these behavioral alterations were associated with reduced neuronal density in the motor cortex and a disruption in motor neuron intrinsic properties and local circuit connectivity. The present study adds to the limited body of work examining PME by providing a comprehensive, translationally relevant characterization of how PME disrupts offspring physical and neurobehavioral development.

Browsing by Author "Grecco, Gregory G."

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