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Browsing by Author "Yoder, Karmen"
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Item The Behavioral Role of Mu Opioid Receptors in Glutamatergic Neurons(2021-10) Reeves, Kaitlin C.; Sheets, Patrick; Baucum, Anthony II; Yamamoto, Bryan; McKinzie, David; Yoder, KarmenMu opioid receptors (MORs) mediate the analgesic and rewarding effects of opioids. Most research has focused on MORs in GABAergic neurons; however, MORs are also in glutamatergic neurons and their role in opioid-related behaviors was unclear. Our lab previously showed that MORs inhibit glutamate transmission from vesicular glutamate transporter 2 (vGluT2)-expressing thalamostriatal synapses. The behavioral relevance of MORs in vGluT2-expressing neurons was unknown; therefore, I utilized a conditional MOR knockout mouse with MORs deleted in vGluT2-expressing neurons (MORflox-vGluT2cre). MORflox-vGluT2cre mice have disrupted opioid reward, locomotor stimulation, and withdrawal, compared to cre-recombinase negative littermate controls. However, other MOR-mediated behaviors, including opioid-induced antinociception, alcohol reward, and palatable substance consumption are intact. MORs are expressed in vGluT2 neurons in several reward-related brain regions, including the thalamus and lateral habenula (LHb). To determine whether MORs in these brain regions modulate opioid-related behaviors, an adeno-associated viral (AAV) vector encoding cre-recombinase was stereotaxically injected into the thalamus or LHb of MORflox mice to specifically delete MORs in these brain regions. Opioid reward and locomotor stimulation remained intact in both thalamic and LHb MOR knockout mice; however, basal locomotor activity was increased in LHb MOR knockout mice. Sucrose consumption was also intact in LHb MOR knockout mice. Interestingly, in LHb MOR KO mice opioid withdrawal-induced paw shakes were increased, while withdrawal-induced jumping was completely ablated. Our lab previously showed that MORs inhibit glutamate transmission from the anterior insular cortex (AIC), which is disrupted by in vivo alcohol exposure. To determine the role of AIC MORs, AIC MORs were deleted with AAV vectors. AIC MOR knockout mice had intact opioid, sucrose, and alcohol reward, but had increased basal locomotor activity. MORs in glutamatergic neurons are critical mediators of opioid reward; however, the specific glutamatergic neurons mediating the rewarding effects of opioids remains to be determined.Item Cognitive complaints in older adults at risk for Alzheimer's disease are associated with altered resting-state networks(Elsevier, 2016-12-22) Contreras, Joey A.; Goni, Joaquin; Risacher, Shannon L.; Amico, Enrico; Yoder, Karmen; Dzemidzic, Mario; West, John D.; McDonald, Brenna C.; Farlow, Martin R.; Sporns, Olaf; Saykin, Andrew J.; Department of Radiology and Imaging Sciences, IU School of MedicineINTRODUCTION: Pathophysiological changes that accompany early clinical symptoms in prodromal Alzheimer's disease (AD) may have a disruptive influence on brain networks. We investigated resting-state functional magnetic resonance imaging (rsfMRI), combined with brain connectomics, to assess changes in whole-brain functional connectivity (FC) in relation to neurocognitive variables. METHODS: Participants included 58 older adults who underwent rsfMRI. Individual FC matrices were computed based on a 278-region parcellation. FastICA decomposition was performed on a matrix combining all subjects' FC. Each FC pattern was then used as a response in a multilinear regression model including neurocognitive variables associated with AD (cognitive complaint index [CCI] scores from self and informant, an episodic memory score, and an executive function score). RESULTS: Three connectivity independent component analysis (connICA) components (RSN, VIS, and FP-DMN FC patterns) associated with neurocognitive variables were identified based on prespecified criteria. RSN-pattern, characterized by increased FC within all resting-state networks, was negatively associated with self CCI. VIS-pattern, characterized by an increase in visual resting-state network, was negatively associated with CCI self or informant scores. FP-DMN-pattern, characterized by an increased interaction of frontoparietal and default mode networks (DMN), was positively associated with verbal episodic memory. DISCUSSION: Specific patterns of FC were differently associated with neurocognitive variables thought to change early in the course of AD. An integrative connectomics approach relating cognition to changes in FC may help identify preclinical and early prodromal stages of AD and help elucidate the complex relationship between subjective and objective indices of cognitive decline and differences in brain functional organization.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 Follow Your Heart: Heart Rate Variability Reveals Sex Differences in Autonomic Regulation During Anxiety-Like Behavior and During Alcohol Drinking in Rats(2024-02) Frasier, Raizel Michele; Yoder, Karmen; Hopf, Woody; McKinzie, David; Lukkes, Jodi; Conroy, SusanMental health conditions remain a substantial and costly challenge to society. Of note, women have a higher prevalence of anxiety disorders than men, and alcohol misuse in women has risen sharply in recent years. However, critical mechanisms underlying these observed sex differences remain incompletely understood. Measures of cardiac function, including heart rate (HR) and HR variability (HRV), reflect dynamic balance between the two opposing branches of the autonomic nervous system: sympathetic (SNS, “fight or flight”) and parasympathetic (PNS, “rest and digest”). Furthermore, recent evidence strongly suggests these measures are potential biomarkers for pathological states, including mental health conditions. To better understand sex differences in autonomic mechanisms related to pathological anxiety and alcohol misuse, we utilized cardiac telemetry to measure HR and HRV. This allowed observation of real-time autonomic tone in awake, freely behaving Wistar rats of both sexes. At baseline, female rats had greater HR and lower SNS influence than males, which concords with human studies. In both anxiety-like behavior and alcohol drinking studies, we observed that females tend to utilize a higher PNS influence to overcome challenge, whereas males tend to utilize higher SNS. Furthermore, female (but not male) baseline HR and HRV are related to within-task behavior, suggesting that baseline state impacts drinking and anxiety-like behavior in a sex-specific way. Again, these data concord with human research suggesting a similar PNS bias in women and SNS bias in men when responding, especially under challenge. Taken together, these data have contributed new knowledge to sex differences in autonomic engagement, especially for anxiety states and alcohol drinking. Importantly, these findings are likely translationally relevant for the development of novel, and more personalized, therapies.Item Indiana Center for Brain Rehabilitation, Advanced Imaging, and Neuroscience (ICBRAIN): An IUPUI Signature Center Initiative(Office of the Vice Chancellor for Research, 2012-04-13) Hammond, Flora; Saykin, Andrew J.; Malec, James; Kean, Jacob; Keiski, Michelle; McDonald, Brenna; Neumann, Dawn; Wang, Yang; Yoder, KarmenThe Mission of the Indiana Center for Brain Rehabilitation, Advanced Imaging, and Neuroscience (ICBRAIN) is: to develop and disseminate techniques and methodologies for advanced neuroimaging and precision behavioral measurement to evaluate novel rehabilitation interventions for people with acquired brain injury. Traumatic and other types of acquired brain injury (ABI) affect millions of U.S. citizens each year, many of whom experience persistent disabilities. For example, among the estimated 1.4 million civilians who sustain a traumatic brain injury (TBI) each year, 50,000 die and a minimum of 80,000 sustain injuries of sufficient severity to require extended rehabilitation. The current conflicts in Iraq and Afghanistan have increased awareness and mobilized interest in medical treatment and rehabilitation for returning soldiers with TBI (designated as the “signature injury” of these conflicts). A 2008 study by the RAND corporation based on a random sample of 1,965 veterans estimated that, among 1.64 million returning veterans, approximately 320,000 experienced a probable TBI (19%). Over the past decade there has been a notable rise in research activities to address serious gaps in the knowledge base of ABI, including neuroimaging, outcome measurement, and intervention studies to change function. However, brain injury researchers have not yet established solid links between these research agendas. Such links are crucial for moving the evidence base forward to improve treatment outcomes. ICBRAIN will fill this gap in neuroscience by bringing together an interdisciplinary team of clinical researchers to (1) advance basic science and clinical knowledge to the next level of integration, (2) translate the knowledge gained directly into clinical care for improved patient outcomes, and (3) use the newly integrated knowledge to drive the leading edge of future research. ICBRAIN represents a unique collaboration among established clinical rehabilitation and measurement researchers in PM&R and at RHI and established researchers at the IU Center for Neuroimaging.Item Targeting Early Vascular Dysfunction Following Spinal Cord Injury(2019-10) Chen, Chen; Cummins, Theodore R.; Jin, Xiaoming; Jones, Kathryn J.; Yoder, Karmen; Xu, Xiao-mingThe vascular network highly coordinates with the central nervous system (CNS) on exchanging oxygen, nutrients and information transfer. The resemblance of the two systems at anatomical, cellular, and molecular levels also demonstrates their interdependence. The spinal cord is an integrated part of the CNS. Traumatic spinal cord injury (SCI) causes rapid systemic vascular responses and local neural tissue damage at the initial phase. The early disruption of the spinal vasculature breaks the supply-and-demand balance and facilitates the deterioration of the spinal cord tissue and functional deficits. Therefore, it is important to dissect the mechanism underlying vascular injury-mediated histological and functional consequences in order to develop potential therapeutic strategies. To visualize dynamic vascular changes after an acute SCI, a novel duo-color in vivo imaging technique was successfully developed in adult rats at the cervical level. This technique overcomes previous technical hurdles allowing real-time observation of vascular changes in live animals. Correlated with histological measures, in vivo vascular outcomes revealed a temporospatial relationship with neuronal and axonal loss, myelin disruption, inflammation, and glial responses. For the first time, we defined a “transitional zone” where significant blood vessel dilation and vascular leakage were observed simultaneously with vascular changes occurred at the injury epicenter acutely after SCI. These vascular changes at the transitional zone happened before any other cellular damage after SCI, suggesting a time window to prevent further neuronal damage in this region. Targeting the observed vascular leakage can work as a proof of concept that early vascular dysfunction contributes to the secondary neural tissue damage. Indeed, intravenous delivery of ferulic acid conjugated with glycol chitosan (FA-GC) to the injured sites immediate after SCI resulted in reduced vascular leakage, ventral horn neuronal loss, and partial recovery of forelimb function following a clinically-relevant contusive SCI at the 7th cervical spinal cord level. In conclusion, this work elucidated a novel role and mechanism of early vascular damage in the “transitional zone” prior to the secondary damage of neural tissue in this region and provided a novel treatment strategy for early neuroprotection and functional recovery.Item Training Physician-Scientists in Social and Behavioral Science: Indiana ADRD Medical Scientist Training Program(Oxford University Press, 2022-12-20) Fowler, Nicole; Herbert, Brittney-Shea; Callahan, Christopher; Peng, Siyun; Perry, Brea; Yoder, Karmen; Landreth, Gary; Truitt, William; Medicine, School of MedicineThere is a critical need to grow and strengthen the pipeline of physician scientists who have expertise in sociomedical and behavioral research and are dedicated to addressing the nation's challenges posed by Alzheimer's disease and related dementias (ADRD). In 2021 The Indiana ADRD Medical Scientist Training Program (IADRD MSTP) was designed to meet this need and is built on the infrastructure of a robust portfolio of ADRD research, graduate training programs in medical neurosciences and sociology, and our existing MD-PhD program at Indiana University School of Medicine. The Aims of the IADRD MSTP are: 1) To recruit and train a competitive pool of diverse students who have an interest and commitment to social and behavioral research and patient care focused on ADRD; 2) To engage MD-PhD students early in mentored sociomedical and behavioral research that integrates IUs systems-based medical training curriculum with our cutting edge ADRD research that reinforces commitment and minimizes attrition of physician-scientists ADRD; and 3) To graduate students with dual MD-PhD degrees with strong methodological training in social and behavioral science and experts in ADRD who will be successful independent investigators at the best academic medical centers nationwide. The program includes rigorous didactic training in social, behavioral, and clinical research methods, with flexibility to allow students to focus their effort on one methodological area of interest; early initiation of ADRD research experiences with multidisciplinary teams of mentors and advisors; and the provision of educational experiences that enhance students' abilities to become independent researchers.