1. Brain regional synchronous activity predicts tauopathy in 3TgAD mice Alzheimer's disease (AD) is characterized by progressive cognitive impairment and by extensive neuronal loss associated with extracellular amyloid -peptide (A) plaques and intraneuronal tau pathology in temporal and parietal lobes. AD patients are at increased risk for epileptic seizures, and data from experimental models of AD suggest that aberrant neuronal network activity occurs early in the disease process before cognitive deficits and neuronal degeneration. The contributions of A and/or tau pathologies to dysregulation of neuronal network activity are unclear. Using a transgenic mouse model of AD (3TgAD mice) in which there occurs differential age-dependent development of tau and A plaque pathologies, we applied analysis of resting state functional magnetic resonance imaging regional homogeneity, a measure of local synchronous activity, to discriminate the effects of A and tau on neuronal network activity throughout the brain. Compared to age-matched wild-type mice, 6- to 8-month-old 3TgAD mice exhibited increased regional homogeneity in the hippocampus and parietal and temporal cortices, regions with tau pathology but not A pathology at this age. By 18-24 months of age, 3TgAD mice exhibited extensive tau and A pathologies involving the hippocampus and multiple functionally related brain regions, with a spatial expansion of increased local synchronous activity to include those regions. Our findings demonstrate that age-related brain regional hypersynchronous activity is associated with early tau pathology in a mouse model, consistent with a role for early tau pathology in the neuronal circuit hyperexcitability that is believed to precede and contribute to neuronal degeneration in AD. (Liu et al., Neurobiology of Aging, 2018) 2. Resting-state functional MRI reveals altered brain connectivity and its correlation with motor dysfunction in a mouse model of Huntington's disease Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder, and no cure is available currently. Treatment of HD is likely to be most beneficial in the early, possibly pre-manifestation stage. The challenge is to determine the best time for intervention and evaluate putative efficacy in the absence of clinical symptoms. Resting-state functional MRI may represent a promising tool to develop biomarker reflecting early neuronal dysfunction in HD brain, because it can examine multiple brain networks without confounding effects of cognitive ability, which makes the resting-state fMRI promising as a translational bridge between preclinical study in animal models and clinical findings in HD patients. In this study, we examined brain regional connectivity and its correlation to brain atrophy, as well as motor function in the 18-week-old N171-82Q HD mice. HD mice exhibited significantly altered functional connectivity in multiple networks. Particularly, the weaker intra-striatum connectivity was positively correlated with striatal atrophy, while striatum-retrosplenial cortex connectivity is negatively correlated with striatal atrophy. The resting-state brain regional connectivity had no significant correlation with motor deficits in HD mice. Our results suggest that altered brain connectivity detected by resting-state fMRI might serve as an early disease biomarker in HD. (Li et a., Scientific Report, 2018) 3. Compulsive Drug Use and the Balance of Prelimbic and Orbitofrontal Connectivity with Striatum Addiction is a chronic relapsing disease characterized by compulsive drug seeking and use despite of negative consequences. Interestingly, some chronic stimulant users are able to curtail their use when faced with adverse consequences while others continue to use compulsively. The mechanisms underlying this dichotomy are poorly understood. Using resting-state functional magnetic resonance imaging (fMRI), we first identified distinct go (orbitofrontal striatum) and stop (dorsal cingulate anterior cortex striatum) brain circuits of addiction; the imbalance of these circuits was associated with loss of control over drug use in human cocaine abusers. Based upon this human finding, a translational longitudinal study was conducted to examine the dynamic circuitry changes during the course of addiction with a rat model of self- administration (SA) in the presence of inescapable foot shock. Drug evoked up- and down- regulation in the putative go and stop circuits was seen in rats, respectively. The compulsive-like SA behavior is correlated with change in the go-stop balance only in rats who continue to self-administer at a relatively high rate despite receiving foot shock. Moreover, rats sensitive to the foot shock exhibit a partial recovery of the stop circuit that weakens in all rats after repeated SA, whereas rats who are resistant show further weakening in this circuit. This result may help guide non-invasive brain stimulation therapies targeting circuit level alterations in stimulant use disorders. (Hu et al., Manuscript in preparation) 4. Individual differences in insular-frontal intrinsic networks predict future nicotine dependence severity Although 60% of the US population has tried cigarette smoking, only 20% are regular smokers. Developing biomarkers of risk susceptibility, before the onset of disease, is critical to preventing and treating nicotine dependence. Preclinical functional neuroimaging prior to chronic nicotine administration provides an important translational tool for biomarker development to assess risk of future disease development. Chronic, intermittent nicotine was administered to outbred male Sprague Dawley rats for 14 days. Precipitated withdrawal behaviors, a verified model of nicotine dependence severity in rodents, were longitudinally collected at baseline (prior to nicotine administration), after dependence development and following sustained abstinence; resting state fMRI was collected at baseline. We developed a quantitative predictor of subsequent nicotine dependence development, as quantified using individual differences in mecamylamine precipitated withdrawal severity, and resting state inter-module functional connectivity (FC) using the graph theory metric participation coefficient (PC). Whole brain modularity analysis identified 5 modules. The PC at pre-drug baseline of a module comprising insular-frontal cortical regions predicted subsequent dependence severity. To determine the most important contributors to this brain-behavior relationship, the insula-frontal module was subjected to a secondary modularity analysis, which segregated it into three submodules (frontal motor; insula; sensory). FC between these sub-modules and three of the 5 identified modules (striatal, frontal executive and sensory association) predicted dependence severity, independent of nicotine dose. Functional connectivity strength within and between several insula-centric brain networks at baseline are predictive of subsequent development of nicotine dependence severity, suggesting that intrinsic differences in predispositional circuit strength can identify those at greatest risk for and resilience from drug dependence development. These data build upon existing evidence implicating insula and frontal regions in nicotine dependence by adding a novel role of pre-exposure, individual differences in network strength that may serve as a predictive biomarker of nicotine dependence susceptibility. (Hsu et al., Manuscript under review)
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