1. Compulsive drug use is associated with imbalance of orbitofrontal- and prelimbic-striatal circuits in punishment resistant individuals: Substance use disorders (SUDs) impose severe negative impacts upon individuals, their families, and society. Clinical studies demonstrate that some chronic stimulant users are able to curtail their drug use when faced with adverse consequences while others continue to compulsively use drugs. The mechanisms underlying this dichotomy are poorly understood, which hampers the development of effective individualized treatments of a disorder that currently has no Food and Drug Administration-approved pharmacological treatments. In the present study, using a rat model of methamphetamine self-administration (SA) in the presence of concomitant foot shocks, thought to parallel compulsive drug taking by humans, we found that SA behavior correlated with alterations in the balance between an increased orbitofrontal cortex-dorsomedial striatal go circuit and a decreased prelimbic cortex-ventrolateral striatal stop circuit. Critically, this correlation was seen only in rats who continued to self-administer at a relatively high rate despite receiving foot shocks of increasing intensity. While the stop circuit functional connectivity became negative after repeated SA in all rats, shock-resistant rats showed strengthening of this negative connectivity after shock exposure. In contrast, shock-sensitive rats showed a return toward their baseline levels after shock exposure. These results may help guide novel noninvasive brain stimulation therapies aimed at restoring the physiological balance between stop and go circuits in SUDs. 2. Heroin addiction engages negative emotional learning brain circuits in rats. Opioid use disorder is associated with the emergence of persistent negative emotional states during drug abstinence that drive compulsive drug taking and seeking. Functional magnetic resonance imaging (fMRI) in rats identified neurocircuits that were activated by stimuli that were previously paired with heroin withdrawal. The activation of amygdala and hypothalamic circuits was related to the degree of heroin dependence, supporting the significance of conditioned negative affect in sustaining compulsive-like heroin seeking and taking and providing neurobiological insights into the drivers of the current opioid crisis. 3. Intrinsic insular-frontal networks predict future nicotine dependence severity. Although 60% of the US population have tried smoking cigarettes, only 16% smoke regularly. Identifying this susceptible subset of the population before the onset of nicotine dependence may encourage targeted early interventions to prevent regular smoking and/or minimize severity. While prospective neuroimaging in human populations can be challenging, preclinical neuroimaging models before chronic nicotine administration can help to develop translational biomarkers of disease risk. Chronic, intermittent nicotine (0, 1.2, or 4.8 mg/kg/d; N = 1011/group) was administered to male Sprague Dawley rats for 14 d; dependence severity was quantified using precipitated withdrawal behaviors collected before, during, and following forced nicotine abstinence. Resting-state fMRI functional connectivity (FC) before drug administration was subjected to a graph theory analytical framework to form a predictive model of subsequent individual differences in nicotine dependence. Whole-brain modularity analysis identified five modules in the rat brain. A metric of intermodule connectivity, participation coefficient, of an identified insularfrontal cortical module predicted subsequent dependence severity, independent of nicotine dose. To better spatially isolate this effect, this module was subjected to a secondary exploratory modularity analysis, which segregated it into three submodules (frontal-motor, insular, and sensory). Higher FC among these three submodules and three of the five originally identified modules (striatal, frontal-executive, and sensory association) also predicted dependence severity. These data suggest that predispositional, intrinsic differences in circuit strength between insular-frontal-based brain networks before drug exposure may identify those at highest risk for the development of nicotine dependence. 4. Delta rhythm orchestrates the neural activity underlying the resting state BOLD signal via phase-amplitude coupling. Spontaneous ongoing neuronal activity is a prominent feature of the mammalian brain. Temporal and spatial patterns of such ongoing activity have been exploited to examine large-scale brain network organization and function. However, the neurophysiological basis of this spontaneous brain activity as detected by resting-state functional Magnetic Resonance Imaging (fMRI) remains poorly understood. To this end, multi-site local field potentials (LFP) and blood oxygenation level-dependent (BOLD) fMRI were simultaneously recorded in the rat striatum along with local pharmacological manipulation of striatal activity. Results demonstrate that delta () band LFP power negatively, while beta () and gamma () band LFPs positively correlated with BOLD fluctuation. Furthermore, there was strong cross-frequency phase-amplitude coupling (PAC), with the phase of LFPs significantly modulating the amplitude of the high frequency signal. Enhancing dopaminergic neuronal activity significantly reduced ventral striatal functional connectivity, LFP-BOLD correlation, and the PAC effect. These data suggest that different frequency bands of the LFP contribute distinctively to BOLD spontaneous fluctuation and that PAC is the organizing mechanism through which low frequency LFPs orchestrate neural activity that underlies resting state functional connectivity. 5. Brain regional synchronous activity predicts taupology in 3xTgAD 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.
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