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Despite increased survivability for people living with HIV (PLWH), HIV-related cognitive deficits persist. Determining biological mechanism(s) underlying abnormalities is critical to minimize the long-term impact of HIV. Positron emission tomography (PET) studies reveal that PLWH exhibit elevated neuroinflammation, potentially contributing to these problems. PLWH are hypersensitive to environmental insults that drive elevated inflammatory profiles. Gp120 is an envelope glycoprotein exposed on the surface of the HIV envelope which enables HIV entry into a cell contributing to HIV-related neurotoxicity. In vivo evidence for mice overexpressing gp120 (transgenic) mice exhibiting neuroinflammation remains unclear. Here, we conducted microPET imaging in gp120 transgenic and wildtype mice, using the radiotracer [(18)F]FEPPA (binds to the translocator protein expressed by activated microglial serving as a neuroinflammatory marker). Imaging was performed at baseline and 24 h after lipopolysaccharide (LPS; 5 mg/kg) treatment (endotoxin that triggers an immune response). Gp120 transgenic mice exhibited elevated [(18F)]FEPPA in response to LPS vs. wildtype mice throughout the brain including dorsal and ventral striata, hypothalamus, and hippocampus. Gp120 transgenic mice are hypersensitive to environmental inflammatory insults, consistent with PLWH, measurable in vivo. It remains to-be-determined whether this heightened sensitivity is connected to the behavioral abnormalities of these mice or sensitive to any treatments., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Compulsive patterns of drug use are thought to be the consequence of drug-induced adaptations in the neural mechanisms that enable behavior to be flexible. Neuroimaging studies have found evidence of robust alterations in glutamate and dopamine receptors within brain regions that are known to be critical for decision-making processes in cocaine-dependent individuals, and these changes have been argued to be the consequence of persistent drug use. The causal relationships among drug-induced alterations, cocaine taking, and maladaptive decision-making processes, however, are difficult to establish in humans., Methods: We assessed decision making in adult male rats using a probabilistic reversal learning task and used positron emission tomography with the [ 11 C]-(+)-PHNO and [ 18 F]FPEB radioligands to quantify regional dopamine D 2/3 and metabotropic glutamate 5 (mGlu5) receptor availability, respectively, before and after 21 days of cocaine or saline self-administration. Tests of motivation and relapse-like behaviors were also conducted., Results: We found that self-administration of cocaine, but not of saline, disrupted behavior in the probabilistic reversal learning task measured by selective impairments in negative-outcome updating and also increased cortical mGlu5 receptor availability following 2 weeks of forced abstinence. D 2/3 and, importantly, midbrain D 3 receptor availability was not altered following 2 weeks of abstinence from cocaine. Notably, the degree of the cocaine-induced increase in cortical mGlu5 receptor availability was related to the degree of disruption in negative-outcome updating., Conclusions: These findings suggest that cocaine-induced changes in mGlu5 signaling may be a mechanism by which disruptions in negative-outcome updating emerge in cocaine-dependent individuals., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Results from neuroimaging studies suggest that disruptions in flexible decision-making functions in substance-dependent individuals are a consequence of drug-induced neural adaptations. In addicted populations, however, the causal relationship between biobehavioral phenotypes of susceptibility and addiction consequence is difficult to dissociate. Indeed, evidence from animals suggests that poor decision making due to preexisting biological factors can independently enhance the risk for developing addiction-like behaviors. Neuroimaging studies in animals provide a unique translational approach for the identification of the neurobiological mechanisms that mediate susceptibility to addiction., Methods: We used positron emission tomography in rats to quantify regional dopamine D 2/3 receptors and metabotropic glutamate receptor 5 (mGluR5) and assessed decision making using a probabilistic reversal learning task. Susceptibility to self-administer cocaine was then quantified for 21 days followed by tests of motivation and relapse-like behaviors., Results: We found that deficits specifically in reward-guided choice behavior on the probabilistic reversal learning task predicted greater escalation of cocaine self-administration behavior and greater motivation for cocaine and, critically, were associated with higher midbrain D 3 receptor availability. Additionally, individual differences in midbrain D 3 receptor availability independently predicted the rate of escalation in cocaine-taking behaviors. No differences in mGluR5 availability, responses during tests of extinction, or cue-induced reinstatement were observed between the groups., Conclusions: These findings indicate that our identified D 3 -mediated decision-making phenotype can be used as a behavioral biomarker for assessment of cocaine use susceptibility in human populations., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Disruptions in the decision-making processes that guide action selection are a core feature of many psychiatric disorders, including addiction. Decision making is influenced by the goal-directed and habitual systems that can be computationally characterized using model-based and model-free reinforcement learning algorithms, respectively. Recent evidence suggests an imbalance in the influence of these reinforcement learning systems on behavior in individuals with substance dependence, but it is unknown whether these disruptions are a manifestation of chronic drug use and/or are a preexisting risk factor for addiction., Methods: We trained adult male rats on a multistage decision-making task to quantify model-free and model-based processes before and after self-administration of methamphetamine or saline., Results: Individual differences in model-free, but not model-based, learning prior to any drug use predicted subsequent methamphetamine self-administration; rats with lower model-free behavior took more methamphetamine than rats with higher model-free behavior. This relationship was selective to model-free updating following a rewarded, but not unrewarded, choice. Both model-free and model-based learning were reduced in rats following methamphetamine self-administration, which was due to a decrement in the ability of rats to use unrewarded outcomes appropriately. Moreover, the magnitude of drug-induced disruptions in model-free learning was not correlated with disruptions in model-based behavior, indicating that drug self-administration independently altered both reinforcement learning strategies., Conclusions: These findings provide direct evidence that model-free and model-based learning mechanisms are involved in select aspects of addiction vulnerability and pathology, and they provide a unique behavioral platform for conducting systems-level analyses of decision making in preclinical models of mental illness., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Schizophrenia is a debilitating neuropsychiatric disorder typically diagnosed from late adolescence to adulthood. Subthreshold behavioral symptoms (e.g., cognitive deficits and substance abuse) often precede the clinical diagnosis of schizophrenia. However, these prodromal symptoms have not been consistently associated with structural and functional brain biomarkers, limiting the chance of early diagnosis of schizophrenia., Methods: Using an extensively multimodal range of magnetic resonance methods (for anatomy, metabolism, and function), we screened early biomarkers in a methylazoxymethanol acetate (MAM) rat model of schizophrenia and saline-treated control (SHAM) rats, in conjunction with immunohistochemistry, myelin staining, and a novel three-choice, reversal-learning task to identify early behavioral markers corresponding the subthreshold symptoms., Results: MAM (vs. SHAM) rats had lower/higher structural connectivity in anterior/posterior corpus callosum. The orbitofrontal cortex of MAM rats showed lower resting-state functional magnetic resonance imaging functional connectivity in conjunction with lower neuronal density, lower glucose oxidation, and attenuated neurotransmission (hypofrontality). In contrast, these measures were all higher in visual cortex of MAM rats (posterior hyperactivity), which might parallel perceptual problems in schizophrenia. In behavioral studies, MAM (vs. SHAM) rats displayed abnormal orbitofrontal cortex-mediated decision-making processes, resulting in a novel reward-sensitive hyperflexible phenotype, which might reflect vulnerability of prodromal patients to substance abuse., Conclusions: We identified two novel biomarkers of early schizophrenia in a preclinical rat model: hypofrontality associated with the hyperflexible phenotype, and posterior hyperactivity. Because each of these magnetic resonance methods is clinically translatable, these markers could contribute to early diagnosis and the development of novel therapies of schizophrenia., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The compulsive and inflexible behaviors that are present in many psychiatric disorders, particularly behavioral addictions and obsessive-compulsive disorder, may be due to neurochemical dysfunction within the circuitry that enables goal-directed behaviors. Experimental removal of serotonin or dopamine within the orbitofrontal cortex or dorsal striatum, respectively, impairs flexible responding in a reversal learning test, suggesting that these neurochemical systems exert important modulatory influences on goal-directed behaviors. Nevertheless, the behavioral impairments present in psychiatric disorders are likely due to subtle neurochemical differences, and it remains unknown whether naturally occurring variation in neurochemical levels associate with individual differences in flexible, reward-directed behaviors., Methods: The current study assessed the ability of 24 individual juvenile monkeys to acquire, retain, and reverse discrimination problems and examined whether monoamine levels in the orbitofrontal cortex, caudate nucleus, and putamen could explain variance in behavior., Results: The interaction between dopamine levels in the putamen and serotonin levels in the orbitofrontal cortex explained 61% of the variance in a measure of behavioral flexibility but not measures of associative learning or memory. The interaction mirrored that of a hyperbolic function, with reversal learning performance being poorest in either monkeys with relatively low levels of orbitofrontal serotonin and putamen dopamine or in monkeys with relatively high levels of orbitofrontal serotonin and putamen dopamine levels., Conclusions: These results support the hypothesis that subcortical and cortical neuromodulatory systems interact to guide aspects of goal-directed behavior, providing insight into the neurochemical dysfunction that may underlie the inflexible and compulsive behaviors present in psychiatric disorders., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)