Translational addiction neurobiology

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

1. Whole brain dynamics during optogenetic self-stimulation of the medial prefrontal cortex. Intracranial self-stimulation is a widely used procedure to study motivated behavior. While local neuronal activity has long been measured immediately before or after the operant, imaging the whole brain in real-time remains a challenge. Herein we report a method that permits functional MRI (fMRI) of brain dynamics while mice are cued to perform an operant task: licking a spout to receive optogenetic stimulation to the medial prefrontal cortex (MPFC) during a cue ON, but not cue OFF. Licking during cue ON results in activation of a widely distributed network consistent with underlying MPFC projections, while licking during cue OFF leads to negative fMRI signal in brain regions involved in acute extinction. Noninvasive whole brain readout combined with circuit-specific neuromodulation opens an avenue for investigating adaptive behavior in both healthy and disease models. 2. Long term cocaine self-administration produces structural brain changes that correlate with altered cognition. An enduring question from cross-sectional clinical studies is whether the structural and functional differences often observed between cocaine users and healthy control subjects result from a history of drug use or instead reflect preexisting differences. To assess causality from drug exposure, true predrug baseline imaging and neurocognitive assessments are needed. We addressed this question of causality using longitudinal anatomical MRI and neurocognitive assessments in rhesus macaques. We identified localized patterns of gray matter density (GMD) changes that were largely concordant with cross-sectional clinical studies. These included decreases in orbitofrontal cortex, insula, amygdala, and temporal cortex. There was also a prominent increase in GMD in the caudate putamen. GMD decreases were significantly correlated with cognitive impairments across individuals only in select cortical regions. Following abstinence, changes in GMD in some regions, including the OFC, insula, and amygdala, were persistent and thus may play an important role in risk of relapse following extended abstinence. 3. Nicotine addiction: Translational insights from circuit neuroscience. We review fMRI-based observations of a circuit that was first shown to be disrupted among human smokers and was recently replicated in rodent models of nicotine dependence. Next, we discuss circuits that predispose to nicotine dependence severity and their interaction with circuits that change as a result of chronic nicotine administration using a rodent model of dependence. 4. Strengths and challenges of longitudinal primate neuroimaging. Longitudinal non-human primate neuroimaging has the potential to greatly enhance our understanding of primate brain structure and function. Here we describe its specific strengths, compared to both cross-sectional non-human primate neuroimaging and longitudinal human neuroimaging, but also its associated challenges. We elaborate on factors guiding the use of different analytical tools, subject-specific versus age-specific templates for analyses, and issues related to statistical power. 5. Translational PET imaging applications for neural circuit mapping and manipulation with transgenic tools. The goal of this review is to summarize current research combining transgenic tools with PET for in vivo mapping and manipulation of brain circuits and to propose future directions for translational applications. 6. Recognition memory is associated with distinct patterns of regional gray matter volumes in young and aged monkeys Cognitive aging varies tremendously across individuals and is often accompanied by regionally specific reductions in gray matter (GM) volume, even in the absence of disease. Rhesus monkeys provide a primate model unconfounded by advanced neurodegenerative disease, and the current study used a recognition memory test (delayed non-matching to sample; DNMS) in conjunction with structural imaging and voxel-based morphometry (VBM) to characterize age-related differences in GM volume and brain-behavior relationships. DNMS performance in young animals prominently correlated with the volume of multiple structures in the medial temporal lobe memory system. Correlations were also observed in the cingulate and cerebellum. In aged monkeys, significant volumetric correlations with DNMS performance were largely restricted to the prefrontal cortex and striatum. Importantly, interaction effects in an omnibus analysis directly confirmed that the associations between volume and task performance in the MTL and prefrontal cortex are age-dependent. These results demonstrate that the regional distribution of GM volumes coupled with DNMS performance changes across the lifespan.