1. Abstinence from cocaine and sucrose self-administration reveals altered mesocorticolimbic circuit connectivity Previous preclinical studies have emphasized that drugs of abuse, through actions within and between mesocorticolimbic (MCL) regions, usurp learning and memory processes normally involved in the pursuit of naturally rewarding stimuli. To distinguish MCL circuit pathobiological neuroadaptations that accompany addiction from general learning processes associated with natural reward goal-directed behavior, we trained two groups of rats to self-administer either cocaine (IV) or sucrose (orally) followed by an identically enforced 30 day abstinence period previously shown to induce behavioral self-administration (SA) plasticity. A third group of sedentary animals served as a negative control group for general handling effects. We examined low-frequency spontaneous fluctuations in the functional magnetic resonance imaging (fMRI) signal, known as resting-state functional connectivity (rsFC), as a measure of intrinsic neurobiological interactions between brain regions. Our data provide evidence of fronto-striatal plasticity across the addiction trajectory, which are consistent with Acb-PFC hypoactivity seen in abstinent human drug addicts, suggesting potential circuit level biomarkers that may inform therapeutic interventions. (Brain Connectivity 4: 499-510) 2. Assessing a cingulate-striatal addiction circuit in a rodent model of nicotine dependence We have demonstrated that the functional connectivity strength between the dorsal anterior cingulate (dACC) and ventral striatum (VS) negatively correlates with nicotine addiction severity in smokers and is not affected by nicotine replacement (NRT), while the connectivity of cortical-cortical circuits increased under NRT. It is not known whether the relationship between addiction severity and dACC-VS connectivity predisposes or results from dependence, and if the latter, could serve as a biomarker for nicotine addiction. We thus developed a rodent model to assess alterations in circuitry following dependence and withdrawal from intermittently administered nicotine, in a manner that mimics nicotine intake in smokers. We implanted an IP osmotic minipump attached to a Lynch coil filled with alternating volumes of nicotine (1.2 mg/kg/d (low) or 4.8 mg/kg/d (high)) or saline and mineral oil, to administer nicotine (n=12 per group) in a 1 hr on/1 hr off pattern for 14 days. Resting-state data were acquired at pre-treatment (Day 0), following 14 days of intermittent nicotine exposure (Day 14), and after 14 days of abstinence (Day 28). Prior to each session, nicotine dependence was assessed following mecamylamine challenge;behavioral signs of withdrawal were scored for 50 min. A generalized linear mixed-effects model revealed a Day Treatment interaction (p=.004), whereby high-dose rats showed more withdrawal signs than both low-dose (p=.05) and saline-treated (p=.001) rats at Day 14 only. Both low- and high-dose induced more withdrawal symptoms at Day 14 than at either Day 0 or Day 28 (p≤.005), suggesting that nicotine dependence did not persist after 14 days of abstinence. Resting BOLD analysis revealed a negative correlation between withdrawal signs and cingulate area Cg1-dorsal striatum connectivity, and a positive correlation between Cg1 and orbitofrontal cortex and Cg1-posterior cingulate cortex (retrosplenial cx) connectivity at Day 14, but not at Day 28. These results effectively back translate those of the above human study and provide evidence that the relationship between dependence severity and circuit strength is induced rather than dispositional. (Presented in Society for Research on Nicotine and Tobacco (SRNT) 2014 Meeting) 3. Longitudinal changes in resting state functional connectivity by cocaine in rhesus monkeys As part of ongoing studies into the cognitive consequences of chronic cocaine use and underlying neural alterations, we have conducted resting state functional connectivity MR imaging in isofluorane-anesthetized control and chronic cocaine self-administering rhesus monkeys (All were age matched and equivalent depth of anesthesia were ensured when in MRI). Two scans were conducted in each group (n=4/group) with an EPI sequence sensitive to BOLD signal. Prior to the first scan, the cocaine animals had previously self-administered cocaine for approx. one year (mean cumulative intake 520 mg/kg), followed by a 26 month drug-free hiatus. After the baseline scan 1, cocaine animals self-administered cocaine for 15 months (additional cumulative intake 1600 mg/kg) and then were drug-free for an average of 5 days prior to scan 2. Control subjects self-administered water using similar procedures between scan 1 and scan 2. As an initial analysis of changes between groups over time, normalized regional homogeneity (mReHo) was examined, a measure that putatively reflects the local synchrony of neural processing as the degree of coherence in low frequency fluctuations in the BOLD signal within a contiguous set of voxels. A 2 X 2 ANOVA of the interaction between groups over time revealed significant differences ( p(corrected)<0.05 by AlphaSim in AFNI) in five prominent contiguous regions: Right superior frontal gyrus, right temporal pole, left putamen (overlapping with neighboring insula), posterior cingulate, and right cerebellum. These changes are consistent with impaired coordinated activity within defined regions known to be important in executive and affective function. Further work will focus on seed-based network analysis to determine changes in intrinsic networks shown to exist in non-human primates analogous to those in humans, with application of contemporaneous neurocognitive assessments as regressors to explore neural changes due to cocaine. (Presented in Society for Neuroscience 2014) 4. Enhanced reinnervation and angiogenesis in stroke rats treated with Cocaine- and amphetamine-regulated transcript (CART) peptide We used diffusion tensor imaging (DTI) to examine changes in white matter structures and susceptibility weighted imaging (SWI) to investigate cerebral angiogenesis following CART treatment in stroke rats. White matter integrity in areas surrounding the lesion, as revealed by fractional anisotropy (FA) of diffusion, improved significantly in the treatment group than the control group. This imaging finding is consistent with our previous report that intranasal CART treatment facilitates neuroregeneration in stroke brain. We further found a significant correlation between changes of FA and behavioral recovery, measured by a body asymmetry test, in CART-treated animals. SWI imaging showed that the CART-treated animals had enhanced SWI values in areas surrounding the infarction, compared with the control groups, supported by histology showing increased density of α-SMA immunoreactivity in the same region. Taking together, the present study demonstrates the feasibility of quantitative SWI and FA as potential noninvasive imaging markers to reflect the level of angiogenesis and neuroregeneration, respectively, and possibly to monitor the progress of stroke recovery. (Presented in International Magnetic Resonance in Medicine (ISMRM) 2014 Meeting)
Showing the most recent 10 out of 12 publications
