1. Neural circuitry associated with nicotine dependence in rats The functional connectivity between the dorsal anterior cingulate (dACC) and ventral striatum (VS) has been demonstrated to be 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. To investigate whether the dACC-VS circuit identified in human smokers was indeed a result of nicotine dependence and could thus serve as a biomarker for human nicotine addiction, we developed a rat model to assess functional neural circuitry before the development of nicotine dependence, after two weeks of chronic, intermittent nicotine administration via an adapted minipump method, and after a two-week period of abstinence. Nicotine dependence severity was inferred based on behavioral scores following mecamylamine-precipitated withdrawal, while resting-state fMRI data were collected at each of the three epochs. We hypothesized that a relationship between dependence severity, as measured by precipitated withdrawal signs, and cortircal-striatum functional connectivity strength would be identifiable in rats, and that this dependence-connectivity relationship would remit following forced withdrawal. By using modularity analysis, we divided striatum into four segments, which included the core of nucleus accumbens (AcbC), the shell of nucleus accumbens (AcbS), dorsal-medial striatum (dm-CPu), and dorsal-lateral striatum (dl-CPu). The connection of circuits in AcbC-prelimbic cortex, AcbS-insula cortex, and md-CPu-motor cortex showed significant correlation with nicotine withdrawal score after two weeks of nicotine treatment, but not before the treatment or after two-weeks of abstinence. 2. Adolescence nicotine exposure effects on adult nicotine withdrawal This project seeks to describe the effects of adolescent nicotine exposure on subsequent response to nicotine in adulthood. The first phase of this project sought to dose-dependently examine the effects of adolescent nicotine exposure on withdrawal scores observed in nicotine-treated adults. The second phase of the project planned to examine the effects of adolescence nicotine exposure on resting state functional connectivity (rsFC) observed in adulthood and the relationship between rsFC and withdrawal behaviour in adults. The first phase of this project is near completion, and there is no evidence to suggest that our adolescent nicotineabstinenceadult nicotine paradigm resulted in significant effects of adolescent nicotine exposure on adult withdrawal behaviour. Furthermore, replicating the results from other researchers, there was no observed dose-response effect of nicotine on adolescent withdrawal behaviour. These results were presented at an internal poster session at NIDA for the summer students. We have decided to explore alternative nicotine administration paradigms that include long-term exposure of nicotine, throughout adolescence as compared to only during early adolescence. This paradigm will closely mimic human smoking behaviour given that most smokers initiate smoking during the adolescent period and continue smoking up to and throughout adulthood. 3. Post-treatment with cocaine- and amphetamine-regulated transcript enhances infarct resolution, reinnervation and angiogenesis in stroke rats Recent studies have shown that post-treatment with cocaine- and amphetamine-regulated transcript (CART) has neuroregenerative effects in animal models of stroke. The purpose of this study was to characterize CART-mediated neuronal and vascular repairments using non-invasive magnetic resonance imaging (MRI) techniques. Adult male rats were subjected to a 90-min middle cerebral artery occlusion (MCAo). Animals were separated into two groups with similar infarction sizes, measured by T2-weighted MRI on Day 2 after MCAo, and were treated with CART or vehicle intranasally from Day 3 to Day 12. Diffusion tensor imaging (DTI) was used to examine changes in plasticity of white matter elements. Susceptibility weighted imaging (SWI) was used to measure angiogenesis. Post-treatment with CART significantly increased fractional anisotropy (FA) in lesioned cortex on Days 10 and 25 post-stroke. A significant correlation between the behavioral recovery in body asymmetry and the change in FA was shown, suggesting that behavioral recovery was associated with reinnervation to the lesioned hemisphere. CART also increased the intensity of SWI and the vascular marker α-smooth-muscle actin immunoreactivity in lesioned cortex. Together, our data support a non-invasive treatment strategy for stroke through angiogenesis and reinnervation by CART. (Under review)
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