Neuroimaging of animal models of neurologic and psychiatric disorders

点击翻译按钮获取中文摘要

1. Pharmacological Manipulations of Brain Regions in a Model of Compulsive Drug Taking Addiction is characterized by compulsive drug use despite negative consequences. Preclinical and clinical studies suggest that impaired frontal system, especially the prelimbic cortex (PrL) and orbitofrontal cortex (OFC) regions, could be crucial in promoting compulsive drug use. However, the PrL and OFC are necessary for both expression and suppression of different drug-related behaviors, and each region may contribute to different functions depend on specifics of the behavior tested. To better understand the roles of PrL and OFC during compulsive drug use, we used a rat model of methamphetamine self-administration (SA) in the presence of concomitant foot shocks, thought to parallel compulsive drug taking by humans, and pharmacologically inactivated each region during this process. In addition, we examined the effects of inactivation during seeking test and progressive ratio (PR) procedure to detect the roles of PrL and OFC in drug-seeking and motivation, respectively. Bilateral inactivation of PrL, but not OFC, repressed the compulsive drug use in the shock resistant rats during punishment SA phase and decreased motivation for drug during PR. No effect of inactivation was found during seeking test. Our data indicate that the PrL regulates both compulsive drug use and motivated behavior, while the role of OFC is not observed in the current experiments. These results provide a basis for further exploration of the circuit mechanism of prefrontal system on compulsive drug use. 2. Intrinsic Differences in Insular Circuits Moderate the Negative Association between Nicotine Dependence and Cingulate-striatal Connectivity Strength The development of brain-based biomarkers to assess nicotine dependence severity and treatment efficacy are essential to improve the current marginally effective treatment outcomes. Cross-sectional resting state functional connectivity (rsFC) studies in humans identified a circuit between the dorsal anterior cingulate cortex and the ventral striatum that negatively correlated with increased nicotine dependence severity but was unaffected by acute nicotine administration, suggesting a trait marker of addiction. However, whether this trait circuit dysregulation is predispositional to or resultant from nicotine dependence is unclear. Using a rat model of nicotine dependence with longitudinal fMRI measurements, we assessed the relationship between ACC-striatal rsFC and nicotine dependence severity. Data-driven modularity-based parcellation of the rat medial prefrontal cortex (mPFC) combined with seed-based connectivity analysis with the striatum recapitulated the cingulate-striatum relationship observed in humans. Furthermore, the relationship between cingulate-striatal brain circuits and nicotine dependence severity as indexed by the intensity of precipitated withdrawal, was fully statistically moderated by a predispositional insular-frontal cortical functional circuit. These data suggest that the identified trans-species ACC-striatal circuit relationship with nicotine dependence severity is dysregulated following chronic nicotine administration-induced dependence and may be biased by individual differences in predispositional insula-based striatal-frontal circuits, highlighting the circuit's potential as a biomarker of dependence severity. (Keeley et al., Neuropsychopharmacology, 2020) 3. Functional Connectivity of Hippocampal CA3 Predicts Neurocognitive Aging via CA1-Frontal Circuit The CA3 and CA1 principal cell fields of the hippocampus are vulnerable to aging, and age-related dysfunction in CA3 may be an early seed event closely linked to individual differences in memory decline. However, whether the differential vulnerability of CA3 and CA1 is associated with broader disruption in network-level functional interactions in relation to age-related memory impairment, and more specifically, whether CA3 dysconnectivity contributes to the effects of aging via CA1 network connectivity, has been difficult to test. Here, using resting-state fMRI in a group of aged rats uncontaminated by neurodegenerative disease, aged rats displayed widespread reductions in functional connectivity of CA3 and CA1 fields. Age-related memory deficits were predicted by connectivity between left CA3 and hippocampal circuitry along with connectivity between left CA1 and infralimbic prefrontal cortex. Notably, the effects of CA3 connectivity on memory performance were mediated by CA1 connectivity with prefrontal cortex. We additionally found that spatial learning and memory were associated with functional connectivity changes lateralized to the left CA3 and CA1 divisions. These results provide novel evidence that network-level dysfunction involving interactions of CA3 with CA1 is an early marker of poor cognitive outcome in aging. (Liang et al., Cerebral Cortex, 2020)