1. The constituents and functional implications of the rat default mode network (DMN). The DMN has been suggested to support a variety of self-referential functions in humans and has been fractionated into subsystems based on distinct responses to cognitive tasks and functional connectivity architecture. Such subsystems are thought to reflect functional hierarchy and segregation within the network. Partitioning of the DMN in nonhuman species, may inform both physiology and pathophysiology of the human DMN. We sought to identify constituents of the rat DMN using resting-state functional MRI (rs-fMRI) and diffusion tensor imaging. After identifying DMN using a group-level independent-component analysis on the rs-fMRI data, modularity analyses fractionated the DMN into an anterior and a posterior subsystem, which were further segregated into five modules. Diffusion tensor imaging tractography demonstrates a close relationship between fiber density and the functional connectivity between DMN regions, and provides anatomical evidence to support the detected DMN subsystems. Finally, distinct modulation was seen within and between these DMN subcomponents using a neurocognitive aging model. Results suggest that the rat DMN can be partitioned into several subcomponents that may support distinct functions. These data encourage further investigation into the neurobiological mechanisms of DMN processing in preclinical models of both normal and disease states. 2. Functional connectivity hubs and networks in the awake marmoset brain. Along with advances in analytical methods, resting-state fMRI is allowing unprecedented access to a better understanding of the network organization of the brain. Evidence suggests that this architecture may incorporate highly functionally connected nodes, or hubs, and we have recently proposed local functional connectivity density (lFCD) mapping to identify highly-connected nodes in the human brain. We imaged awake marmosets to test whether, like the human brain, their brain contains FC hubs. Ten adult marmosets were acclimated to mild, comfortable restraint using individualized helmets and resting BOLD data were acquired during eight consecutive 10 min scans each. lFCD revealed prominent cortical and subcortical hubs of connectivity; specifically, in primary and secondary visual cortices (V1/V2), higher-order visual association areas (A19M/V6DM), posterior parietal and posterior cingulate areas (PGM and A23b/A31), thalamus, dorsal and ventral striatal areas (caudate, putamen, lateral septal nucleus, and anterior cingulate cortex (A24a). lFCD hubs were highly connected to widespread areas, and further revealed significant network-network interactions. These data provide a baseline platform for future investigations in a nonhuman primate model of the brain's network topology. 3. Short access to nicotine self administration is sufficient to upregulate expression of 42* nicotinic acetylcholine receptors in non-human primates. Although nicotine exposure upregulates the 42* subtype of nicotinic acetylcholine receptors (nAChRs), the upregulation of nAChRs in non-human primates voluntarily self-administering nicotine has never been demonstrated. To determine if short access to nicotine in a non-human primate model of nicotine self-administration is sufficient to induce nAChRs upregulation we combined a nicotine self-administration paradigm with in vivo measure of 42* nAChRs using 2-(18)Ffluoro-A-85380 (2-FA) and positron emission tomography (PET) in six squirrel monkeys. PET measurement was performed before and after IV nicotine self-administration (unit dose 10 g/kg per injection under a fixed-ratio (FR) schedule of reinforcement. Intermittent access (1 h daily per weekday) to nicotine was allowed for 4wks and levels of 42* nAChRs were measured 4days later. This intermittent access was sufficient to induce upregulation of 42* receptors in the whole brain (31 % upregulation) and in specific brain areas (+36 % in amygdala and +62 % in putamen). These results indicate that intermittent nicotine exposure is sufficient to produce change in nAChRs expression. 4. A novel method to induce nicotine dependence by intermittent drug delivery using osmotic minipumps. Although osmotic minipumps are a reliable method for inducing nicotine dependence in rodents, continuous nicotine administration does not accurately model the intermittent pattern of nicotine intake in cigarette smokers. We therefore investigated whether intermittent nicotine delivery via osmotic minipumps could induce dependence in rats, and to compare the magnitude and duration of withdrawal following forced abstinence from intermittent nicotine to that induced by continuous nicotine administration. Rats were implanted with saline-filled osmotic minipumps attached to polyethylene tubing that contained hourly unit doses of nicotine alternating with mineral oil to mimic injections. Three doses of nicotine (1.2, 2.4, and 4.8mg/kg/day) and saline were administered for 14days. A second group of rats was implanted with minipumps with tubing that delivered continuous nicotine for 14 days. Rats were administered a 1.5mg/kg subcutaneous mecamylamine challenge and observed for somatic signs of withdrawal on days 7, 14, 21, and 28 following minipump implantation. Fifteen somatic withdrawal signs were summed within a 50min observation period to obtain a composite Dependence Score. A generalized linear mixed-effects model revealed a significant DayDoseMethod interaction. Amongst continuously-treated rats, only 4.8mg/kg/d nicotine resulted in dependence scores significantly greater than those of controls at 14 days of exposure. In contrast, all intermittent nicotine groups showed significantly higher scores beginning at 7days exposure and persisting beyond 7days abstinence. In general, intermittent delivery produced a more robust withdrawal syndrome than continuous delivery, at a lower dose threshold and with greater persistence after forced abstinence. 5. Delayed emergence of methamphetamines enhanced cardiovascular effects in nonhuman primates during protracted methamphetamine abstinence. Methamphetamine abuse is linked with brain abnormalities, but its peripheral effects constitute an integral aspect of long-term methamphetamine use. Eight male rhesus monkeys with long histories of IV methamphetamine self-administration were evaluated 1 day, and 1, 4, 12, 26, and 52wks after their last methamphetamine self-administration session. On test days, isoflurane-anesthetized animals received a 0.35 mg/kg IV methamphetamine challenge. Controls consisted of 10 age and gender matched drug nave monkeys. Cardiovascular responses to methamphetamine were followed for 2.5h and EKGs were acquired at 3 & 12mos of abstinence and in the controls. No pre-methamphetamine baseline differences existed among 7 physiological measures across all conditions and controls. As expected, methamphetamine increased HR and BP in controls. However, immediately following the self-administration period, the BP response to methamphetamine challenge was reduced when compared to control monkeys. The peak and 150min average HR increases, as well as peak BP increases post-methamphetamine were significantly elevated between weeks 12 to 26 of abstinence. These data indicate the development of tolerance followed by sensitization to methamphetamine cardiovascular effects. The EKGs demonstrated decreased left ventricular ejection fraction and cardiac output at 3mos abstinence. Importantly, both cardiovascular sensitization and cardiotoxicity appeared to be reversible as they returned toward control group levels after 1 year of abstinence. Enhanced cardiovascular effects may occur after prolonged abstinence in addicts relapsing to methamphetamine and may underlie clinically reported acute cardiotoxic events.
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