1. Rats possess a default mode brain network The default mode network (DMN) in humans has been suggested to support a variety of cognitive functions and has been implicated in an array of neuropsychological disorders. However, its function(s) remains poorly understood. We show for the first time that such a network also exists in the rat brain, and that the functional connectivity within this network is modified by neuroplastic changes induced by cocaine self-administration and withdrawal. Our data suggest that, despite the distinct evolutionary paths between rodent and primate brain, a well-organized, intrinsically coherent default brain network is a fundamental feature in the mammalian brain, whose primary functions might be to integrate multi-modal sensory and affective information to guide behavior in anticipation of changing environmental contingencies. 2. Modulation of on-going electrophysiological signal using whisker stimulation - Implications on resting state fMRI The aim of this study is to investigate how tasks modulate on-going spontaneous fluctuations. Previous studies have demonstrated that fMRI response is strongly correlated to evoked EEG signal. In this study, epidural EEG recordings were performed in bilateral whisker barrel cortices (WB) of alpha-chloralose-anesthetized rat brain, with visual cortex (VC) serving as a control site (n=12). Whisker stimulation was delivered by mechanically moving the whiskers along the rostral-cordal direction with a comb that was controlled by a computer. Time-frequency analysis was conducted using a sliding-window multi-taper analysis method, which were then split into 7 conventional frequency bands ranging from delta to high gamma. Power time course correlations between recording sites (bilateral WB and VC) were calculated. Whisker stimulation significantly augmented EEG power from alpha to high-gamma bands, but decreased power only in the delta band. Such modulations were specific to the contralateral WB as expected. Furthermore, whisker stimulation significantly decreased power correlations between bilateral WB only in gamma and very high-gamma bands;between either side of WB and VC, there was no significant changes in any of the frequency band. These data could have strong implications on identifying the major electrophysiological sources that contribute to resting state fMRI signal. 3. Characterization of activity-dependent entry and transport of manganese within the habenulointerpeduncular pathway using manganese-enhanced MRI As a calcium analog, manganese (Mn2+) enters neurons through a variety of voltage and ligand-gated ion channels. When injected intracerebrally, Mn2+ accumulates in neurons and is orthogradely transported via the fast axonal transport system. The paramagnetic properties of Mn2+ ions shorten the relaxation time of water protons in a magnetic field enhancing the T1-weighted magnetic resonance signal and enabling high resolution imaging of pathways containing the cation. Based on the premise that its entry into neurons is unambiguously activity-dependent, Mn2+-enhanced magnetic resonance imaging (MEMRI) is frequently used to assess functional connectivity between brain regions in vivo. In the present series of experiments, we sought to test this hypothesis by comparing the effectiveness of Mn2+ transport between the habenula (Hb) and interpeduncular nucleus (IPN) under conditions in which neuronal activity was pharmacologically manipulated. We found that Mn2+ injection into the Hb significantly increased the relaxation rate in the IPN when compared to sham controls. Addition of either NMDA or AMPA to the Mn2+ solution increased the change of R1. Surprisingly, prior injection of the fast Na channel blocker TTX, failed to prevent Mn2+-induced enhancement of R1 in the IPN or to block the potentiation induced by AMPA. Addition of NiCl2 to the TTX-containing cocktail prevented AMPA-induced potentiation of Mn2+ signal intensity in the IPN. However, the signal enhancement attributed to Mn2+ alone was not altered . These data are consistent with previous electrophysiological studies showing that Hb neurons exhibit Ca2+-dependent, TTX-insensitive oscillations in membrane potential and serve to illustrate the importance of considering the intrinsic electrical properties of neurons when evaluating results from MEMRI studies. 4. Magnetic resonance spectroscopy (MRS) techniques Proton magnetic resonance spectroscopy (MRS) provides a powerful tool for in vivo neurochemical quantification of the brain. At high fields (>7T), MRS with ultra-short spin-echo time (TE <10 ms) is capable of achieving reliable detection of neurotransmitters like glutamate, glutamine, GABA and even NAAG. Several ultra-short TE MRS techniques including STEAM, PRESS, SPECIAL and LASER have been developed and improved on our 9.4 T scanner. Better localization profiles and much less chemical shift displacement were achieved by optimized pulse shapes and localization schemes. Signal stability was improved by optimized broadband outer-volume suppression. Furthermore, a macromolecular suppression scheme was proposed to improve the measurement accuracy of the neurotransmitters from the contamination of macromolecular signals. Editing MRS techniques, which are dedicated to detect one or two neurotransmitters with the suppression of other metabolites, achieve cleaner signal background and thus better quantifications than ultra-short TE MRS. One of the editing techniques, difference spectroscopy, was developed and implemented on our high-field scanner. Quantification methods for GABA and Glutamate were also explored. 5. Development of imaging conscious marmosets using fMRI The aim of this project is to train marmosets in a mock scanner condition to tolerate restraint for awake imaging purposes. Preliminary work has begun, and we are in the process of training several animals for awake procedures. Once trained, marmosets will be submitted to several types of functional scans, with the larger goal of characterizing changes in brain and behavior following acute and protracted cocaine exposure. Resting state, drug- and cue-induced BOLD activity, and brain metabolite measurements will be taken using multimodal neuroimaging. Progress has been made in the following aspects: 1) Acquisition of anatomical MRI scans and head image processing used for computerized helmet production;2) Safe and reliable method of long term intravenous cocaine administration via the tail vein has been developed;and 3) Behavioral profile to evaluate and study cocaine-induced behaviors in freely-moving non-human primates has been developed. 6. Development of imaging conscious rats using fMRI The eventual aim is to investigate structural and functional plasticity occurring during incubation of heroin craving in awake behaving rats. This requires the development of methods to allow self-administration (SA) in a restrained rat. Therefore, initial work is aimed at developing a head and body restraint system, in addition to habituation training methods, in order to image animals in the magnet self-administering drugs i.v., or reinstating SA behavior induced by cues associated with the drug. Progress has been made in the following: 1) Creating a new body restraint jacket;and 2) Developing a rat holder that will contain the rat and to which the head will be fixed. 7. Optical stimulation and inhibition of prefrontal cortical neurons on whole brain fMRI signals.
We aim to investigate the effects of optical stimulation and inhibition of prefrontal cortical neurons on whole brain fMRI signals in anesthetized rats that are addicted to cocaine using a punishment self-administration model. This project is in its early development stage.
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