1. The relationship between spontaneous ongoing activity and task-evoked activity Spontaneous fluctuations in the resting state fMRI signal exhibit structured spatial and temporal patterns. However, the underlying mechanisms of the fluctuations are still poorly understood. The goal of this study is to investigate how tasks modulate ongoing spontaneous activity. To this end, we modulated brain activity by continuous unilateral deflection of rat whiskers at different frequencies, and performed epidural electroencephalogram (EEG) recording and fMRI experiments. We have found that functional connectivity in bilateral WBC was modulated by unilateral continuous whisker stimulation at 2 Hz, but surprisingly not at 6 Hz. Electrophysiologically, epidural EEG recording reveals that, in the high frequency ranges, power correlation in bilateral WBC was significantly modulated across all stimulation conditions. However, only in the delta frequency range was the power correlation significantly modulated at 2 Hz, but not at 6 Hz, thus distinguishing these two experimental conditions. We reason that if LFP signal in the high frequency bands are the major contributors, then by modulating brain electrical activity within these bands, one should expect modulations in corresponding functional connectivity measured by fMRI. This is not supported by our data. On the other hand, when the stimulation induced power correlation in the delta band, we also observed changes in functional connectivity. These findings together support the view that spontaneous activity in the delta band drives the rsMRI signal as manifested in functional connectivity (Presented in SfN 2012) 2. Large scale brain networks in the awake, truly resting marmoset monkey Resting state functional MRI is a powerful tool that is increasingly employed as a non-invasive method for investigating whole-brain circuitry, and holds great potential as a possible diagnostic for disease. Despite this potential, few resting state studies have utilized animal models (of which nonhuman primates represent our best chance of understanding complex human neuropsychiatric disease), and no work has characterized networks in awake, truly resting animals. Here we present results from a small New World monkey that allows for the characterization of resting state networks in the awake state. Six adult common marmosets (Callithrix jacchus) were acclimated to light, comfortable restraint using individualized helmets. Following behavioral training, resting BOLD data were acquired during eight consecutive 10-minute scans for each conscious subject. Group independent component analysis (gICA) revealed twelve brain networks that overlap substantially with known anatomically constrained circuits seen in the awake human. Specifically, we found eight sensory and lower-order networks (four visual, two somatomotor, a cerebellar, and a caudate-putamen network), and four higher-order association networks (a default mode-like network, an orbitofrontal, a fronto-polar, and a network resembling the human salience network). In addition to their functional relevance, these network patterns bear great correspondence to those previously described in awake humans. This first of its kind report in an awake New World nonhuman primate provides a platform for mechanistic neurobiological examination for existing disease models established in the marmoset. (Under revision) 3. Glutamate mapping using chemical exchange saturation transfer (CEST) imaging In vivo measurement of glutamate (Glu) in brain subcortex can elucidate the role these structures play in cognition and neuropsychiatric disorders. Traditional MRS/MRSI methods to detect Glu are hindered by their low sensitivity and thus low spatial resolution. Recently, a novel MRI method based on the Glu chemical exchange saturation transfer (GluCEST) effect has been developed for detecting brain Glu in millimolar concentrations. The new method improve the sensitivity of Glu detection for 700 times and could open the door to Glu mapping with high spatial resolution comparable to MRI. We has implemented and optimized this novel method on our 9.4 T animal MRI scanner and successfully obtained primary results on both phantom and rat. Further validation study is being carried out and the newly developed method could be a very useful tool to observe local transmitter changes of whole brain in neurological diseases and potentially the therapy effect of medicine. 4. Ultra-short TE single-voxel neurochemical profiling techniques A group of localized in vivo 1-H MR spectroscopy (MRS) techniques with spin-echo time (TE) <10 ms were developed/optimized on the 9.4 T animal MRI scanner. Using the widely acknowledged MRS quantification tool LCModel, 13 metabolites/neurotransmitters including creatine (Cr), phosphocreatine (PCr), -aminobutyric acid (GABA), glucose (Glc), glutamine (Gln), glutamate (Glu), glutathione (GSH), phosphocholine (PCh), myo-inositol(mI), lactate (Lac), N-acetylaspartate (NAA), N-acetylaspartylglutamate (NAAG) and taurine (Tau) can be simultaneously detected and reliably quantified (CramerRao lower bounds <10%) with a reasonable SNR and shimming. Also every method has its specific features such as extreme short TE, minimal chemical shift displacement, insensitive to motion, macromolecule suppression etc., and could have its applications in studies with specific requirements. These ultra-short TE MRS may lead to a noninvasive assessment of neurochemical profile in vivo and time-resolved functional NMR spectroscopy for the study of animal models of brain diseases. 5. A novel method to induce nicotine dependence by intermittent drug delivery using osmotic minipumps Osmotic pumps have been routinely used to automatically deliver various drugs and hormones systemically in preclinical neuroscience models, including rodent models of nicotine, cocaine and opiate dependence. However, this continuous method of drug administration fails to accurately mimic the typical pattern of nicotine intake in humans and also does not incorporate the rapid nicotinic receptor alterations that are known to occur in vivo. Intermittent drug delivery in rodents provides a more authentic model, but requires labor intensive intravenous surgery as well as instrumentation for and training with passive or self-administration procedures. In order to determine whether nicotine dependence can be induced by a simpler intermittent delivery system, rats were implanted (i.p.) with an osmotic pump attached to a Lynch coil, which was filled with alternating nicotine solution and mineral oil in volumes calculated to deliver a single nicotine injection every hr for 14 days. Two doses of nicotine (0.1 mg/kg/hr and 0.2 mg/kg/hr) and saline vehicle were administered (n=6 per group) using a model 2ML4 pump (Alzet). Animals were challenged with mecamylamine (1.5 mg/kg s.c.) and observed for somatic signs of nicotine withdrawal for 50 min (Malin et al., 1992) at 7, 14, and 21 days after pump implantation. The summation of these signs gave a withdrawal score for each rat, which was used to compare the degree of dependence between treatment groups and time points. A Group x Day ANOVA revealed a significant main effect of Group, whereby both low and moderate nicotine dose groups had significantly greater withdrawal scores than the saline group at 7, 14, and 21 days F (2, 15) = 8.87, P <0.05. Though somatic signs showed a trend for increased scores in a dose-dependent manner, the two nicotine groups did not significantly differ from one another. To our knowledge, this is the first study to demonstrate dose-dependent nicotine dependence following non-continuous delivery via an osmotic pump.

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Brynildsen, Julia K; Najar, Julie; Hsu, Li-Ming et al. (2016) A novel method to induce nicotine dependence by intermittent drug delivery using osmotic minipumps. Pharmacol Biochem Behav 142:79-84
Hsu, Li-Ming; Liang, Xia; Gu, Hong et al. (2016) Constituents and functional implications of the rat default mode network. Proc Natl Acad Sci U S A 113:E4541-7
Belcher, Annabelle M; Yen, Cecil Chern-Chyi; Notardonato, Lucia et al. (2016) Functional Connectivity Hubs and Networks in the Awake Marmoset Brain. Front Integr Neurosci 10:9
Wang, Leiming; Lu, Hanbing; Brown, P Leon et al. (2015) Manganese-Enhanced MRI Reflects Both Activity-Independent and Activity-Dependent Uptake within the Rat Habenulomesencephalic Pathway. PLoS One 10:e0127773
Jiang, Xia; Lu, Hanbing; Shigeno, Shuichi et al. (2014) Octopus visual system: a functional MRI model for detecting neuronal electric currents without a blood-oxygen-level-dependent confound. Magn Reson Med 72:1311-9
Belcher, Annabelle M; Yen, Cecil C; Stepp, Haley et al. (2013) Large-scale brain networks in the awake, truly resting marmoset monkey. J Neurosci 33:16796-804
Xu, Su; Ji, Yadong; Chen, Xi et al. (2013) In vivo high-resolution localized (1) H MR spectroscopy in the awake rat brain at 7 T. Magn Reson Med 69:937-43
Lu, Hanbing; Zou, Qihong; Gu, Hong et al. (2012) Rat brains also have a default mode network. Proc Natl Acad Sci U S A 109:3979-84
Luo, Qingfei; Lu, Huo; Lu, Hanbing et al. (2010) Comparison of visually evoked local field potentials in isolated turtle brain: patterned versus blank stimulation. J Neurosci Methods 187:26-32
Lu, Hanbing; Demny, Steven; Zuo, Yantao et al. (2010) Temporary disruption of the rat blood-brain barrier with a monoclonal antibody: a novel method for dynamic manganese-enhanced MRI. Neuroimage 50:7-14

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