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Previous work, using membrane receptor binding techniques, demonstrated an increase in hippocampal MK-801 binding sites in mice after chronic ethanol ingestion. The current studies, using quantitative autoradiography, demonstrate that chronic ethanol ingestion also produces increases in MK-801 binding in cerebral cortex, striatum and thalamus, as well as in hippocampus. The persistence of changes in MK-801 binding paralleled the time-course for ethanol withdrawal seizure susceptibility. These results support the hypothesis that an increase in the number of NMDA receptor/channel complexes in hippocampus, and possibly other brain regions, plays a role in the generation or expression of ethanol withdrawal seizures.

AbstractObjective: The marked increase in the prevalence of obesity in the United States has recently been attributed to the increased fructose consumption. To determine if and how fructose might promote obesity in an animal model, we measured body composition, energy intake, energy expenditure, substrate oxidation, and several endocrine parameters related to energy homeostasis in mice consuming fructose.Research Methods and Procedures: We compared the effects of ad libitum access to fructose (15% solution in water), sucrose (10%, popular soft drink), and artificial sweetener (0% calories, popular diet soft drink) on adipogenesis and energy metabolism in mice.Results: Exposure to fructose water increased adiposity, whereas increased fat mass after consumption of soft drinks or diet soft drinks did not reach statistical significance (n = 9 each group). Total intake of energy was unaltered, because mice proportionally reduced their caloric intake from chow. There was a trend toward reduced energy expenditure and increased respiratory quotient, albeit not significant, in the fructose group. Furthermore, fructose produced a hepatic lipid accumulation with a characteristic pericentral pattern.Discussion: These data are compatible with the conclusion that a high intake of fructose selectively enhances adipogenesis, possibly through a shift of substrate use to lipogenesis.

Recent theories and data suggest that adapted behavior involves economic computations during which multiple trade-offs between reward value, accuracy requirement, energy expenditure, and elapsing time are solved so as to obtain rewards as soon as possible while spending the least possible amount of energy. However, the relative impact of movement energy and duration costs on perceptual decision-making and movement initiation is poorly understood. Here, we tested 31 healthy subjects on a perceptual decision-making task in which they executed reaching movements to report probabilistic choices. In distinct blocks of trials, the reaching duration (“Time” condition) and energy (“Effort” condition) costs were independently varied compared to a “Reference” block, while decision difficulty was maintained similar at the block level. Participants also performed a simple delayed-reaching (DR) task aimed at estimating movement initiation duration in each motor condition. Results in that DR task show that long duration movements extended reaction times (RTs) in most subjects, whereas energy-consuming movements led to mixed effects on RTs. In the decision task, about half of the subjects decreased their decision durations (DDs) in the Time condition, while the impact of energy on DDs were again mixed across subjects. Decision accuracy was overall similar across motor conditions. These results indicate that movement duration and, to a lesser extent, energy expenditure, idiosyncratically affect perceptual decision-making and action initiation. We propose that subjects who shortened their choices in the time-consuming condition of the decision task did so to limit a drop of reward rate.

This study is divided into two parts; each designed to answer a separate but related question: Which brain regions are activated in humans by the rewarding properties of ethanol administration? Is it possible to demonstrate a conditioned response to a stimulus paired with rising blood alcohol concentrations (BAC) in humans and can this response be observed in the brain using functional magnetic resonance images (fMRI) techniques? Part 1. In order to determine which brain regions are activated by the rewarding properties of ethanol administration, we propose to use Blood Oxygenation Level Dependent (BOLD) fMRI techniques to test the hypothesis that during the time of rising and peak BAC, mesolimbic, mesocortical, and nigrostriatal dopamine (DA) terminal areas of the brain will show significant increases in cerebral blood flow. Healthy, non-alcoholic subjects will be given intravenous (IV) ethanol or placebo infusions on separate days. The infusions will have three phases. On each day, during the first phase a saline infusion will be used to measure basal brain blood flow. The second phase will be an ethanol infusion delivered at rates calculated to produce a BAC of 0.08 plus or minus 0.005 g/dl at 10 minutes. The rate of the infusion for the next 10 minutes (third phase) will be calculated to maintain BAC at the target level of 0.08 plus or minus 0.005 g/dl for the duration of the infusion. On the placebo day, subjects will receive a saline infusion at the same set of rates for phases two and three as used during their ethanol infusion. Continuous multi-slice fMRI data will be collected during each infusion. Part 2. In order to investigate conditioned response to ethanol, three groups of healthy, non-alcoholic subjects will be given a series of IV infusions on separate days. The experimental group will receive ethanol infusion paired with a conditioned stimulus (CS) which will be presented while the BAC is rising. One control group (I) of healthy, non-alcoholic subjects will also be given a series of intravenous ethanol infusions on separate days, but these infusions will not be paired with a CS. The other control group (II) will be given only saline infusions during the CS presentation. After three training sessions, all three groups will undergo an fMRI scan during which the CS will be paired with saline infusion. This will allow the response to the CS alone to be observed. After 10 minutes of CS presentation, the ethanol infusion will begin and continue for another 15 minutes. Conditioned response (CR) will be demonstrated if the experimental group shows greater increase in BOLD signal than the control groups in motivation areas such as mesolimbic, mesocortical, and nigrostriatal dopamine (DA) terminal areas of the brain in response to the CS while they receive the saline infusion. Control group II will also undergo an fMRI scan and will be given saline infusion followed by ethanol infusion during their last 15 minutes in the scanner to control for the non-specific effects of repeated infusions & scans on BOLD response to ethanol. If we are able to produce a CR in brain regions associated with motivation, it may be possible to use this CR as an experimental model for human alcohol craving. This study is designed to answer four questions: 1. Which brain regions are activated in humans by the rewarding properties of ethanol administration? 2. How does ethanol administration affect the brain response to visual cues known to evoke positive or negative emotion? 3. Do individuals who regularly drink in ethanol in large amounts (heavy drinkers) differ from individuals who do not regularly drink large amounts of ethanol (social drinkers) in how ethanol affects brain function? 4. Does ethanol administration affect the brain regions activated in a risk-taking task in social drinkers and heavy drinkers? In order to determine which brain regions are activated by the rewarding properties of ethanol administration, we propose to use Blood Oxygenation Level Dependent (BOLD) fMRI techniques to test the hypothesis that during the time of rising and peak BAC, mesolimbic, mesocortical, and nigrostriatal dopamine (DA) terminal areas of the brain will show significant increases in cerebral blood flow. Healthy, subjects who are not seeking treatment for an alcohol use disorder will be given intravenous (IV) ethanol or placebo infusions on separate days. An ethanol infusion will delivered at rates calculated to produce a BAC of 0.08 plus or minus. An ethanol infusion will delivered at rates calculated to produce a BAC of 0.08 plus or minus 0.005 g/dl at 15 minutes. Then the rate of the infusion will be adjusted so that for the next 30 minutes (second phase) BAC will be maintained at the target level of 0.08 0.005 g/dl. On the placebo day, subjects will receive a saline infusion at the same set of rates as used during their ethanol infusion. Continuous multi-slice fMRI data will be collected during each infusion. During each infusion, BOLD response to visual stimuli designed to evoke emotion will also be examined. In addition, we will compare the BOLD response of healthy social drinkers to that of healthy heavy drinkers. We will also compare the BOLD response elicited by risk-taking during the ethanol infusion to that during the placebo infusion in both social and heavy drinkers.

The brain is a non-linear dynamical system with a self-restoration process, which protects itself from external damage but is often a bottleneck for clinical treatment. To treat the brain to induce the desired functionality, formulation of a self-restoration process is necessary for optimal brain control. This study proposes a computational model for the brain's self-restoration process following the free-energy and degeneracy principles. Based on this model, a computational framework for brain control is established. We posited that the pre-treatment brain circuit has long been configured in response to the environmental (the other neural populations') demands on the circuit. Since the demands persist even after treatment, the treated circuit's response to the demand may gradually approximate the pre-treatment functionality. In this framework, an energy landscape of regional activities, estimated from resting-state endogenous activities by a pairwise maximum entropy model, is used to represent the pre-treatment functionality. The approximation of the pre-treatment functionality occurs via reconfiguration of interactions among neural populations within the treated circuit. To establish the current framework's construct validity, we conducted various simulations. The simulations suggested that brain control should include the self-restoration process, without which the treatment was not optimal. We also presented simulations for optimizing repetitive treatments and optimal timing of the treatment. These results suggest a plausibility of the current framework in controlling the non-linear dynamical brain with a self-restoration process.

AbstractA pulse sequence was implemented to observe the magnetization transfer (MT) effect on metabolites, water, and macromolecules in human frontal lobes in vivo at 1.5 Tesla. Signals were compared following the application of three hard pulses of 0.745 μT amplitude, applied at frequency offsets of either 2500 Hz or 30 kHz, preceding a conventional point‐resolved spectroscopy (PRESS)‐localized acquisition with an echo time (TE) of 30 ms and repetition time (TR) of 3 s. This gave an MT effect on water in vivo of 46%, while direct saturation by the MT pulses at 2.5 kHz offset was confirmed to be under 4% for all metabolites. We observed significant MT saturation in vivo for N‐acetylated compounds, choline (Cho), myo‐inositol, and lactate (Lac); a trend of an effect on glutamate + glutamine (Glx); and the typically observed effect on creatine (Cr). No significant MT effect was seen on the macromolecule signal, which was observed using metabolite nulling. Magn Reson Med, 2005. © 2005 Wiley‐Liss, Inc.