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Eric J. Nestler - One of the best experts on this subject based on the ideXlab platform.
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Mesolimbic Dopamine Neurons in the Brain Reward Circuit Mediate Susceptibility to Social Defeat and Antidepressant Action
Journal of Neuroscience, 2010Co-Authors: A. K. Friedman, M.-h. Han, H. E. Covington, J.-l. Cao, D.c. Cooper, J. J. Walsh, Eric J. Nestler, M B WilkinsonAbstract:We previously reported that the activity of mesolimbic dopamine neurons of the ventral tegmental area (VTA) is a key determinant of behavioral susceptibility vs resilience to chronic social defeat stress. However, this was based solely on ex vivo measurements, and the in vivo firing properties of VTA dopamine neurons in susceptible and resilient mice, as well as the effects of antidepressant treatments, remain completely unknown. Here, we show that chronic (10 d) social defeat stress significantly increased the in vivo spontaneous firing rates and bursting events in susceptible mice but not in the resilient subgroup. Both the firing rates and bursting events were significantly negatively correlated with social avoidance behavior, a key behavioral abnormality induced by chronic social defeat stress. Moreover, the increased firing rates, bursting events, and avoidance behavior in susceptible mice were completely reversed by chronic (2 week), but not acute (single dose), treatments with the antidepressant medication fluoxetine (20 mg/kg). Chronic social defeat stress increased hyperpolarization-activated cation current (I(h)) in VTA dopamine neurons, an effect that was also normalized by chronic treatment with fluoxetine. As well, local infusion of I(h) inhibitors ZD7288 (0.1 μg) or DK-AH 269 (0.6 μg) into the VTA exerted antidepressant-like behavioral effects. Together, these data suggest that the firing patterns of mesolimbic dopamine neurons in vivo mediate an individual's responses to chronic stress and antidepressant action.
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the mesolimbic dopamine Reward Circuit in depression
Biological Psychiatry, 2006Co-Authors: Eric J. Nestler, William A CarlezonAbstract:The neural Circuitry that mediates mood under normal and abnormal conditions remains incompletely understood. Most attention in the field has focused on hippocampal and frontal cortical regions for their role in depression and antidepressant action. While these regions no doubt play important roles in these phenomena, there is compelling evidence that other brain regions are also involved. Here we focus on the potential role of the nucleus accumbens (NAc; ventral striatum) and its dopaminergic input from the ventral tegmental area (VTA), which form the mesolimbic dopamine system, in depression. The mesolimbic dopamine system is most often associated with the Rewarding effects of food, sex, and drugs of abuse. Given the prominence of anhedonia, reduced motivation, and decreased energy level in most individuals with depression, we propose that the NAc and VTA contribute importantly to the pathophysiology and symptomatology of depression and may even be involved in its etiology. We review recent studies showing that manipulations of key proteins (e.g. CREB, dynorphin, BDNF, MCH, or Clock) within the VTA-NAc Circuit of rodents produce unique behavioral phenotypes, some of which are directly relevant to depression. Studies of these and other proteins in the mesolimbic dopamine system have established novel approaches to modeling key symptoms of depression in animals, and could enable the development of antidepressant medications with fundamentally new mechanisms of action.
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regulation of dopaminergic transmission and cocaine Reward by the clock gene
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Colleen A Mcclung, Kyriaki Sidiropoulou, Martha Hotz Vitaterna, Joseph S Takahashi, Francis J White, Donald C Cooper, Eric J. NestlerAbstract:Although there are clear interactions between circadian rhythms and drug addiction, mechanisms for such interactions remain unknown. Here we establish a role for the Clock gene in regulating the brain's Reward Circuit. Mice lacking a functional Clock gene display an increase in cocaine Reward and in the excitability of dopamine neurons in the midbrain ventral tegmental area, a key brain Reward region. These phenotypes are associated with increased expression and phosphorylation of tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis), as well as changes in several genes known to regulate dopamine activity in the ventral tegmental area. These findings demonstrate the involvement of a circadian-associated gene, Clock, in regulating dopamine function and cocaine Reward.
Miquel Martin - One of the best experts on this subject based on the ideXlab platform.
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operant behavior to obtain palatable food modifies erk activity in the brain Reward Circuit
European Neuropsychopharmacology, 2013Co-Authors: Thomas Guegan, Rafael Maldonado, Laura Cutando, Emanuela Santini, Gilberto Fisone, Albert Martinez, Emmanuel Valjent, Giuseppe Gangarossa, Miquel MartinAbstract:Food palatability produces behavioral modifications that resemble those induced by drugs of abuse. Palatability-induced behavioral changes require both, the activation of the endogenous cannabinoid system, and changes in structural plasticity in neurons of the brain Reward pathway. The ERK intracellular pathway is activated by CB1 receptors (CB1-R) and plays a crucial role in neuroplasticity. We investigated the activation of the ERK signaling cascade in the mesocorticolimbic system induced by operant training to obtain highly palatable isocaloric food and the involvement of the CB1-R in these responses. Using immunofluorescence techniques, we analyzed changes in ERK intracellular pathway activation in the mesocorticolimbic system of wild-type and CB1 knockout mice (CB1-/-) trained on an operant paradigm to obtain standard, highly caloric or highly palatable isocaloric food. Operant training for highly palatable isocaloric food, but not for standard or highly caloric food, produced a robust activation of the ERK signaling cascade in the same brain areas where this training modified structural plasticity. These changes induced by the operant training were absent in CB1-/-. We can conclude that the activation of the ERK pathway is associated to the neuroplasticity induced by operant training for highly palatable isocaloric food and might be involved in CB1-R mediated alterations in behavior and structural plasticity.
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operant behavior to obtain palatable food modifies neuronal plasticity in the brain Reward Circuit
European Neuropsychopharmacology, 2013Co-Authors: Thomas Guegan, Rafael Maldonado, Laura Cutando, Eduard Ayuso, Emanuela Santini, Gilberto Fisone, Fatima Bosch, Albert Martinez, Emmanuel Valjent, Miquel MartinAbstract:Palatability enhances food intake by hedonic mechanisms that prevail over caloric necessities. Different studies have demonstrated the role of endogenous cannabinoids in the mesocorticolimbic system in controlling food hedonic value and consumption. We hypothesize that the endogenous cannabinoid system could also be involved in the development of food-induced behavioral alterations, such as food-seeking and binge-eating, by a mechanism that requires neuroplastic changes in the brain Reward pathway. For this purpose, we evaluated the role of the CB1 cannabinoid receptor (CB1-R) in the behavioral and neuroplastic changes induced by operant training for standard, highly caloric or highly palatable isocaloric food using different genetics, viral and pharmacological approaches. Neuroplasticity was evaluated by measuring changes in dendritic spine density in neurons previously labeled with the dye DiI. Only operant training to obtain highly palatable isocaloric food induced neuroplastic changes in neurons of the nucleus accumbens shell and prefrontal cortex that were associated to changes in food-seeking behavior. These behavioral and neuroplastic modifications induced by highly palatable isocaloric food were dependent on the activity of the CB1-R. Neuroplastic changes induced by highly palatable isocaloric food are similar to those produced by some drugs of abuse and may be crucial in the alteration of food-seeking behavior leading to overweight and obesity.
Brian Knutson - One of the best experts on this subject based on the ideXlab platform.
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4 www.neuropsychopharmacology.org REVIEW The Reward Circuit: Linking Primate Anatomy and
2013Co-Authors: Human Imaging, Suzanne N. Haber, Brian KnutsonAbstract:Although cells in many brain regions respond to Reward, the cortical-basal ganglia Circuit is at the heart of the Reward system. The key structures in this network are the anterior cingulate cortex, the orbital prefrontal cortex, the ventral striatum, the ventral pallidum, and the midbrain dopamine neurons. In addition, other structures, including the dorsal prefrontal cortex, amygdala, hippocampus, thalamus, and lateral habenular nucleus, and specific brainstem structures such as the pedunculopontine nucleus, and the raphe nucleus, are key components in regulating the Reward Circuit. Connectivity between these areas forms a complex neural network that mediates different aspects of Reward processing. Advances in neuroimaging techniques allow better spatial and temporal resolution. These studies now demonstrate that human functional and structural imaging results map increasingly close to primate anatomy
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The Reward Circuit: Linking primate anatomy and human imaging
Neuropsychopharmacology, 2010Co-Authors: Suzanne N. Haber, Brian KnutsonAbstract:Although cells in many brain regions respond to Reward, the cortical-basal ganglia Circuit is at the heart of the Reward system. The key structures in this network are the anterior cingulate cortex, the orbital prefrontal cortex, the ventral striatum, the ventral pallidum, and the midbrain dopamine neurons. In addition, other structures, including the dorsal prefrontal cortex, amygdala, hippocampus, thalamus, and lateral habenular nucleus, and specific brainstem structures such as the pedunculopontine nucleus, and the raphe nucleus, are key components in regulating the Reward Circuit. Connectivity between these areas forms a complex neural network that mediates different aspects of Reward processing. Advances in neuroimaging techniques allow better spatial and temporal resolution. These studies now demonstrate that human functional and structural imaging results map increasingly close to primate anatomy.
Godfrey D. Pearlson - One of the best experts on this subject based on the ideXlab platform.
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robust changes in Reward Circuitry during Reward loss in current and former cocaine users during performance of a monetary incentive delay task
Biological Psychiatry, 2013Co-Authors: Krishna T Patel, Michael C. Stevens, Godfrey D. Pearlson, Marc N Potenza, Shashwath A Meda, Christine Muska, Andre D ThomasAbstract:Background Abnormal function in Reward Circuitry in cocaine addiction could predate drug use as a risk factor, follow drug use as a consequence of substance-induced alterations, or both. Methods We used a functional magnetic resonance imaging monetary incentive delay task (MIDT) to investigate Reward-loss neural response differences among 42 current cocaine users, 35 former cocaine users, and 47 healthy subjects who also completed psychological measures and tasks related to impulsivity and Reward. Results We found various Reward processing-related group differences in several MIDT phases. Across task phases we found a control > current user > former user activation pattern, except for loss outcome, where former compared with current cocaine users activated ventral tegmental area more robustly. We also found regional prefrontal activation differences during loss anticipation between cocaine-using groups. Both groups of cocaine users scored higher than control subjects on impulsivity, compulsivity and Reward-punishment sensitivity factors. In addition, impulsivity-related factors correlated positively with activation in amygdala and negatively with anterior cingulate activation during loss anticipation. Conclusions Compared with healthy subjects, both former and current users displayed abnormal brain activation patterns during MIDT performance. Both cocaine groups differed similarly from healthy subjects, but differences between former and current users were localized to the ventral tegmental area during loss outcome and to prefrontal regions during loss anticipation, suggesting that long-term cocaine abstinence does not normalize most Reward Circuit abnormalities. Elevated impulsivity-related factors that relate to loss processing in current and former users suggest that these tendencies and relationships may pre-exist cocaine addiction.
Michael C. Stevens - One of the best experts on this subject based on the ideXlab platform.
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robust changes in Reward Circuitry during Reward loss in current and former cocaine users during performance of a monetary incentive delay task
Biological Psychiatry, 2013Co-Authors: Krishna T Patel, Michael C. Stevens, Godfrey D. Pearlson, Marc N Potenza, Shashwath A Meda, Christine Muska, Andre D ThomasAbstract:Background Abnormal function in Reward Circuitry in cocaine addiction could predate drug use as a risk factor, follow drug use as a consequence of substance-induced alterations, or both. Methods We used a functional magnetic resonance imaging monetary incentive delay task (MIDT) to investigate Reward-loss neural response differences among 42 current cocaine users, 35 former cocaine users, and 47 healthy subjects who also completed psychological measures and tasks related to impulsivity and Reward. Results We found various Reward processing-related group differences in several MIDT phases. Across task phases we found a control > current user > former user activation pattern, except for loss outcome, where former compared with current cocaine users activated ventral tegmental area more robustly. We also found regional prefrontal activation differences during loss anticipation between cocaine-using groups. Both groups of cocaine users scored higher than control subjects on impulsivity, compulsivity and Reward-punishment sensitivity factors. In addition, impulsivity-related factors correlated positively with activation in amygdala and negatively with anterior cingulate activation during loss anticipation. Conclusions Compared with healthy subjects, both former and current users displayed abnormal brain activation patterns during MIDT performance. Both cocaine groups differed similarly from healthy subjects, but differences between former and current users were localized to the ventral tegmental area during loss outcome and to prefrontal regions during loss anticipation, suggesting that long-term cocaine abstinence does not normalize most Reward Circuit abnormalities. Elevated impulsivity-related factors that relate to loss processing in current and former users suggest that these tendencies and relationships may pre-exist cocaine addiction.
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individuals family history positive for alcoholism show functional magnetic resonance imaging differences in Reward sensitivity that are related to impulsivity factors
Biological Psychiatry, 2011Co-Authors: Melissa M Andrews, Michael C. Stevens, Marc N Potenza, Shashwath A Meda, Andre D Thomas, Stephanie S Omalley, John H Krystal, Patrick D Worhunsky, Gregory A. BookAbstract:Background Substance-abusing individuals tend to display abnormal Reward processing and a vulnerability to being impulsive. Detoxified alcoholics show differences in regional brain activation during a monetary incentive delay task. However, there is limited information on whether this uncharacteristic behavior represents a biological predisposition toward alcohol abuse, a consequence of chronic alcohol use, or both. Methods We investigated proposed neural correlates of substance disorder risk by examining Reward system activity during a monetary incentive delay task with separate Reward prospect, Reward anticipation, and Reward outcome phases in 30 individuals with and 19 without family histories of alcoholism. All subjects were healthy, lacked DSM-IV past or current alcohol or substance abuse histories, and were free of illegal substances as verified by a urine toxicology screening at the time of scanning. Additionally, we explored specific correlations between task-related nucleus accumbens (NAcc) activation and distinct factor analysis-derived domains of behavioral impulsivity. Results During Reward anticipation, functional magnetic resonance imaging data confirmed blunted NAcc activation in family history positive subjects. In addition, we found atypical activation in additional Reward-associated brain regions during additional task phases. We further found a significant negative correlation between NAcc activation during Reward anticipation and an impulsivity construct. Conclusions Overall, results demonstrate that sensitivity of the Reward Circuit, including NAcc, is functionally different in alcoholism family history positive individuals in multiple regards.