Ernest Gallo Clinic and Research Center

Emeryville, CA, United States

Ernest Gallo Clinic and Research Center

Emeryville, CA, United States
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Navarro-Cebrian A.,University of California at San Francisco | Navarro-Cebrian A.,Ernest Gallo Clinic and Research Center | Knight R.T.,University of California at Berkeley | Kayser A.S.,University of California at San Francisco | And 2 more authors.
Journal of Neuroscience | Year: 2013

Whether humans adjust their behavior in response to unaware errors remains a controversial issue relevant to insight in neuropsychiatric conditions. Initial error awareness studies found that the error-related negativity (ERN), an event-related potential (ERP) originating in the medial prefrontal cortex after errors, activated equally for aware and unaware errors, suggesting a candidate preconscious mechanism. However, recent studies demonstrate that the ERN decreases after unaware errors. We hypothesized that the ERN is dependent upon awareness, and predicted that previous discrepancies might be due to unaware errors not being differentiated from perceptually uncertain, low-confidence responses that might increase the ERN amplitude. Here we addressed this hypothesis by distinguishing between aware errors, unaware errors, and uncertain responses, and using stimuli (faces) associated with well established sensory ERPs to evaluate the degree of stimulus processing for each trial type. We found that while aware and unaware errors were related to failures at the time of response, uncertain responses were due to failures at the time of stimulus processing indexed by lower amplitude sensory ERPs. Moreover, uncertain responses showed similar ERN activity as aware errors, in comparison with decreased activity for unaware errors. Finally, compared with aware errors, uncertain responses and unaware errors showed reduced neural compensations, such as alpha suppression. Together these findings suggest that the ERN is activated by aware motor errors as well as sensory failures, and that both awareness and certainty are necessary for neural adaptations after errors. © 2013 the authors.


Hnasko T.S.,University of California at San Francisco | Hnasko T.S.,Ernest Gallo Clinic and Research Center | Hnasko T.S.,University of California at San Diego | Hjelmstad G.O.,University of California at San Francisco | And 4 more authors.
Journal of Neuroscience | Year: 2012

The ventral tegmental area (VTA) has a central role in the neural processes that underlie motivation and behavioral reinforcement. Although thought to contain only dopamine and GABA neurons, the VTA also includes a recently discovered population of glutamate neurons identified through the expression of the vesicular glutamate transporter VGLUT2. A subset of VGLUT2 + VTA neurons corelease dopamine with glutamate at terminals in the NAc, but others do not express dopaminergic markers and remain poorly characterized. Using transgenic mice that express fluorescent proteins in distinct cell populations, we now find that both dopamine and glutamate neurons in the medial VTA exhibit a smaller hyperpolarization-activated current (Ih) than more lateral dopamine neurons and less consistent inhibition by dopamine D2 receptor agonists. In addition, VGLUT2 + VTA neurons project to the nucleus accumbens (NAc), lateral habenula, ventral pallidum (VP), and amygdala. Optical stimulation of VGLUT2 + projections expressing channelrhodopsin-2 further reveals functional excitatory synapses in the VP as well as the NAc. Thus, glutamate neurons form a physiologically and anatomically distinct subpopulation of VTA projection neurons. © 2012 the authors.


Erickson D.T.,University of California at San Francisco | Erickson D.T.,Ernest Gallo Clinic and Research Center | Kayser A.S.,University of California at San Francisco | Kayser A.S.,Ernest Gallo Clinic and Research Center | Kayser A.S.,VA Northern California Health Care System
NeuroImage | Year: 2013

Humans can quickly engage a neural network to transform complex visual stimuli into a motor response. Activity from a key region within this network, the intraparietal sulcus (IPS), has been associated with evidence accumulation and motor planning, thus implicating it in sensorimotor transformations. If such transformations occur within a brain region, a key and untested prediction is that neural activity reflecting both the parametric amount of evidence available and the timing of motor planning can be independently manipulated. To investigate these ideas, we constructed a dot motion discrimination task in which information about response modality (what to use) and response mapping (how to use it) was provided independently either before or after presentation of a dot motion coherence stimulus whose strength varied across trials. Consistent with our hypothesis, activity within IPS covaried with dot motion coherence during the stimulus phase, and as information necessary for the response was delayed, the peak of IPS activity shifted to the response phase. In contrast, areas such as the motion-sensitive region MT. + and the supplementary motor area demonstrated activity limited to the stimulus and response phases of the task, respectively. These results show that activity in IPS correlates with temporally dissociable representations consistent with both evidence accumulation and motor planning, and suggest that IPS is a core component for sensorimotor transformations within the perceptual decision-making network. © 2013 Elsevier Inc.


Tai L.-H.,Ernest Gallo Clinic and Research Center | Lee A.M.,Ernest Gallo Clinic and Research Center | Lee A.M.,University of California at San Francisco | Benavidez N.,Ernest Gallo Clinic and Research Center | And 5 more authors.
Nature Neuroscience | Year: 2012

In changing environments, animals must adaptively select actions to achieve their goals. In tasks involving goal-directed action selection, striatal neural activity has been shown to represent the value of competing actions. Striatal representations of action value could potentially bias responses toward actions of higher value. However, no study to date has demonstrated the direct effect of distinct striatal pathways in goal-directed action selection. We found that transient optogenetic stimulation of dorsal striatal dopamine D1 and D2 receptorg-expressing neurons during decision-making in mice introduced opposing biases in the distribution of choices. The effect of stimulation on choice was dependent on recent reward history and mimicked an additive change in the action value. Although stimulation before and during movement initiation produced a robust bias in choice behavior, this bias was substantially diminished when stimulation was delayed after response initiation. Together, our data suggest that striatal activity is involved in goal-directed action selection. © 2012 Nature America, Inc. All rights reserved.


Lee A.M.,University of Oregon | Lee A.M.,University of California at San Francisco | Hoy J.L.,University of Oregon | Bonci A.,U.S. National Institute on Drug Abuse | And 5 more authors.
Neuron | Year: 2014

Sensory processing is dependent upon behavioral state. In mice, locomotion is accompanied by changes in cortical state and enhanced visual responses. Although recent studies have begun to elucidate intrinsic cortical mechanisms underlying this effect, the neural circuits that initially couple locomotion to cortical processing are unknown. The mesencephalic locomotor region (MLR) has been shown to be capable of initiating running and is associated with the ascending reticular activating system. Here, we find that optogenetic stimulation of the MLR in awake, head-fixed mice can induce both locomotion and increases in the gain of cortical responses. MLR stimulation below the threshold forovert movement similarly changed cortical processing, revealing that MLR's effects on cortex are dissociable from locomotion. Likewise, stimulation of MLR projections to the basal forebrain also enhanced cortical responses, suggesting a pathway linking the MLR to cortex. These studies demonstrate that the MLR regulates cortical state in parallel with locomotion. © 2014 Elsevier Inc.


Kotowski S.,University of California at San Francisco | Hopf F.W.,University of California at San Francisco | Hopf F.W.,Ernest Gallo Clinic and Research Center | Seif T.,Ernest Gallo Clinic and Research Center | And 4 more authors.
Neuron | Year: 2011

D 1 dopamine receptors are primary mediators of dopaminergic signaling in the CNS. These receptors internalize rapidly following agonist-induced activation, but the functional significance of this process is unknown. We investigated D 1 receptor endocytosis and signaling in HEK293 cells and cultured striatal neurons using real-time fluorescence imaging and cAMP biosensor technology. Agonist-induced activation of D 1 receptors promoted endocytosis of receptors with a time course overlapping that of acute cAMP accumulation. Inhibiting receptor endocytosis blunted acute D 1 receptor-mediated signaling in both dissociated cells and striatal slice preparations. Although endocytic inhibition markedly attenuated acute cAMP accumulation, inhibiting the subsequent recycling of receptors had no effect. Further, D 1 receptors localized in close proximity to endomembrane-associated trimeric G protein and adenylyl cyclase immediately after endocytosis. Together, these results suggest a previously unanticipated role of endocytosis, and the early endocytic pathway, in supporting rapid dopaminergic neurotransmission. © 2011 Elsevier Inc.


Milan-Lobo L.,Ernest Gallo Clinic and Research Center | Whistler J.L.,Ernest Gallo Clinic and Research Center | Whistler J.L.,University of California at San Francisco
Journal of Pharmacology and Experimental Therapeutics | Year: 2011

Heteromerization of opioid receptors has been shown to alter opioid receptor pharmacology. However, how receptor heteromerization affects the processes of endocytosis and postendocytic sorting has not been closely examined. This question is of particular relevance for heteromers of the μ-opioid receptor (MOR) and δ-opioid receptor (DOR), because the MOR is recycled primarily after endocytosis and the DOR is degraded in the lysosome. Here, we examined the endocytic and postendocytic fate of MORs, DORs, and DOR/MOR heteromers in human embryonic kidney 293 cells stably expressing each receptor alone or coexpressing both receptors. We found that the clinically relevant MOR agonist methadone promotes endocytosis of MOR but also the DOR/MOR heteromer. Furthermore, we show that DOR/MOR heteromers that are endocytosed in response to methadone are targeted for degradation, whereas MORs in the same cell are significantly more stable. It is noteworthy that we found that the DOR-selective antagonist naltriben mesylate could block both methadone- and [D-Ala2,NMe-Phe4,Gly-ol5]-enkephalin-induced endocytosis of the DOR/ MOR heteromers but did not block signaling from this heteromer. Together, our results suggest that the MOR adopts novel trafficking properties in the context of the DOR/MOR heteromer. In addition, they suggest that the heteromer shows "biased antagonism," whereby DOR antagonist can inhibit trafficking but not signaling of the DOR/MOR heteromer. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.


Kayser A.S.,University of California at San Francisco | Kayser A.S.,Ernest Gallo Clinic and Research Center | Kayser A.S.,VA Northern California Health Care System | Mitchell J.M.,University of California at San Francisco | And 4 more authors.
Neuropsychopharmacology | Year: 2015

Whether to continue to exploit a source of reward, or to search for a new one of potentially greater value, is a fundamental and underconstrained decision. Recent computational studies of this exploration-exploitation tradeoff have found that variability in exploration across individuals is influenced by a functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene, whose protein product degrades synaptically released dopamine. However, these and other genotype-phenotype associations have rarely been causally tested. To directly test this association and to evaluate additional behavioral characteristics, including perceived locus of control (LOC), here we used the COMT inhibitor tolcapone in a randomized, double-blind, counterbalanced, within-subject study of 66 subjects genotyped for the Val158Met allele to assess the hypothesis that reducing COMT enzymatic activity interacts with genotype to increase uncertainty-driven exploration. In keeping with our initial hypothesis, tolcapone led to an increase in exploratory, but not exploitative, behavior in Met/Met rather than Val/Val subjects. Independent of genotype, those subjects with a more external LOC also showed increases in uncertainty-driven exploration on tolcapone relative to placebo. However, we did not replicate our previous finding that Met/Met subjects show greater exploration at baseline. Together these findings support a model in which exploration is hypothesized to have a dopaminergic basis. Moreover, in keeping with findings in other behavioral and cognitive domains, the response to an increase in presumptively frontal dopamine is dependent upon baseline dopamine tone. © 2015 American College of Neuropsychopharmacology. All rights reserved.


Enquist J.,Ernest Gallo Clinic and Research Center | Ferwerda M.,Ernest Gallo Clinic and Research Center | Madhavan A.,Ernest Gallo Clinic and Research Center | Hok D.,Ernest Gallo Clinic and Research Center | And 2 more authors.
Neuropsychopharmacology | Year: 2012

Alleviating anxiety and depression is pivotal for reducing the risk of relapse in alcoholics. Currently available anxiolytic treatments are limited by side effects, including reduced efficacy in alcoholics, addiction, and sedation. We examined whether the neuropeptide S receptor (NPSR) was effective at controlling ethanol consumption and the anxiety and depression produced by forced abstinence from ethanol. We found that the anxiolytic and anti-depressant effects of NPS are enhanced in acute ethanol abstinent mice. In addition, we found that NPS reduced ethanol consumption and is not in and of itself rewarding. We also provide evidence that ethanol consumption increases the ability of NPS to modulate neuronal activity in the basolateral amygdala. Finally, we found that local injection of NPS in the basolateral amygdala promotes anxiolysis after chronic ethanol consumption, thereby providing insight into the molecular mechanism underlying the changes in behavioral response to NPS. In light of the improved anxiolytic efficacy and benign side effects of NPS in ethanol-withdrawn animals, the NPSR may prove a suitable target for reducing relapse in alcoholism. © 2012 American College of Neuropsychopharmacology. All rights reserved.


Feduccia A.A.,Ernest Gallo Clinic and Research Center | Chatterjee S.,Ernest Gallo Clinic and Research Center | Bartlett S.E.,Ernest Gallo Clinic and Research Center | Bartlett S.E.,Queensland University of Technology
Frontiers in Molecular Neuroscience | Year: 2012

Addictive drugs can activate systems involved in normal reward-related learning, creating long-lasting memories of the drug's reinforcing effects and the environmental cues surrounding the experience. These memories significantly contribute to the maintenance of compulsive drug use as well as cue-induced relapse which can occur even after long periods of abstinence. Synaptic plasticity is thought to be a prominent molecular mechanism underlying drug-induced learning and memories. Ethanol and nicotine are both widely abused drugs that share a common molecular target in the brain, the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are ligand-gated ion channels that are vastly distributed throughout the brain and play a key role in synaptic neurotransmission. In this review, we will delineate the role of nAChRs in the development of ethanol and nicotine addiction. We will characterize both ethanol and nicotine's effects on nAChR-mediated synaptic transmission and plasticity in several key brain areas that are important for addiction. Finally, we will discuss some of the behavioral outcomes of drug-induced synaptic plasticity in animal models. An understanding of the molecular and cellular changes that occur following administration of ethanol and nicotine will lead to better therapeutic strategies. © 2012 Feduccia, Chatterjee and Bartlett.

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