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Open Access Publications from the University of California

Scholarly Works (11 results)

  • Article
  • Peer Reviewed
UC San Francisco Previously Published Works (2022)
Dopamine modulation of nucleus accumbens (NAc) circuitry is central to theories of reward seeking and reinforcement learning. Despite decades of effort, the acute dopamine actions on the NAc microcircuitry remain puzzling. Here, we dissect out the direct actions of dopamine on lateral inhibition between medium spiny neurons (MSNs) in mouse brain slices and find that they are pathway specific. Dopamine potently depresses GABAergic transmission from presynaptic dopamine D2 receptor-expressing MSNs (D2-MSNs), whereas it potentiates transmission from presynaptic dopamine D1 receptor-expressing MSNs (D1-MSNs) onto other D1-MSNs. To our surprise, presynaptic D2 receptors mediate only half of the depression induced by endogenous and exogenous dopamine. Presynaptic serotonin 5-HT1B receptors are responsible for a significant component of dopamine-induced synaptic depression. This study clarifies the mechanistic understanding of dopamine actions in the NAc by showing pathway-specific modulation of lateral inhibition and involvement of D2 and 5-HT1B receptors in dopamine depression of D2-MSN synapses.
    Cover page: Serotonin receptors contribute to dopamine depression of lateral inhibition in the nucleus accumbens
    • Article
    Working Papers (2003)

    This research involves the development of a tool that can be used to assess the changes in traffic safety tendencies that result from changes in traffic flow. The tool uses data from single inductive loop detectors, converting 30-second observations of volume and occupancy for multiple freeway lanes into traffic flow regimes. Each regime has a specific pattern of crash types, which were determined through nonlinear multivariate analyses of over 1,000 crashes on freeways in Southern California. These analyses revealed ways in which differences in variances in speeds and volumes across lanes, as well as central tendencies of speeds and volumes, combine in complex ways to explain crash taxonomy. This research may provide the foundation to forecast the crash rates, in terms of vehicle miles of travel, for vehicles that are exposed to different traffic flow conditions.

      Cover page: A Tool to Evaluate the Safety Effects of Changes in Freeway Traffic Flow
      • Article
      Working Papers (2003)

      One source of vehicle conflict is the freeway weaving section, where a merge and diverge in close proximity require vehicles either entering or exiting the freeway to execute one or more lane changes. Using accident data for a portion of Southern California, we examined accidents that occurred on three types of weaving sections defined in traffic engineering: Type A, where every merging or diverging vehicle must execute one lane change, Type B, where either merging or diverging can be done without changing lanes, and Type C, where one maneuver requires at least two lane changes. We found no difference among these three types in terms of overall accident rates for 55 weaving sections over one year (1998). However, there were significant differences in terms of the types of accidents that occur within these types in terms of severity, and location of the primary collision, the factors causing the accident, and the time period in which the accident is most likely to occur. These differences in aspects of safety lead to implications for traffic engineering improvements.

        Cover page: Safety Aspects of Freeway Weaving Sections
        • Article
        Research Reports (2002)
        Understanding the benefits of improved traffic flow (reduced congestion) is critical to the assessment of investments in infrastructure or traffic management and control. Improved flow should lead to reductions in travel time, vehicle emissions, fuel usage, psychological stress on drivers, and improved safety.    However, the manner in which safety is improved by smoothing traffic flow is not well understood. The documented research is aimed at shedding light on the complex relationships between traffic flow and traffic accidents (crashes).
          Cover page: Freeway Safety as a Function of Traffic Flow: The FITS Tool for Evaluating ATMS Operations
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2021)
          Fyn kinase in the dorsomedial striatum (DMS) of rodents plays a central role in mechanisms underlying excessive alcohol intake. The DMS is comprised of medium spiny neurons (MSNs) that project directly (dMSNs) or indirectly (iMSNs) to the substantia nigra. Here, we examined the cell-type specificity of Fyns actions in alcohol use. First, we knocked down Fyn selectively in DMS dMSNs or iMSNs of mice and measured the level of alcohol consumption. We found that downregulation of Fyn in dMSNs, but not in iMSNs, reduces excessive alcohol but not saccharin intake. D1Rs are coupled to Gαs/olf, which activate cAMP signaling. To examine whether Fyns actions are mediated through cAMP signaling, DMS dMSNs were infected with GαsDREADD, and the activation of Fyn signaling was measured following CNO treatment. We found that remote stimulation of cAMP signaling in DMS dMSNs activates Fyn and promotes the phosphorylation of the Fyn substrate, GluN2B. In contract, remote activation of GαsDREADD in DLS dMSNs did not alter Fyn signaling. We then tested whether activation of GαsDREADD in DMS dMSNs or iMSNs alters alcohol intake and observed that CNO-dependent activation of GαsDREADD in DMS dMSNs but not iMSNs increases alcohol but not saccharin intake. Finally, we examined the contribution of Fyn to GαsDREADD-dependent increase in alcohol intake, and found that systemic administration of the Fyn inhibitor, AZD0503 blocks GαsDREADD-dependent increase in alcohol consumption. Our results suggest that the cAMP-Fyn axis in the DMS dMSNs is a molecular transducer of mechanisms underlying the development of excessive alcohol consumption.
            Cover page: cAMP-Fyn signaling in the dorsomedial striatum direct pathway drives excessive alcohol use.
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2021)
            Fyn kinase in the dorsomedial striatum (DMS) of rodents plays a central role in mechanisms underlying excessive alcohol intake. The DMS is comprised of medium spiny neurons (MSNs) that project directly (dMSNs) or indirectly (iMSNs) to the substantia nigra. Here, we examined the cell-type specificity of Fyn's actions in alcohol use. First, we knocked down Fyn selectively in DMS dMSNs or iMSNs of mice and measured the level of alcohol consumption. We found that downregulation of Fyn in dMSNs, but not in iMSNs, reduces excessive alcohol but not saccharin intake. D1Rs are coupled to Gαs/olf, which activate cAMP signaling. To examine whether Fyn's actions are mediated through cAMP signaling, DMS dMSNs were infected with GαsDREADD, and the activation of Fyn signaling was measured following CNO treatment. We found that remote stimulation of cAMP signaling in DMS dMSNs activates Fyn and promotes the phosphorylation of the Fyn substrate, GluN2B. In contract, remote activation of GαsDREADD in DLS dMSNs did not alter Fyn signaling. We then tested whether activation of GαsDREADD in DMS dMSNs or iMSNs alters alcohol intake and observed that CNO-dependent activation of GαsDREADD in DMS dMSNs but not iMSNs increases alcohol but not saccharin intake. Finally, we examined the contribution of Fyn to GαsDREADD-dependent increase in alcohol intake, and found that systemic administration of the Fyn inhibitor, AZD0503 blocks GαsDREADD-dependent increase in alcohol consumption. Our results suggest that the cAMP-Fyn axis in the DMS dMSNs is a molecular transducer of mechanisms underlying the development of excessive alcohol consumption.
              Cover page: cAMP-Fyn signaling in the dorsomedial striatum direct pathway drives excessive alcohol useCreative Commons 'BY' version 4.0 license
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2015)
              A prominent aspect of drug addiction is the ability of drug-associated cues to elicit craving and facilitate relapse. Understanding the factors that regulate cue reactivity will be vital for improving treatment of addictive disorders. Low availability of dopamine (DA) D2 receptors (D2Rs) in the striatum is associated with high cocaine intake and compulsive use. However, the role of D2Rs of nonstriatal origin in cocaine seeking and taking behavior and cue reactivity is less understood and possibly underestimated. D2Rs expressed by midbrain DA neurons function as autoreceptors, exerting inhibitory feedback on DA synthesis and release. Here, we show that selective loss of D2 autoreceptors impairs the feedback inhibition of DA release and amplifies the effect of cocaine on DA transmission in the nucleus accumbens (NAc) in vitro. Mice lacking D2 autoreceptors acquire a cued-operant self-administration task for cocaine faster than littermate control mice but acquire similarly for a natural reward. Furthermore, although mice lacking D2 autoreceptors were able to extinguish self-administration behavior in the absence of cocaine and paired cues, they exhibited perseverative responding when cocaine-paired cues were present. This enhanced cue reactivity was selective for cocaine and was not seen during extinction of sucrose self-administration. We conclude that low levels of D2 autoreceptors enhance the salience of cocaine-paired cues and can contribute to the vulnerability for cocaine use and relapse.
                Cover page: Loss of Feedback Inhibition via D2 Autoreceptors Enhances Acquisition of Cocaine Taking and Reactivity to Drug-Paired Cues
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2022)
                Low dopamine D2 receptor (D2R) availability in the striatum can predispose for cocaine abuse; though how low striatal D2Rs facilitate cocaine reward is unclear. Overexpression of D2Rs in striatal neurons or activation of D2Rs by acute cocaine suppresses striatal Penk mRNA. Conversely, low D2Rs in D2-striatal neurons increases striatal Penk mRNA and enkephalin peptide tone, an endogenous mu-opioid agonist. In brain slices, met-enkephalin and inhibition of enkephalin catabolism suppresses intra-striatal GABA transmission. Pairing cocaine with intra-accumbens met-enkephalin during place conditioning facilitates acquisition of preference, while mu-opioid receptor antagonist blocks preference in wild-type mice. We propose that heightened striatal enkephalin potentiates cocaine reward by suppressing intra-striatal GABA to enhance striatal output. Surprisingly, a mu-opioid receptor antagonist does not block cocaine preference in mice with low striatal D2Rs, implicating other opioid receptors. The bidirectional regulation of enkephalin by D2R activity and cocaine offers insights into mechanisms underlying the vulnerability for cocaine abuse.
                  Cover page: Dopamine D2 receptors bidirectionally regulate striatal enkephalin expression: Implications for cocaine reward.
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2017)
                  The mammalian target of rapamycin complex 1 (mTORC1), a transducer of local dendritic translation, participates in learning and memory processes as well as in mechanisms underlying alcohol-drinking behaviors. Using an unbiased RNA-seq approach, we identified Prosapip1 as a novel downstream target of mTORC1 whose translation and consequent synaptic protein expression are increased in the nucleus accumbens (NAc) of mice excessively consuming alcohol. We demonstrate that alcohol-dependent increases in Prosapip1 levels promote the formation of actin filaments, leading to changes in dendritic spine morphology of NAc medium spiny neurons (MSNs). We further demonstrate that Prosapip1 is required for alcohol-dependent synaptic localization of GluA2 lacking AMPA receptors in NAc shell MSNs. Finally, we present data implicating Prosapip1 in mechanisms underlying alcohol self-administration and reward. Together, these data suggest that Prosapip1 in the NAc is a molecular transducer of structural and synaptic alterations that drive and/or maintain excessive alcohol use.
                    Cover page: Prosapip1-Dependent Synaptic Adaptations in the Nucleus Accumbens Drive Alcohol Intake, Seeking, and Reward
                    • Article
                    • Peer Reviewed
                    UC San Francisco Previously Published Works (2024)
                    Alcohol use disorder (AUD) is frequently comorbid with anxiety disorders, yet whether alcohol abuse precedes or follows the expression of anxiety remains unclear. Rodents offer control over the first drink, an advantage when testing the causal link between anxiety and AUD. Here, we utilized a risk-avoidance task to determine anxiety-like behaviors before and after alcohol exposure. We found that alcohols anxiolytic efficacy varied among inbred mice and mice with high risk-avoidance showed heightened alcohol relief. While dopamine D1 receptors in the striatum are required for alcohols relief, their levels alone were not correlated with relief. Rather, the ratio between striatal D1 and D2 receptors was a determinant factor for risk-avoidance and alcohol relief. We show that increasing striatal D1 to D2 receptor ratio was sufficient to promote risk-avoidance and enhance alcohol relief, even at initial exposure. Mice with high D1 to D2 receptor ratio were more prone to continue drinking despite adverse effects, a hallmark of AUD. These findings suggest that an anxiety phenotype may be a predisposing factor for AUD.
                      Cover page: Preexisting risk-avoidance and enhanced alcohol relief are driven by imbalance of the striatal dopamine receptors in mice.
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