Dual Modes of Dopamine Underly Distinct Facets of Impulsive Actions

During the pursuit of basic needs, animals sometimes fail to suppress actions that are maladaptive and counterproductive to their survival. In humans, these actions are often called impulsive because they can incur negative consequences. Impulsivity is ubiquitous across psychiatric disorders and related to debilitating outcomes such as substance abuse, crime and suicidality. Despite its risks, a lack of a neural mechanism understanding of impulsive actions impedes the development of effective treatments.In this dissertation, I set out to bridge the knowledge gained from the parallel fields of neuropsychopharmacology, experimental psychology, and systems neuroscience to uncover neural mechanisms of impulsive actions. Clinicians and scientists have produced mounting evidence of the involvement of the neuromodulator, dopamine (DA), but variability in the conceptualization and assessment of impulsivity have precluded a granular understanding akin to that of DA’s role in optimal behavior in classical conditioning paradigms, which is accounted for by reinforcement learning frameworks to a remarkable degree. Nonetheless, this framework fails to explain the counterintuitive phenomenon of negative auto-maintenance - that when reward is contingent on inaction, animals persistently fail to suppress approach behaviors and undermine the reinforcement learning tenet of reward optimization. I argue that we are now poised to exploit this phenomenon to uncover DA’s role in impulsive actions in light of recent insights on DA’s role in optimal behavior. To achieve this, I designed the cued reward approach suppression task, a twist on classical conditioning paradigms that pits reward pursuit against behavioral suppression in mice. The task provides quantitative real-time measurements of impulsive actions that were precisely related to mesolimbic DA activity, recorded with bulk imaging of midbrain DA cell activity and striatal DA release. I found that two features of DA activity predict distinct behavioral modes. The first is the canonical “phasic” activation, or synchronous bursts of activity, known to encode errors in reward prediction. The second is asynchronous population activity in between task related events, which I argue is suggestive of the elusive “tonic” DA, continuous levels of DA hypothesized to underlie many psychiatric disorders involving impulsivity. I found that phasic DA evoked by reward predicting cues reflected reward expectation and underlying motivational state. In contrast, variability in asynchronous DA activity prior to the trial start independently predicted vigor of adaptive and impulsive reward approach and tracked the local reward rate that drove moment-to-moment changes in action impulsivity. Furthermore, the rate of DA decay during reward approach specifically predicted the suppression of impulsive actions, highlighting a potential target for the exertion of behavioral control. Therefore, these results provide evidence that distinct facets of DA activity are related to dissociable aspects of impulsive actions with implications for refining the field’s current conception of mesolimbic DA’s role across a wider range of behavior

Midbrain Dopamine Neuron Activity Predicts Impulsive Actions in Mice

Background: Impulsivity, or acting without forethought or self-control despite negative consequences, increases the risk of suicidality, substance abuse, and violence. Dopamine (DA) is central to impulsivity, as posited by human neuroimaging data that highlight differences in DA-rich regions between healthy individuals and those with impulsivity-related disorders. DA is also central to reward processing, learning and motivation. While we understand that motivated behaviors are driven by phasic DA responses to reward information, we have yet to uncover how DA activity could drive the ability to suppress motivated behaviors when they are maladaptive. Methods: We developed a novel cued-reward lick-withholding task in which head-fixed mice must suppress anticipatory licking during a reward predicting cue (2s) in order to earn water reward. Three different auditory cues that predicted three different reward sizes (big, small, none) were randomly interleaved. The cue was restarted as many times as the animal licked prematurely (before the 2 second cue period was over). The total duration of the tone was used as a trial-by-trial measure of the degree of impulsivity. The task accomplishes the following: 1. It places Pavlovian cue responses in conflict with self-restraint, enabling us to study the neural substrates of action impulsivity. 2, It manipulates the degree of impulsivity by manipulating expected reward value, and 3. It provides a quantitative, trial-by-trial measure of action impulsivity that can be precisely related to neural activity. We measured DA neuron activity using fiber photometry, in which fluorescence emitted from GCaMP6f, a Calcium sensor, is used as a proxy for neural population activity. We specifically targeted DA cells by injecting GCaMP6f in the Ventral Tegmental Area (VTA) of DAT-Cre transgenic mice. An optical fiber was then implanted in the VTA to collect the bulk fluorescence signal. Results: Our behavioral results show that mice can discriminate between the three trial types and exhibit a learned waiting behavior. In addition, mice behaved more impulsively in anticipation of the larger reward, despite it resulting in a reduced rate of reward receipt. As expected, neural recordings demonstrate that phasic DA encodes expected and received reward value at reward cue and reward onset, respectively. However, when controlling for expected reward size, DA dynamically encodes the failure to suppress conditioned responses throughout the trial structure. First, cue-induced phasic DA activity is predictive of impulsivity level and may explain trial-to-trial variability in impulsivity. Second, DA ramping during the wait period predicts the onset of impulsive actions in a manner that reflects changes in reward expectation over time. Lastly, impulsive actions lead to greater DA reward responses, suggesting a mechanism for the persistence of this maladaptive behavior. Conclusions: These data suggest that phasic cue-induced DA activity may drive action impulsivity in addition to their role in learning and motivation

Exogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung

Invasive aspergillosis (IA) remains the primary cause of morbidity and mortality in chronic granulomatous disease (CGD) patients, often due to infection by Aspergillus species refractory to antifungals. This motivates the search for alternative treatments, including immunotherapy. We investigated the effect of exogenous type I interferon (IFN) activation on the outcome of IA caused by three Aspergillus species, A. fumigatus, A. nidulans, and A. tanneri, in CGD mice. The animals were treated with poly(I):poly(C) carboxymethyl cellulose poly-l-lysine (PICLC), a mimetic of double-stranded RNA, 24 h preinfection and postinfection. The survival rates and lung fungal burdens were markedly improved by PICLC immunotherapy in animals infected with any one of the three Aspergillus species. While protection from IA was remarkable, PICLC induction of type I IFN in the lungs surged 24 h posttreatment and returned to baseline levels by 48 h, suggesting that PICLC altered early events in protection against IA. Immunophenotyping of recruited leukocytes and histopathological examination of tissue sections showed that PICLC induced similar cellular infiltrates as those in untreated-infected mice, in both cases dominated by monocytic cells and neutrophils. However, the PICLC immunotherapy resulted in a marked earlier recruitment of the leukocytes. Unlike with conidia, infection with A. nidulans germlings reduced the protective effect of PICLC immunotherapy. Additionally, antibody depletion of neutrophils totally reversed the protection, suggesting that neutrophils are crucial for PICLC-mediated protection. Together, these data show that prophylactic PICLC immunotherapy prerecruits these cells, enabling them to attack the conidia and thus resulting in a profound protection from IA