The functionally selective 5-HT2C receptor ligand SB242084 can increase motivation and have rapid onset anti-depressant-like effects. We sought to identify the specific behavioral effects of SB242084 treatment and elucidate the mechanism in female and male mice. Using a quantitative behavioral approach, we determined that SB242084 increases the vigor and persistence of goal-directed activity across different types of physical work, particularly when work requirements are demanding. We found this influence of SB242084 on effort, rather than reward to be reflected in striatal DA measured during behavior. Using fast scan cyclic voltammetry, we found that SB242084 has no effect on reward-related phasic DA release in the NAc. Using microdialysis to measure tonic changes in extracellular DA, we also found no changes in the NAc. In contrast, SB242084 treatment increases extracellular DA in the dorsomedial striatum, an area that plays a key role in response vigor. These findings have several implications. At the behavioral level, this work shows that the capacity to work in demanding situations can be increased, without a generalized increase in motor activity or reward value. At the circuit level, we identified a pathway restricted potentiation of DA release and showed that this was the reason for the increased response vigor. At the cellular level, we show that a specific serotonin receptor cross talks to the DA system. Together, this information provides promise for the development of treatments for apathy, a serious clinical condition that can afflict patients with psychiatric and neurological disorders. Motivated behaviors are modulated by reward value, effort demands, and cost-benefit computations. This information drives the decision to act, which action to select, and the intensity with which the selected action is performed. Because these behavioral processes are all regulated by DA signaling, it is very difficult to influence selected aspects of motivated behavior without affecting others. Here we identify a pharmacological treatment that increases the vigor and persistence of responding in mice, without increasing generalized activity or changing reactions to rewards. We show that the 5-HT2C-selective ligand boosts motivation by potentiating activity-dependent DA release in the dorsomedial striatum. These results reveal a novel strategy for treating patients with motivational deficits, avolition, or apathy.

Highlights d 5XFAD mice have weakened inhibitory synaptic efficacy during behavior d Weakened inhibition in 5XFAD mice occurs during sharpwave ripples d 5XFAD mice have fewer and shorter sharp-wave ripples d Place cell reactivation is impaired during the remaining ripples in 5XFAD mice

Optimal behavior requires interpreting environmental cues that indicate when to perform actions. Dopamine is important for learning about reward-predicting events, but its role in adapting to inhibitory cues is unclear. Here we show that when mice can earn rewards in the absence but not presence of an auditory cue, dopamine level in the ventral striatum accurately reflects reward availability in real-time over a sustained period (80 s). In addition, unpredictable transitions between different states of reward availability are accompanied by rapid (~1–2 s) dopamine transients that deflect negatively at the onset and positively at the offset of the cue. This Dopamine encoding of reward availability and transitions between reward availability states is not dependent on reward or activity evoked dopamine release, appears before mice learn the task and is sensitive to motivational state. Our findings are consistent across different techniques including electrochemical recordings and fiber photometry with genetically encoded optical sensors for calcium and dopamine.

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Rhythmic neural activity, which coordinates brain regions and neurons to achieve multiple brain functions, is impaired in many diseases. Despite the therapeutic potential of driving brain rhythms, methods to noninvasively target deep brain regions are limited. Accordingly, we recently introduced a noninvasive stimulation approach using flickering lights and sounds (“flicker”). Flicker drives rhythmic activity in deep and superficial brain regions. Gamma flicker spurs immune function, clears pathogens, and rescues memory performance in mice with amyloid pathology. Here we present substantial improvements to this approach that is flexible, user-friendly, and generalizable across multiple experimental settings and species. We present novel open-source methods for flicker stimulation across rodents and humans. We demonstrate rapid, cross-species induction of rhythmic activity without behavioral confounds in multiple settings from electrophysiology to neuroimaging. This flicker approach provides an exceptional opportunity to discover the therapeutic effects of brain rhythms across scales and species.Significance StatementDespite many studies showing abnormal brain rhythms in multiple diseases, limited means to target deep brain regions noninvasively has restricted the therapeutic potential of driving brain rhythms. Accordingly, we developed a noninvasive millisecond precise sensory stimulation to drive brain rhythms. Here we introduce for the first time newly developed open-source software and instructions for building, testing, debugging, and using BrainWAVE (Brain Wide-spectrum Audio/Visual Exposure) stimulation. We demonstrate BrainWAVE stimulation across multiple species and different experimental settings. These methods constitute a customizable, open-source, accessible, and non-invasive technology that stimulates brain oscillations to causally test how rhythmic brain activity impacts brain function.

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As the global scientific and engineering powerhouse, the United States has pioneered numerous inventions such as the telephone, alternating current, radio broadcasting, and controlled nuclear chain reactions. Some may be surprised to find that these were products of immigrants, who pushed the boundaries of science and technology. In the past years, however, the U.S. has been losing its competitive advantage in the global labor market. A key reason for this is that the U.S. is failing to attract and retain international graduate students in STEM fields. Historically, a large portion of these students stayed after graduation and drove innovations that fueled the nation’s trillion-dollar economy. That trend is changing, with many now opting to go elsewhere for their graduate education. Critical flaws in U.S. visa and immigration policy and a lack of federal funding mechanisms for international graduate students are exacerbating this trend. As a result, the U.S. is losing promising junior scientists to other countries with more aggressive foreign recruitment strategies. To counter this trend, we outline in detail the areas with room for growth and propose policy solutions to be implemented by the federal government. These solutions will help the U.S. excel in STEM research workforce diversity, equality, cultural competence, and ultimately, retain its global leadership.

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