Lights, fiber, action! A primer on in vivo fiber photometry.

Fiber photometry is a key technique for characterizing brain-behavior relationships in vivo. Initially, it was primarily used to report calcium dynamics as a proxy for neural activity via genetically encoded indicators. This generated new insights into brain functions including movement, memory, and motivation at the level of defined circuits and cell types. Recently, the opportunity for discovery with fiber photometry has exploded with the development of an extensive range of fluorescent sensors for biomolecules including neuromodulators and peptides that were previously inaccessible in vivo. This critical advance, combined with the new availability of affordable "plug-and-play" recording systems, has made monitoring molecules with high spatiotemporal precision during behavior highly accessible. However, while opening exciting new avenues for research, the rapid expansion in fiber photometry applications has occurred without coordination or consensus on best practices. Here, we provide a comprehensive guide to help end-users execute, analyze, and suitably interpret fiber photometry studies.

Dopamine transporter blockade during adolescence increases adult dopamine function, impulsivity, and aggression.

Sensitive developmental periods shape neural circuits and enable adaptation. However, they also engender vulnerability to factors that can perturb developmental trajectories. An understanding of sensitive period phenomena and mechanisms separate from sensory system development is still lacking, yet critical to understanding disease etiology and risk. The dopamine system is pivotal in controlling and shaping adolescent behaviors, and it undergoes heightened plasticity during that time, such that interference with dopamine signaling can have long-lasting behavioral consequences. Here we sought to gain mechanistic insight into this dopamine-sensitive period and its impact on behavior. In mice, dopamine transporter (DAT) blockade from postnatal (P) day 22 to 41 increases aggression and sensitivity to amphetamine (AMPH) behavioral stimulation in adulthood. Here, we refined this sensitive window to P32-41 and identified increased firing of dopaminergic neurons in vitro and in vivo as a neural correlate to altered adult behavior. Aggression can result from enhanced impulsivity and cognitive dysfunction, and dopamine regulates working memory and motivated behavior. Hence, we assessed these behavioral domains and found that P32-41 DAT blockade increases impulsivity but has no effect on cognition, working memory, or motivation in adulthood. Lastly, using optogenetics to drive dopamine neurons, we find that increased VTA but not SNc dopaminergic activity mimics the increase in impulsive behavior in the Go/NoGo task observed after adolescent DAT blockade. Together our data provide insight into the developmental origins of aggression and impulsivity that may ultimately improve diagnosis, prevention, and treatment strategies for related neuropsychiatric disorders.

Dopamine D2 receptors bidirectionally regulate striatal enkephalin expression: Implications for cocaine reward.

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.

A missense mutation in Kcnc3 causes hippocampal learning deficits in mice.

Although a wide variety of genetic tools has been developed to study learning and memory, the molecular basis of memory encoding remains incompletely understood. Here, we undertook an unbiased approach to identify novel genes critical for memory encoding. From a large-scale, in vivo mutagenesis screen using contextual fear conditioning, we isolated in mice a mutant, named Clueless, with spatial learning deficits. A causative missense mutation (G434V) was found in the voltage-gated potassium channel, subfamily C member 3 (Kcnc3) gene in a region that encodes a transmembrane voltage sensor. Generation of a Kcnc3G434V CRISPR mutant mouse confirmed this mutation as the cause of the learning defects. While G434V had no effect on transcription, translation, or trafficking of the channel, electrophysiological analysis of the G434V mutant channel revealed a complete loss of voltage-gated conductance, a broadening of the action potential, and decreased neuronal firing. Together, our findings have revealed a role for Kcnc3 in learning and memory.

Dopamine encodes real-time reward availability and transitions between reward availability states on different timescales.

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.

How changes in dopamine D2 receptor levels alter striatal circuit function and motivation.

It was first posited, more than five decades ago, that the etiology of schizophrenia involves overstimulation of dopamine receptors. Since then, advanced clinical research methods, including brain imaging, have refined our understanding of the relationship between striatal dopamine and clinical phenotypes as well as disease trajectory. These studies point to striatal dopamine D2 receptors, the main target for all current antipsychotic medications, as being involved in both positive and negative symptoms. Simultaneously, animal models have been central to investigating causal relationships between striatal dopamine D2 receptors and behavioral phenotypes relevant to schizophrenia. We begin this article by reviewing the circuit, cell-type and subcellular locations of dopamine D2 receptors and their downstream signaling pathways. We then summarize results from several mouse models in which D2 receptor levels were altered in various brain regions, cell-types and developmental periods. Behavioral, electrophysiological and anatomical consequences of these D2 receptor perturbations are reviewed with a selective focus on striatal circuit function and alterations in motivated behavior, a core negative symptom of schizophrenia. These studies show that D2 receptors serve distinct physiological roles in different cell types and at different developmental time points, regulating motivated behaviors in sometimes opposing ways. We conclude by considering the clinical implications of this complex regulation of striatal circuit function by D2 receptors.

Dissociating the effects of dopamine D2 receptors on effort-based versus value-based decision making using a novel behavioral approach.

Cost-benefit decision making is essential for organisms to adapt to their ever-changing environment. Most studies of cost-benefit decision making involve choice conditions in which effort and value are varied simultaneously. This prevents identification of the aspects of cost-benefit decision making that are affected by experimental manipulations. We developed operant assays to isolate the individual impacts of effort and value manipulations on cost-benefit decision making. In the concurrent effort choice (CEC) task, mice choose between exerting two distinct types of effort: the number of responses and the duration of a response, to earn the same reward. By parametrically varying response cost, psychometric functions are obtained that reflect how the two types of effort scale against one another. Direct manipulations of effort shift the functions. Because reward value is held constant in this task, differences in scaling of the two response types must be related to the effort manipulations. In the concurrent value choice (CVC) task, mice make the same type of response to earn rewards of different value (e.g., pellets vs. sucrose solutions). Here the effort required to earn one reward type is parametrically varied to obtain the psychometric function that scales the value of the two rewards into the number of responses subjects will pay to earn one reward over the other. Direct value manipulations shift these functions. We tested the effect of the dopamine D2 receptor antagonist, haloperidol, on performance in the CEC and CVC assays and found that D2R signaling is important for effort-based, but not value-based decision making. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Emerging roles of striatal dopamine D2 receptors in motivated behaviour: Implications for psychiatric disorders.

Impaired motivation has been a long recognized negative symptom of schizophrenia, as well as a common feature of non-psychotic psychiatric disorders, responsible for a significant share of functional burden, and with limited treatment options. The striatum and dopamine signalling system play a central role in extracting motivationally relevant information from the environment, selecting which behavioural direction the animal should follow, and the vigour with which to engage it. Much of this function relies on striatal projection neurons, known as medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2Rs), or D2-MSNs. However, determining the precise nature of D2-MSNs in regulating motivated behaviour in both healthy individuals and experimental manipulations of D2-MSN function has at times yielded a somewhat confusing picture since their activity has been linked to either enhancement or dampening of motivation in animal models. In this MiniReview, we describe the latest data from rodent studies that investigated how D2Rs exert their modulatory effect on motivated behaviour by regulating striatal indirect pathway neuronal activity. We will include a discussion about how functional selectivity of D2Rs towards G protein-dependent or ß-arrestin-dependent signalling differentially affects motivated behaviour. Lastly, we will describe a recent preclinical attempt to improve motivation by exploiting serotonin receptor-mediated modulation of dopamine transmission in the striatum.

Overexpression of striatal D2 receptors reduces motivation thereby decreasing food anticipatory activity.

Dopamine has been implicated in circadian timing underlying the food entrainable oscillator (FEO) circuitry and overexpression of the dopamine D2 receptor (D2R) in the striatum has been reported to reduce motivation to obtain food rewards in operant tasks. In the present study, we explored both of these mechanisms by examining food anticipatory activity (FAA) in dopamine D2 receptor-overexpressing (D2R-OE) mice under various durations of food availability. First, we noted that at baseline, there were no differences between D2R-OE mice and their littermates in activity level, food intake, and body weight or in circadian activity. Under conditions of very restricted food availability (4 or 6 hr), both genotypes displayed FAA. In contrast, under 8-hr food availability, control mice showed FAA, but D2R-OE mice did not. Normalization of D2R by administration of doxycycline, a tetracycline analogue, rescued FAA under 8-hr restricted food. We next tested for circadian regulation of FAA. When given ad libitum access to food, neither D2R-OE nor controls were active during the daytime. However, after an interval of food restriction, all mice showed elevated locomotor activity at the time of previous food availability in the day, indicating circadian timing of anticipatory activity. In summary, motivation is reduced in D2R-OE mice but circadian timing behavior is not affected. We conclude that an increase in striatal D2R reduces FAA by modulating motivation and not by acting on a clock mechanism.

Striatal dopamine 2 receptor upregulation during development predisposes to diet-induced obesity by reducing energy output in mice.

Dopaminergic signaling in the striatum, particularly at dopamine 2 receptors (D2R), has been a topic of active investigation in obesity research in the past decades. However, it still remains unclear whether variations in striatal D2Rs modulate the risk for obesity and if so in which direction. Human studies have yielded contradictory findings that likely reflect a complex nonlinear relationship, possibly involving a combination of causal effects and compensatory changes. Animal work indicates that although chronic obesogenic diets reduce striatal D2R function, striatal D2R down-regulation does not lead to obesity. In this study, we evaluated the consequences of striatal D2R up-regulation on body-weight gain susceptibility and energy balance in mice. We used a mouse model of D2R overexpression (D2R-OE) in which D2Rs were selectively up-regulated in striatal medium spiny neurons. We uncover a pathological mechanism by which striatal D2R-OE leads to reduced brown adipose tissue thermogenesis, reduced energy expenditure, and accelerated obesity despite reduced eating. We also show that D2R-OE restricted to development is sufficient to promote obesity and to induce energy-balance deficits. Together, our findings indicate that striatal D2R-OE during development persistently increases the propensity for obesity by reducing energy output in mice. This suggests that early alterations in the striatal dopamine system could represent a key predisposition factor toward obesity.

Striatal dopamine D2 receptors regulate effort but not value-based decision making and alter the dopaminergic encoding of cost.

Deficits in goal-directed motivation represent a debilitating symptom for many patients with schizophrenia. Impairments in motivation can arise from deficits in processing information about effort and or value, disrupting effective cost-benefit decision making. We have previously shown that upregulated dopamine D2 receptor expression within the striatum (D2R-OE mice) decreases goal-directed motivation. Here, we determine the behavioral and neurochemical mechanisms behind this deficit. Female D2R-OE mice were tested in several behavioral paradigms including recently developed tasks that independently assess the impact of Value or Effort manipulations on cost-benefit decision making. In vivo microdialysis was used to measure extracellular dopamine in the striatum during behavior. In a value-based choice task, D2R-OE mice show normal sensitivity to changes in reward value and used reward value to guide their actions. In an effort-based choice task, D2R-OE mice evaluate the cost of increasing the number of responses greater relative to the effort cost of longer duration responses compared to controls. This shift away from choosing to repeatedly execute a response is accompanied by a dampening of extracellular dopamine in the striatum during goal-directed behavior. In the ventral striatum, extracellular dopamine level negatively correlates with response cost in controls, but this relationship is lost in D2R-OE mice. These results show that D2R signaling in the striatum, as observed in some patients with schizophrenia, alters the relationship between effort expenditure and extracellular dopamine. This dysregulation produces motivation deficits that are specific to effort but not value-based decision making, paralleling the effort-based motivational deficits observed in schizophrenia.

Impaired recruitment of dopamine neurons during working memory in mice with striatal D2 receptor overexpression.

The dopamine (DA) system plays a major role in cognitive functions through its interactions with several brain regions including the prefrontal cortex (PFC). Conversely, disturbances in the DA system contribute to cognitive deficits in psychiatric diseases, yet exactly how they do so remains poorly understood. Here we show, using mice with disease-relevant alterations in DA signaling (D2R-OE mice), that deficits in working memory (WM) are associated with impairments in the WM-dependent firing patterns of DA neurons in the ventral tegmental area (VTA). The WM-dependent phase-locking of DA neurons to 4 Hz VTA-PFC oscillations is absent in D2R-OE mice and VTA-PFC synchrony deficits scale with their WM impairments. We also find reduced 4 Hz synchrony between VTA DA neurons and selective impairments in their representation of WM demand. These results identify how altered DA neuron activity-at the level of long-range network activity and task-related firing patterns-may underlie cognitive impairments.

Neuregulin1 modulation of experimental autoimmune encephalomyelitis (EAE).

Neuregulin1 (NRG1) is a differentiation factor that regulates glial development, survival, synaptogenesis, axoglial interactions, and microglial activation. We previously reported that a targeted NRG1 antagonist (HBD-S-H4) given intrathecally, reduces inflammatory microglial activation in a spinal cord pain model and a neurodegenerative disease mouse model in vivo, suggesting that it may have effects in neuroninflammatory and neuronal disorders. We hypothesized that expression of HBD-S-H4 in the central nervous system (CNS) could reduce disease severity in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for multiple sclerosis (MS). In the present study, we generated tetO-HBD-S-H4, a single transgenic (Tg) mouse line in, which the fusion protein in expressed in the brain, resulting in reduction of disease severity in both male and female mice when compared to sex- and age-matched wild type littermates. We also generated GFAP-tTA:tetO-HBD-S-H4 double Tg mice, which express this fusion protein in the brain and the spinal cord, they displayed sex differences in the reduction of disease severity. In healthy mice, expression of HBD-S-H4 in the CNS does not result in any significant neurological or other overt phenotypes. In myelin oligodendrocyte glycoprotein (MOG)-induced EAE, female double Tg mice show delayed disease onset and reduced disease severity compared to male double Tg as well as wild type littermates. In male double Tg mice, the levels of HBD-S-H4 gene expression negatively correlates with disease severity and increased microglia associated genes' expression. In conclusion, expression of neuregulin antagonist in the brain and spinal cord protects females but not males, suggesting a complex interplay between NRG1 and sex difference in EAE that may be associated with microglia-mediated inflammation. This study provides important information for understanding the heterogeneity of disease pathology and the therapeutic potential of targeting microglial activation in male and female MS patients.

An Interaction between Serotonin Receptor Signaling and Dopamine Enhances Goal-Directed Vigor and Persistence in Mice.

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 in vivo fast scan cyclic voltammetry, we found that SB242084 has no effect on reward-related phasic DA release in the NAc. Using in vivo 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.SIGNIFICANCE STATEMENT 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.

Slowing disease progression in the SOD1 mouse model of ALS by blocking neuregulin-induced microglial activation.

There are no effective treatments to slow disease progression in ALS. We previously reported that neuregulin (NRG) receptors are constitutively activated on microglia in the ventral horns in both ALS patients and SOD1 mice and in the corticospinal tracts of ALS patients, and that NRG receptor activation occurs prior to significant clinical disease onset in SOD1 mice. Here, we hypothesize that blocking NRG signaling on microglia would slow disease progression in SOD1 mice using a targeted NRG antagonist (HBD-S-H4). Recombinant HBD-S-H4 directly delivered into the central nervous system (CNS) through implanted intracerebroventricular cannulas showed no signs of toxicity and significantly inhibited NRG receptor activation on microglia resulting in reduced microglial activation and motor neuron loss. The treatment also resulted in a delay in disease onset and an increase in survival. The therapeutic effect was dose-dependent that varied as a function of genetic background in two different strains of SOD1 mice. As a complementary drug delivery approach, transgenic mice expressing HBD-S-H4 driven by an astrocytic promoter (GFAP) had slower disease progression in a dose dependent manner, based on the level of HBD-S-H4 expression. These studies provide mechanistic insights into how NRG signaling on microglia may lead to disease progression and demonstrate the utility of a humanized fusion protein that blocks NRG as a novel therapeutic for human ALS.

Insights About Striatal Circuit Function and Schizophrenia From a Mouse Model of Dopamine D2 Receptor Upregulation.

The dopamine hypothesis of schizophrenia is supported by a large number of imaging studies that have identified an increase in dopamine binding at the D2 receptor selectively in the striatum. We review a decade of work using a regionally restricted and temporally regulated transgenic mouse model to investigate the behavioral, molecular, electrophysiological, and anatomical consequences of selective D2 receptor upregulation in the striatum. These studies have identified new and potentially important biomarkers at the circuit and molecular level that can now be explored in patients with schizophrenia. They provide an example of how animal models and their detailed level of neurobiological analysis allow a deepening of our understanding of the relationship between neuronal circuit function and symptoms of schizophrenia, and as a consequence generate new hypotheses that are testable in patients.

Neural substrates underlying effort, time, and risk-based decision making in motivated behavior.

All mobile organisms rely on adaptive motivated behavior to overcome the challenges of living in an environment in which essential resources may be limited. A variety of influences ranging from an organism's environment, experiential history, and physiological state all influence a cost-benefit analysis which allows motivation to energize behavior and direct it toward specific goals. Here we review the substantial amount of research aimed at discovering the interconnected neural circuits which allow organisms to carry-out the cost-benefit computations which allow them to behave in adaptive ways. We specifically focus on how the brain deals with different types of costs, including effort requirements, delays to reward and payoff riskiness. An examination of this broad literature highlights the importance of the extended neural circuits which enable organisms to make decisions about these different types of costs. This involves Cortical Structures, including the Anterior Cingulate Cortex (ACC), the Orbital Frontal Cortex (OFC), the Infralimbic Cortex (IL), and prelimbic Cortex (PL), as well as the Baso-Lateral Amygdala (BLA), the Nucleus Accumbens (NAcc), the Ventral Pallidal (VP), the Sub Thalamic Nucleus (STN) among others. Some regions are involved in multiple aspects of cost-benefit computations while the involvement of other regions is restricted to information relating to specific types of costs.

The effects of pharmacological modulation of the serotonin 2C receptor on goal-directed behavior in mice.

RATIONALE: Impaired goal-directed motivation represents a debilitating class of symptoms common to psychological disorders including schizophrenia and some affective disorders. Despite the known negative impact of impaired motivation, there are currently no effective pharmacological interventions to treat these symptoms. OBJECTIVES: Here, we evaluate the effectiveness of the serotonin 2C (5-HT2C) receptor selective ligand, SB242084, as a potential pharmacological intervention for enhancing goal-directed motivation in mice. The studies were designed to identify not only efficacy but also the specific motivational processes that were affected by the drug treatment. METHODS: We tested subjects following treatment with SB242084 (0.75 mg/kg) in several operant lever pressing assays including the following: a progressive ratio (PR) schedule of reinforcement, an effort-based choice task, a progressive hold down task (PHD), and various food intake tests. RESULTS: Acute SB242084 treatment leads to an increase in instrumental behavior. Using a battery of behavioral tasks, we demonstrate that the major effect of SB242084 is an increase in the amount of responses and duration of effort that subjects will make for food rewards. This enhancement of behavior is not the result of non-specific hyperactivity or arousal nor is it due to changes in food consumption. CONCLUSIONS: Because of this specificity of action, we suggest that the 5-HT2C receptor warrants further attention as a novel therapeutic target for treating pathological impairments in goal-directed motivation.

The Behavioral Neuroscience of Motivation: An Overview of Concepts, Measures, and Translational Applications.

Motivation, defined as the energizing of behavior in pursuit of a goal, is a fundamental element of our interaction with the world and with each other. All animals share motivation to obtain their basic needs, including food, water, sex and social interaction. Meeting these needs is a requirement for survival, but in all cases the goals must be met in appropriate quantities and at appropriate times. Therefore motivational drive must be modulated as a function of both internal states as well as external environmental conditions. The regulation of motivated behaviors is achieved by the coordinated action of molecules (peptides, hormones, neurotransmitters etc), acting within specific circuits that integrate multiple signals in order for complex decisions to be made. In the past few decades, there has been a great deal of research on the biology and psychology of motivation. This work includes the investigation of specific aspects of motived behavior using multiple levels of analyses, which allows for the identification of the underpinning neurobiological mechanisms that support relevant psychological processes. In this chapter we provide an overview to the volume "The Behavioural Neuroscience of Motivation". The volume includes succinct summaries of; The neurobiology of components of healthy motivational drive, neural measures and correlates of motivation in humans and other animals as well as information on disorders in which abnormal motivation plays a major role. Deficits in motivation occur in a number of psychiatric disorders, affecting a large population, and severe disturbance of motivation can be devastating. Therefore, we also include a section on the development of treatments for disorders of motivation. It is hoped that the collection of reviews in the volume will expose scientists to a breadth of ideas from several different subdisciplines, thereby inspiring new directions of research that may increase our understanding of motivational regulation and bring us closer to effective treatments for disorders of motivation.

Improving temporal cognition by enhancing motivation.

Increasing motivation can positively impact cognitive performance. Here we employed a cognitive timing task that allows us to detect changes in cognitive performance that are not influenced by general activity or arousal factors such as the speed or persistence of responding. This approach allowed us to manipulate motivation using three different methods; molecular/genetic, behavioral and pharmacological. Increased striatal D2Rs resulted in deficits in temporal discrimination. Switching off the transgene improved motivation in earlier studies, and here partially rescued the temporal discrimination deficit. To manipulate motivation behaviorally, we altered reward magnitude and found that increasing reward magnitude improved timing in control mice and partially rescued timing in the transgenic mice. Lastly, we manipulated motivation pharmacologically using a functionally selective 5-HT2C receptor ligand, SB242084, which we previously found to increase incentive motivation. SB242084 improved temporal discrimination in both control and transgenic mice. Thus, while there is a general intuitive belief that motivation can affect cognition, we here provide a direct demonstration that enhancing motivation, in a variety of ways, can be an effective strategy for enhancing temporal cognition. Understanding the interaction of motivation and cognition is of clinical significance since many psychiatric disorders are characterized by deficits in both domains.