Stimulus-dependent differences in cortical versus subcortical contributions to visual detection in mice.

The primary visual cortex (V1) and the superior colliculus (SC) both occupy stations early in the processing of visual information. They have long been thought to perform distinct functions, with the V1 supporting the perception of visual features and the SC regulating orienting to visual inputs. However, growing evidence suggests that the SC supports the perception of many of the same visual features traditionally associated with the V1. To distinguish V1 and SC contributions to visual processing, it is critical to determine whether both areas causally contribute to the detection of specific visual stimuli. Here, mice reported changes in visual contrast or luminance near their perceptual threshold while white noise patterns of optogenetic stimulation were delivered to V1 or SC inhibitory neurons. We then performed a reverse correlation analysis on the optogenetic stimuli to estimate a neuronal-behavioral kernel (NBK), a moment-to-moment estimate of the impact of V1 or SC inhibition on stimulus detection. We show that the earliest moments of stimulus-evoked activity in the SC are critical for the detection of both luminance and contrast changes. Strikingly, there was a robust stimulus-aligned modulation in the V1 contrast-detection NBK but no sign of a comparable modulation for luminance detection. The data suggest that behavioral detection of visual contrast depends on both V1 and SC spiking, whereas mice preferentially use SC activity to detect changes in luminance. Electrophysiological recordings showed that neurons in both the SC and V1 responded strongly to both visual stimulus types, while the reverse correlation analysis reveals when these neuronal signals actually contribute to visually guided behaviors.

Temporal weighting of cortical and subcortical spikes reveals stimulus dependent differences in their contributions to behavior.

The primary visual cortex (V1) and the superior colliculus (SC) both occupy stations early in the processing of visual information. They have long been thought to perform distinct functions, with V1 supporting perception of visual features and the SC regulating orienting to visual inputs. However, growing evidence suggests that the SC supports perception of many of the same visual features traditionally associated with V1. To distinguish V1 and SC contributions to visual processing, it is critical to determine whether both areas causally contribute to perception of specific visual stimuli. Here, mice reported changes in visual contrast or luminance near perceptual threshold while we presented white noise patterns of optogenetic stimulation to V1 or SC inhibitory neurons. We then performed a reverse correlation analysis on the optogenetic stimuli to estimate a neuronal-behavioral kernel (NBK), a moment-to-moment estimate of the impact of V1 or SC inhibition on stimulus detection. We show that the earliest moments of stimulus-evoked activity in SC are critical for detection of both luminance or contrast changes. Strikingly, there was a robust stimulus-aligned modulation in the V1 contrast-detection NBK, but no sign of a comparable modulation for luminance detection. The data suggest that perception of visual contrast depends on both V1 and SC spiking, whereas mice preferentially use SC activity to detect changes in luminance. Electrophysiological recordings showed that neurons in both SC and V1 responded strongly to both visual stimulus types, while the reverse correlation analysis reveals when these neuronal signals actually contribute to visually-guided behaviors.

Homeostatic Reinforcement Theory Accounts for Sodium Appetitive State- and Taste-Dependent Dopamine Responding.

Seeking and consuming nutrients is essential to survival and the maintenance of life. Dynamic and volatile environments require that animals learn complex behavioral strategies to obtain the necessary nutritive substances. While this has been classically viewed in terms of homeostatic regulation, recent theoretical work proposed that such strategies result from reinforcement learning processes. This theory proposed that phasic dopamine (DA) signals play a key role in signaling potentially need-fulfilling outcomes. To examine links between homeostatic and reinforcement learning processes, we focus on sodium appetite as sodium depletion triggers state- and taste-dependent changes in behavior and DA signaling evoked by sodium-related stimuli. We find that both the behavior and the dynamics of DA signaling underlying sodium appetite can be accounted for by a homeostatically regulated reinforcement learning framework (HRRL). We first optimized HRRL-based agents to sodium-seeking behavior measured in rodents. Agents successfully reproduced the state and the taste dependence of behavioral responding for sodium as well as for lithium and potassium salts. We then showed that these same agents account for the regulation of DA signals evoked by sodium tastants in a taste- and state-dependent manner. Our models quantitatively describe how DA signals evoked by sodium decrease with satiety and increase with deprivation. Lastly, our HRRL agents assigned equal preference for sodium versus the lithium containing salts, accounting for similar behavioral and neurophysiological observations in rodents. We propose that animals use orosensory signals as predictors of the internal impact of the consumed good and our results pose clear targets for future experiments. In sum, this work suggests that appetite-driven behavior may be driven by reinforcement learning mechanisms that are dynamically tuned by homeostatic need.

Perceptual Weighting of V1 Spikes Revealed by Optogenetic White Noise Stimulation.

During visually guided behaviors, mere hundreds of milliseconds can elapse between a sensory input and its associated behavioral response. How spikes occurring at different times are integrated to drive perception and action remains poorly understood. We delivered random trains of optogenetic stimulation (white noise) to excite inhibitory interneurons in V1 of mice of both sexes while they performed a visual detection task. We then performed a reverse correlation analysis on the optogenetic stimuli to generate a neuronal-behavioral kernel, an unbiased, temporally precise estimate of how suppression of V1 spiking at different moments around the onset of a visual stimulus affects detection of that stimulus. Electrophysiological recordings enabled us to capture the effects of optogenetic stimuli on V1 responsivity and revealed that the earliest stimulus-evoked spikes are preferentially weighted for guiding behavior. These data demonstrate that white noise optogenetic stimulation is a powerful tool for understanding how patterns of spiking in neuronal populations are decoded in generating perception and action.SIGNIFICANCE STATEMENT During visually guided actions, continuous chains of neurons connect our retinas to our motoneurons. To unravel circuit contributions to behavior, it is crucial to establish the relative functional position(s) that different neural structures occupy in processing and relaying the signals that support rapid, precise responses. To address this question, we randomly inhibited activity in mouse V1 throughout the stimulus-response cycle while the animals did many repetitions of a visual task. The period that led to impaired performance corresponded to the earliest stimulus-driven response in V1, with no effect of inhibition immediately before or during late stages of the stimulus-driven response. This approach offers experimenters a powerful method for uncovering the temporal weighting of spikes from stimulus to response.

Descending Dopaminergic Inputs to Reticulospinal Neurons Promote Locomotor Movements.

Meso-diencephalic dopaminergic neurons are known to modulate locomotor behaviors through their ascending projections to the basal ganglia, which in turn project to the mesencephalic locomotor region, known to control locomotion in vertebrates. In addition to their ascending projections, dopaminergic neurons were found to increase locomotor movements through direct descending projections to the mesencephalic locomotor region and spinal cord. Intriguingly, fibers expressing tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine synthesis, were also observed around reticulospinal neurons of lampreys. We now examined the origin and the role of this innervation. Using immunofluorescence and tracing experiments, we found that fibers positive for dopamine innervate reticulospinal neurons in the four reticular nuclei of lampreys. We identified the dopaminergic source using tracer injections in reticular nuclei, which retrogradely labeled dopaminergic neurons in a caudal diencephalic nucleus (posterior tuberculum [PT]). Using voltammetry in brain preparations isolated in vitro, we found that PT stimulation evoked dopamine release in all four reticular nuclei, but not in the spinal cord. In semi-intact preparations where the brain is accessible and the body moves, PT stimulation evoked swimming, and injection of a D1 receptor antagonist within the middle rhombencephalic reticular nucleus was sufficient to decrease reticulospinal activity and PT-evoked swimming. Our study reveals that dopaminergic neurons have access to command neurons that integrate sensory and descending inputs to activate spinal locomotor neurons. As such, our findings strengthen the idea that dopamine can modulate locomotor behavior both via ascending projections to the basal ganglia and through descending projections to brainstem motor circuits.SIGNIFICANCE STATEMENT Meso-diencephalic dopaminergic neurons play a key role in modulating locomotion by releasing dopamine in the basal ganglia, spinal networks, and the mesencephalic locomotor region, a brainstem region that controls locomotion in a graded fashion. Here, we report in lampreys that dopaminergic neurons release dopamine in the four reticular nuclei where reticulospinal neurons are located. Reticulospinal neurons integrate sensory and descending suprareticular inputs to control spinal interneurons and motoneurons. By directly modulating the activity of reticulospinal neurons, meso-diencephalic dopaminergic neurons control the very last instructions sent by the brain to spinal locomotor circuits. Our study reports on a new direct descending dopaminergic projection to reticulospinal neurons that modulates locomotor behavior.

Mice Preferentially Use Increases in Cerebral Cortex Spiking to Detect Changes in Visual Stimuli.

Whenever the retinal image changes, some neurons in visual cortex increase their rate of firing whereas others decrease their rate of firing. Linking specific sets of neuronal responses with perception and behavior is essential for understanding mechanisms of neural circuit computation. We trained mice of both sexes to perform visual detection tasks and used optogenetic perturbations to increase or decrease neuronal spiking primary visual cortex (V1). Perceptual reports were always enhanced by increments in V1 spike counts and impaired by decrements, even when increments and decrements in spiking were generated in the same neuronal populations. Moreover, detecting changes in cortical activity depended on spike count integration rather than instantaneous changes in spiking. Recurrent neural networks trained in the task similarly relied on increments in neuronal activity when activity has costs. This work clarifies neuronal decoding strategies used by cerebral cortex to translate cortical spiking into percepts that can be used to guide behavior.SIGNIFICANCE STATEMENT Visual responses in the primary visual cortex (V1) are diverse, in that neurons can be either excited or inhibited by the onset of a visual stimulus. We selectively potentiated or suppressed V1 spiking in mice while they performed contrast change detection tasks. In other experiments, excitation or inhibition was delivered to V1 independent of visual stimuli. Mice readily detected increases in V1 spiking while equivalent reductions in V1 spiking suppressed the probability of detection, even when increases and decreases in V1 spiking were generated in the same neuronal populations. Our data raise the striking possibility that only increments in spiking are used to render information to structures downstream of V1.

Different Inhibitory Interneuron Cell Classes Make Distinct Contributions to Visual Contrast Perception.

While recent work has revealed how different inhibitory interneurons influence responses of cortical neurons to sensory stimuli, little is known about their distinct contributions to sensory perception. Here, we optogenetically activated different genetically defined interneurons [parvalbumin (PV), somatostatin (SST), vasoactive intestinal peptide (VIP)] in visual cortex (V1) of mice working at threshold in a contrast increment detection task. The visual stimulus was paired with optogenetic stimulation to assess how enhancing V1 inhibitory neuron activity during visual processing altered task performance. PV or SST activation impaired, while VIP stimulation improved, contrast increment detection. The impairment produced by PV or SST activation persisted over several weeks of testing. In contrast, mice learned to reliably detect VIP activation in the absence of any natural visual stimulus. Thus, different inhibitory signals make distinct contributions to visual contrast perception.

Electrical Microstimulation of Visual Cerebral Cortex Elevates Psychophysical Detection Thresholds.

Sensory prostheses can restore aspects of natural sensation by delivering electrical current directly into sensory circuits. An effective sensory prosthetic should be capable of generating reliable real-time perceptual signals for hours each day over many years. However, we still know little regarding the stability of percepts produced by electrical microstimulation of cerebral sensory cortex when stimulation is delivered repeatedly over long periods. Developing methods that yield highly sensitive and reliable assessments of a subject's sensitivity to stimulation is important for developing prosthetic devices that can mimic the constant stream of information inherent in daily experience. Here, we trained rhesus monkeys to report electrical microstimulation of their primary visual cortex (V1) and measured how repeated stimulation affected the minimal electrical current needed to generate a percept (behavioral detection threshold). Using adaptive staircase procedures with a two-alternative forced-choice (2AFC) detection task, we obtained highly reliable detection threshold measures with as few as 100 trials. Using either chronically implanted or acutely inserted microelectrodes, we found that repeated electrical microstimulation elevated detection thresholds, with effects persisting between daily testing sessions. Our results demonstrate task designs that can support rapid and reliable measurements of detection thresholds, and point to the need for validation that detection thresholds in targeted structures will be sufficiently stable in the face of the amount of chronic stimulation that will be required for effective sensory prosthetics.

The value of interleukin 6 as a peripheral diagnostic marker in schizophrenia.

BACKGROUND: Associations between a pro-inflammatory state and schizophrenia have been one of the more enduring findings of psychiatry, with various lines of evidence suggesting a compelling role for IL-6 in the underlying pathogenesis of schizophrenia. METHODS: In this study, we examined IL-6 mRNA levels by real-time RT-PCR from fresh extracted peripheral blood mononuclear cells (PBMC) in normal controls and participants with schizophrenia. RESULTS: We found that peripheral PBMC IL-6 mRNA levels, in the absence of any other information, reliably discriminated between a diagnosis of schizophrenia and normal controls. Furthermore, in participants with schizophrenia, we also found elevated levels of IL-6 mRNA with earlier ages of illness onset and worse positive symptom presentation, as measured by the Positive and Negative Syndrome Scale. CONCLUSIONS: These findings provide important and continued support for a pathophysiological role of inflammation in patients with schizophrenia. Future utilization of peripheral IL-6 mRNA levels could be clinically useful during an initial diagnosis and help tailor individualized treatment plans for patients with schizophrenia.

A descending dopamine pathway conserved from basal vertebrates to mammals.

Dopamine neurons are classically known to modulate locomotion indirectly through ascending projections to the basal ganglia that project down to brainstem locomotor networks. Their loss in Parkinson's disease is devastating. In lampreys, we recently showed that brainstem networks also receive direct descending dopaminergic inputs that potentiate locomotor output. Here, we provide evidence that this descending dopaminergic pathway is conserved to higher vertebrates, including mammals. In salamanders, dopamine neurons projecting to the striatum or brainstem locomotor networks were partly intermingled. Stimulation of the dopaminergic region evoked dopamine release in brainstem locomotor networks and concurrent reticulospinal activity. In rats, some dopamine neurons projecting to the striatum also innervated the pedunculopontine nucleus, a known locomotor center, and stimulation of the dopaminergic region evoked pedunculopontine dopamine release in vivo. Finally, we found dopaminergic fibers in the human pedunculopontine nucleus. The conservation of a descending dopaminergic pathway across vertebrates warrants re-evaluating dopamine's role in locomotion.

Physiological state gates acquisition and expression of mesolimbic reward prediction signals.

Phasic dopamine signaling participates in associative learning by reinforcing associations between outcomes (unconditioned stimulus; US) and their predictors (conditioned stimulus; CS). However, prior work has always engendered these associations with innately rewarding stimuli. Thus, whether dopamine neurons can acquire prediction signals in the absence of appetitive experience and update them when the value of the outcome changes remains unknown. Here, we used sodium depletion to reversibly manipulate the appetitive value of a hypertonic sodium solution while measuring phasic dopamine signaling in rat nucleus accumbens. Dopamine responses to the NaCl US following sodium depletion updated independent of prior experience. In contrast, prediction signals were only acquired through extensive experience with a US that had positive affective value. Once learned, dopamine prediction signals were flexibly expressed in a state-dependent manner. Our results reveal striking differences with respect to how physiological state shapes dopamine signals evoked by outcomes and their predictors.

Ghrelin regulates phasic dopamine and nucleus accumbens signaling evoked by food-predictive stimuli.

Environmental stimuli that signal food availability hold powerful sway over motivated behavior and promote feeding, in part, by activating the mesolimbic system. These food-predictive cues evoke brief (phasic) changes in nucleus accumbens (NAc) dopamine concentration and in the activity of individual NAc neurons. Phasic fluctuations in mesolimbic signaling have been directly linked to goal-directed behaviors, including behaviors elicited by food-predictive cues. Food-seeking behavior is also strongly influenced by physiological state (i.e., hunger vs. satiety). Ghrelin, a stomach hormone that crosses the blood-brain barrier, is linked to the perception of hunger and drives food intake, including intake potentiated by environmental cues. Notwithstanding, whether ghrelin regulates phasic mesolimbic signaling evoked by food-predictive stimuli is unknown. Here, rats underwent Pavlovian conditioning in which one cue predicted the delivery of rewarding food (CS+) and a second cue predicted nothing (CS-). After training, we measured the effect of ghrelin infused into the lateral ventricle (LV) on sub-second fluctuations in NAc dopamine using fast-scan cyclic voltammetry and individual NAc neuron activity using in vivo electrophysiology in separate groups of rats. LV ghrelin augmented both phasic dopamine and phasic increases in the activity of NAc neurons evoked by the CS+. Importantly, ghrelin did not affect the dopamine nor NAc neuron response to the CS-, suggesting that ghrelin selectively modulated mesolimbic signaling evoked by motivationally significant stimuli. These data demonstrate that ghrelin, a hunger signal linked to physiological state, can regulate cue-evoked mesolimbic signals that underlie food-directed behaviors. Cues that predict food availability powerfully regulate food-seeking behavior. Here we show that cue-evoked changes in both nucleus accumbens (NAc) dopamine (DA) and NAc cell activity are modulated by intra-cranial infusions of the stomach hormone ghrelin--a hormone known to act centrally to promote food intake. These data demonstrate that hormones associated with physiological state (i.e., hunger) can affect encoding of food-predictive cues in brain regions that drive food-motivated behavior.

Amylin modulates the mesolimbic dopamine system to control energy balance.

Amylin acts in the CNS to reduce feeding and body weight. Recently, the ventral tegmental area (VTA), a mesolimbic nucleus important for food intake and reward, was identified as a site-of-action mediating the anorectic effects of amylin. However, the long-term physiological relevance and mechanisms mediating the intake-suppressive effects of VTA amylin receptor (AmyR) activation are unknown. Data show that the core component of the AmyR, the calcitonin receptor (CTR), is expressed on VTA dopamine (DA) neurons and that activation of VTA AmyRs reduces phasic DA in the nucleus accumbens core (NAcC). Suppression in NAcC DA mediates VTA amylin-induced hypophagia, as combined NAcC D1/D2 receptor agonists block the intake-suppressive effects of VTA AmyR activation. Knockdown of VTA CTR via adeno-associated virus short hairpin RNA resulted in hyperphagia and exacerbated body weight gain in rats maintained on high-fat diet. Collectively, these findings show that VTA AmyR signaling controls energy balance by modulating mesolimbic DA signaling.

Optical suppression of drug-evoked phasic dopamine release.

Brief fluctuations in dopamine concentration (dopamine transients) play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc) of urethane-anesthetized rats. We targeted halorhodopsin (NpHR) specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA) of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre(+) rats). Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug-evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior.

Ghrelin acts as an interface between physiological state and phasic dopamine signaling.

Brief, high-concentration (phasic) spikes in nucleus accumbens dopamine critically participate in aspects of food reward. Although physiological state (e.g., hunger, satiety) and associated hormones are known to affect dopamine tone in general, whether they modulate food-evoked, phasic dopamine specifically is unknown. Here, we used fast-scan cyclic voltammetry in awake, behaving rats to record dopamine spikes evoked by delivery of sugar pellets while pharmacologically manipulating central receptors for the gut "hunger" hormone ghrelin. Lateral ventricular (LV) ghrelin increased, while LV ghrelin receptor antagonism suppressed the magnitude of dopamine spikes evoked by food. Ghrelin was effective when infused directly into the lateral hypothalamus (LH), but not the ventral tegmental area (VTA). LH infusions were made in close proximity to orexin neurons, which are regulated by ghrelin and project to the VTA. Thus, we also investigated and found potentiation of food-evoked dopamine spikes by intra-VTA orexin-A. Importantly, intra-VTA blockade of orexin receptors attenuated food intake induced by LV ghrelin, thus establishing a behaviorally relevant connection between central ghrelin and VTA orexin. Further analysis revealed that food restriction increased the magnitude of dopamine spikes evoked by food independent of any pharmacological manipulations. The results support the regulation of food-evoked dopamine spikes by physiological state with endogenous fluctuations in ghrelin as a key contributor. Our data highlight a novel mechanism by which signals relating physiological state could influence food reinforcement and food-directed behavior.

Nicotinic receptors regulate the dynamic range of dopamine release in vivo.

Nicotinic acetylcholine receptors (nAChRs) are expressed presynaptically on dopamine axon terminals, and their activation by endogenous acetylcholine from striatal cholinergic interneurons enhances dopamine release both independently of and in concert with dopamine neuron activity. Acute nAChR inactivation is believed to enhance the contrast between low- and high-frequency dopamine cell activity. Although these studies reveal a key role for acute activation and inactivation of nAChRs in striatal microcircuitry, it remains unknown if chronic inactivation/desensitization of nAChRs can alter dopamine release dynamics. Using in vivo cyclic voltammetry in anaesthetized mice, we examined whether chronic inactivation of nAChRs modulates dopamine release across a parametric range of stimulation, varying both frequency and pulse number. Deletion of ß2*nAChRs and chronic nicotine exposure greatly diminished dopamine release across the entire range of stimulation parameters. In addition, we observed a facilitation of dopamine release at low frequency and pulse number in wild-type mice that is absent in the ß2* knockout and chronic nicotine mice. These data suggest that deletion or chronic desensitization of nAChRs reduces the dynamic range of dopamine release in response to dopamine cell activity, decreasing rather than increasing contrast between high and low dopamine activity.

Forebrain dopamine neurons project down to a brainstem region controlling locomotion.

The contribution of dopamine (DA) to locomotor control is traditionally attributed to ascending dopaminergic projections from the substantia nigra pars compacta and the ventral tegmental area to the basal ganglia, which in turn project down to the mesencephalic locomotor region (MLR), a brainstem region controlling locomotion in vertebrates. However, a dopaminergic innervation of the pedunculopontine nucleus, considered part of the MLR, was recently identified in the monkey. The origin and role of this dopaminergic input are unknown. We addressed these questions in a basal vertebrate, the lamprey. Here we report a functional descending dopaminergic pathway from the posterior tuberculum (PT; homologous to the substantia nigra pars compacta and/or ventral tegmental area of mammals) to the MLR. By using triple labeling, we found that dopaminergic cells from the PT not only project an ascending pathway to the striatum, but send a descending projection to the MLR. In an isolated brain preparation, PT stimulation elicited excitatory synaptic inputs into patch-clamped MLR cells, accompanied by activity in reticulospinal cells. By using voltammetry coupled with electrophysiological recordings, we demonstrate that PT stimulation evoked DA release in the MLR, together with the activation of reticulospinal cells. In a semi-intact preparation, stimulation of the PT elicited reticulospinal activity together with locomotor movements. Microinjections of a D1 antagonist in the MLR decreased the locomotor output elicited by PT stimulation, whereas injection of DA had an opposite effect. It appears that this descending dopaminergic pathway has a modulatory role on MLR cells that are known to receive glutamatergic projections and promotes locomotor output.

Prolonged high fat diet reduces dopamine reuptake without altering DAT gene expression.

The development of diet-induced obesity (DIO) can potently alter multiple aspects of dopamine signaling, including dopamine transporter (DAT) expression and dopamine reuptake. However, the time-course of diet-induced changes in DAT expression and function and whether such changes are dependent upon the development of DIO remains unresolved. Here, we fed rats a high (HFD) or low (LFD) fat diet for 2 or 6 weeks. Following diet exposure, rats were anesthetized with urethane and striatal DAT function was assessed by electrically stimulating the dopamine cell bodies in the ventral tegmental area (VTA) and recording resultant changes in dopamine concentration in the ventral striatum using fast-scan cyclic voltammetry. We also quantified the effect of HFD on membrane associated DAT in striatal cell fractions from a separate group of rats following exposure to the same diet protocol. Notably, none of our treatment groups differed in body weight. We found a deficit in the rate of dopamine reuptake in HFD rats relative to LFD rats after 6 but not 2 weeks of diet exposure. Additionally, the increase in evoked dopamine following a pharmacological challenge of cocaine was significantly attenuated in HFD relative to LFD rats. Western blot analysis revealed that there was no effect of diet on total DAT protein. However, 6 weeks of HFD exposure significantly reduced the 50 kDa DAT isoform in a synaptosomal membrane-associated fraction, but not in a fraction associated with recycling endosomes. Our data provide further evidence for diet-induced alterations in dopamine reuptake independent of changes in DAT production and demonstrates that such changes can manifest without the development of DIO.

Primary food reward and reward-predictive stimuli evoke different patterns of phasic dopamine signaling throughout the striatum.

Phasic changes in dopamine activity play a critical role in learning and goal-directed behavior. Unpredicted reward and reward-predictive cues evoke phasic increases in the firing rate of the majority of midbrain dopamine neurons--results that predict uniformly broadcast increases in dopamine concentration throughout the striatum. However, measurement of dopamine concentration changes during reward has cast doubt on this prediction. We systematically measured phasic changes in dopamine in four striatal subregions [nucleus accumbens shell and core (Core), dorsomedial (DMS) and dorsolateral striatum] in response to stimuli known to activate a majority of dopamine neurons. We used fast-scan cyclic voltammetry in awake and behaving rats, which measures changes in dopamine on a similar timescale to the electrophysiological recordings that established a relationship between phasic dopamine activity and reward. Unlike the responses of midbrain dopamine neurons, unpredicted food reward and reward-predictive cues evoked a phasic increase in dopamine that was subregion specific. In rats with limited experience, unpredicted food reward evoked an increase exclusively in the Core. In rats trained on a discriminative stimulus paradigm, both unpredicted reward and reward-predictive cues evoked robust phasic dopamine in the Core and DMS. Thus, phasic dopamine release in select target structures is dynamic and dependent on context and experience. Because the four subregions assayed receive different inputs and have differential projection targets, the regional selectivity of phasic changes in dopamine has important implications for information flow through the striatum and plasticity that underlies learning and goal-directed behavior.

MSI-1436 reduces acute food intake without affecting dopamine transporter activity.

Many therapies designed to reduce food intake and body weight act, in part, by blocking the dopamine transporter (DAT) - a protein responsible for clearing extracellular dopamine (DA) after release thereby terminating its action. Here, we found that a single injection of the drug trodusquemine (MSI-1436) decreased food intake in rats. To assess the effects of MSI-1436 on DAT function, fast-scan cyclic voltammetry was used to measure DA concentration changes in the ventral striatum. DA release was evoked by electrical stimulation of the ventral tegmental area every 5 min. After 3 baseline measurements, rats were injected with MSI-1436 (10 mg/kg), the known DAT blocker bupropion (80 mg/kg) or saline and evoked DA release and reuptake were monitored for an additional hour. Neither saline nor MSI-1436 caused a significant change in the magnitude of evoked release from baseline values whereas bupropion caused a significant increase. In addition, neither saline nor MSI-1436 significantly increased DA decay rates while such an increase was observed with bupropion. Thus, over a time course when MSI-1436 suppresses food intake it does not affect DAT function. The results support MSI-1436 as an anti-obesity treatment which spares DAT.