Two Distinct Neuronal Populations in the Rat Parafascicular Nucleus Oppositely Encode the Engagement in Stimulus-driven Reward-seeking.

BACKGROUND: The thalamus is a phylogenetically well-preserved structure. Known to densely contact cortical regions, its role in the transmission of sensory information to the striatal complex has been widely reconsidered in recent years. METHODS: The parafascicular nucleus of the thalamus (Pf) has been implicated in the orientation of attention toward salient sensory stimuli. In a stimulus-driven reward-seeking task, we sought to characterize the electrophysiological activity of Pf neurons in rats. RESULTS: We observed a predominance of excitatory over inhibitory responses for all events in the task. Neurons responded more strongly to the stimulus compared to lever-pressing and reward collecting, confirming the strong involvement of the Pf in sensory information processing. The use of long sessions allowed us to compare neuronal responses to stimuli between trials when animals were engaged in action and those when they were not. We distinguished two populations of neurons with opposite responses: MOTIV+ neurons responded more intensely to stimuli followed by a behavioral response than those that were not. Conversely, MOTIV- neurons responded more strongly when the animal did not respond to the stimulus. In addition, the latency of excitation of MOTIV- neurons was shorter than that of MOTIV+ neurons. CONCLUSION: Through this encoding, the Pf could perform an early selection of environmental stimuli transmitted to the striatum according to motivational level.

Basolateral amygdala population coding of a cued reward seeking state depends on orbitofrontal cortex.

Basolateral amygdala (BLA) neuronal responses to conditioned stimuli are closely linked to the expression of conditioned behavior. An area of increasing interest is how the dynamics of BLA neurons relate to evolving behavior. Here, we recorded the activity of individual BLA neurons across the acquisition and extinction of conditioned reward seeking and employed population-level analyses to assess ongoing neural dynamics. We found that, with training, sustained cue-evoked activity emerged that discriminated between the CS+ and CS- and correlated with conditioned responding. This sustained population activity continued until reward receipt and rapidly extinguished along with conditioned behavior during extinction. To assess the contribution of orbitofrontal cortex (OFC), a major reciprocal partner to BLA, to this component of BLA neural activity, we inactivated OFC while recording in BLA and found blunted sustained cue-evoked activity in BLA that accompanied reduced reward seeking. Optogenetic disruption of BLA activity and OFC terminals in BLA also reduced reward seeking. Our data suggest that sustained cue-driven activity in BLA, which in part depends on OFC input, underlies conditioned reward-seeking states.

Optogenetic Globus Pallidus Stimulation Improves Motor Deficits in 6-Hydroxydopamine-Lesioned Mouse Model of Parkinson's Disease.

Excessive inhibition of the external globus pallidus (GPe) by striatal GABAergic neurons is considered a central mechanism contributing to motor symptoms of Parkinson's disease (PD). While electrophysiological findings support this view, behavioral studies assessing the beneficial effects of global GPe activations are scarce and the reported results are controversial. We used an optogenetic approach and the standard unilateral 6-hydroxydopamine nigrostriatal dopamine (DA) lesion model of PD to explore the effects of GPe photostimulation on motor deficits in mice. Global optogenetic GPe inhibition was used in normal mice to verify whether it reproduced the typical motor impairment induced by DA lesions. GPe activation improved ipsilateral circling, contralateral forelimb akinesia, locomotor hypoactivity, and bradykinesia in 6-OHDA-lesioned mice at ineffective photostimulation parameters (532 nm, 5 Hz, 3 mW) in normal mice. GPe photoinhibition (450 nm, 12 mW) had no effect on locomotor activity and forelimb use in normal mice. Bilateral photoinhibition (450 nm, 6 mW/side) reduced directed exploration and improved working memory performances indicating that recruitment of GPe in physiological conditions may depend on the behavioral task involved. Collectively, these findings shed new light on the functional role of GPe and suggest that it is a promising target for neuromodulatory restoration of motor deficits in PD.

Microstructural meal pattern analysis reveals a paradoxical acute increase in food intake after nicotine despite its long-term anorexigenic effects.

RATIONALE: Nicotine consumption in both human and animal studies has been strongly associated with changes in feeding-related behaviors and metabolism. The current dogma is that nicotine is an anorexic agent that decreases food intake and increases metabolism, leading to decreased body weight gain. However, there are conflicting reports about the acute effects of nicotine on hunger in humans. No study has reported nicotine-induced decreases in food intake within minutes of consumption, suggesting that our understanding of the pharmacological effects of nicotine on appetite and feeding may be incorrect. OBJECTIVES: The aim of this study was to elucidate effects of acute nicotine intake on feeding and drinking behavior. METHODS: Adult male Wistar rats were trained to intravenously self-administer nicotine. Microstructural and macrostructural behavioral analyses were employed to look at changes in food and water intake at different timescales. RESULTS: At the macrostructural level (hours to days), nicotine decreased body weight gain, decreased feeding, and was associated with increases in feeding and body weight gain during abstinence. At the microstructural level (seconds to minutes), nicotine increased feeding and drinking behavior during the first 5 min after nicotine self-administration. This effect was also observed in animals that passively received nicotine, but the effect was not observed in animals that self-administered saline or passively received saline. CONCLUSIONS: These results challenge the notion that the initial pharmacological effect of nicotine is anorexigenic and paradoxically suggest that an acute increase in food intake minutes after exposure to nicotine may contribute to the long-term anorexigenic effects of nicotine.

The Nucleus Accumbens Core Is Necessary for Responding to Incentive But Not Instructive Stimuli.

An abundant literature has highlighted the importance of the nucleus accumbens core (NAcC) in behavioral tasks dependent on external stimuli. Yet, some studies have also reported the absence of involvement of the NAcC in stimuli processing. We aimed at comparing, in male rats, the underlying neuronal determinants of incentive and instructive stimuli in the same task. We developed a variant of a GO/NOGO task that reveals important differences in these two types of stimuli. The incentive stimulus invites the rat to engage in the task sequence. Once the rat has decided to initiate a trial, it remains engaged in the task until the end of the trial. This task revealed the differential contribution of the NAcC to responding to different types of stimuli: responding to the incentive stimulus depended on NAcC AMPA/NMDA and dopamine D1 receptors, but the retrieval of the response associated with the instructive stimuli (lever pressing on GO, withholding on NOGO) did not. Our electrophysiological study showed that more NAcC neurons responded more strongly to the incentive than the instructive stimuli. Furthermore, when animals did not respond to the incentive stimulus, the induced excitation was suppressed for most projection neurons, whereas interneurons were strongly activated at a latency preceding that found in projection neurons. This work provides insight on the underlying neuronal processes explaining the preferential implication of the NAcC in deciding whether and when to engage in reward-seeking rather than to decide which action to perform.SIGNIFICANCE STATEMENT The nucleus accumbens core (NAcC) is essential to process information carried by reward-predicting stimuli. Yet, stimuli have distinct properties: incentive stimuli orient the attention toward reward-seeking, whereas instructive stimuli inform about the action to perform. Our study shows that, in male rats, NAcC perturbation with glutamate or dopamine antagonists impeded responses to the incentive but not to the instructive stimulus. NAcC neuronal recordings revealed a stronger representation of incentive than instructive stimuli. Furthermore, we found that interneurons are recruited when rats fail to respond to incentive stimuli. This work provides insight on the underlying neuronal processes explaining the preferential implication of the NAcC in deciding whether and when to engage in reward-seeking rather than to decide which action to perform.

Orexin in the Posterior Paraventricular Thalamus Mediates Hunger-Related Signals in the Nucleus Accumbens Core.

Animals use exteroceptive stimuli that have acquired, through learning, the ability to predict available resources allowing them to engage in adaptive behaviors. Meanwhile, peripheral signals related to internal state (e.g., hunger) provide information about current needs, modulating the ability of exteroceptive stimuli to drive food-seeking behavior [1, 2]. The nucleus accumbens core (NAcC) is essential for encoding the value of reward-predictive cues and controlling the level of behavioral responding [3-7]. However, the way in which interoceptive information related to physiological needs is integrated in the NAcC remains to be clarified. Located in the lateral and perifornical hypothalamic regions, orexin neurons [8, 9] are implicated in a wide range of functions, including arousal, feeding, and reward seeking [10-16]. Paraventricular thalamus (PVT) neurons receive a strong orexinergic projection [17] and are excited by orexins [18-20]. Hence, Kelley et al. [21] proposed that the PVT serves as an integrative relay, conveying hypothalamic energy-balance information to the NAc through its glutamatergic projection. Here, we test whether NAcC encoding of reward-predictive cues is modulated by the integration of posterior PVT (pPVT) orexin-mediated hunger-related signals. Using a cue-driven reward-seeking task, we show that satiety decreases cue responses in NAcC and pPVT neurons. Blockade of pPVT orexin-2 receptors reduces responding in hungry rats. Activation of pPVT neurons, either with local infusion of orexin-A or via optogenetics, positively controls NAcC cue responses and restores behavioral responding in sated rats, highlighting a circuit that integrates reward-predictive cues perceived in the environment with the current metabolic state of the animal.

Ventral Pallidum Neurons Encode Incentive Value and Promote Cue-Elicited Instrumental Actions.

The ventral pallidum (VP) is posited to contribute to reward seeking by conveying upstream signals from the nucleus accumbens (NAc). Yet, very little is known about how VP neuron responses contribute to behavioral responses to incentive cues. Here, we recorded activity of VP neurons in a cue-driven reward-seeking task previously shown to require neural activity in the NAc. We find that VP neurons encode both learned cue value and subsequent reward seeking and that activity in VP neurons is required for robust cue-elicited reward seeking. Surprisingly, the onset of VP neuron responses occurs at a shorter latency than cue-elicited responses in NAc neurons. This suggests that this VP encoding is not a passive response to signals generated in the NAc and that VP neurons integrate sensory and motivation-related information received directly from other mesocorticolimbic inputs.

Glucocorticoid receptor gene inactivation in dopamine-innervated areas selectively decreases behavioral responses to amphetamine.

The meso-cortico-limbic system, via dopamine release, encodes the rewarding and reinforcing properties of natural rewards. It is also activated in response to abused substances and is believed to support drug-related behaviors. Dysfunctions of this system lead to several psychiatric conditions including feeding disorders and drug addiction. These disorders are also largely influenced by environmental factors and in particular stress exposure. Stressors activate the corticotrope axis ultimately leading to glucocorticoid hormone (GCs) release. GCs bind the glucocorticoid receptor (GR) a transcription factor ubiquitously expressed including within the meso-cortico-limbic tract. While GR within dopamine-innervated areas drives cocaine's behavioral responses, its implication in responses to other psychostimulants such as amphetamine has never been clearly established. Moreover, while extensive work has been made to uncover the role of this receptor in addicted behaviors, its contribution to the rewarding and reinforcing properties of food has yet to be investigated. Using mouse models carrying GR gene inactivation in either dopamine neurons or in dopamine-innervated areas, we found that GR in dopamine responsive neurons is essential to properly build amphetamine-induced conditioned place preference and locomotor sensitization. c-Fos quantification in the nucleus accumbens further confirmed defective neuronal activation following amphetamine injection. These diminished neuronal and behavioral responses to amphetamine may involve alterations in glutamate transmission as suggested by the decreased MK801-elicited hyperlocomotion and by the hyporeactivity to glutamate of a subpopulation of medium spiny neurons. In contrast, GR inactivation did not affect rewarding and reinforcing properties of food suggesting that responding for natural reward under basal conditions is preserved in these mice.

Prefrontal cortex mediates extinction of responding by two distinct neural mechanisms in accumbens shell.

Suppression of ill-timed or competing actions optimizes goal-directed behaviors. Diminished inhibitory control over such actions is a central feature of such disorders as impulsivity, obesity, and drug addiction. The ventromedial prefrontal cortex (vmPFC) is involved in suppression of unreinforced actions. Using reversible inactivation in rats, we demonstrate that vmPFC activity is also required for inhibition of unreinforced actions extinguished during learning of a cued appetitive task and that behavioral disinhibition following vmPFC inactivation depends on dopamine signaling in nucleus accumbens shell (NAcS). Combining electrophysiological recording in NAcS with vmPFC inactivation in rats reveals two neural mechanisms by which vmPFC inhibits unreinforced actions. The first is by suppressing phasic excitations that promote behavioral cue responding. The second is by increasing the basal firing of NAcS neurons that tonically inhibit reward seeking. These results identify the vmPFC and the NAcS as critical elements of the circuits relevant to suppression of inappropriate actions.

Roles of nucleus accumbens core and shell in incentive-cue responding and behavioral inhibition.

The nucleus accumbens (NAc) is involved in many reward-related behaviors. The NAc has two major components, the core and the shell. These two areas have different inputs and outputs, suggesting that they contribute differentially to goal-directed behaviors. Using a discriminative stimulus (DS) task in rats and inactivating the NAc by blocking excitatory inputs with glutamate antagonists, we dissociated core and shell contributions to task performance. NAc core but not shell inactivation decreased responding to a reward-predictive cue. In contrast, inactivation of either subregion induced a general behavioral disinhibition. This reveals that the NAc actively suppresses actions inappropriate to the DS task. Importantly, selective inactivation of the shell but not core significantly increased responding to the nonrewarded cue. To determine whether the different contributions of the NAc core and shell depend on the information encoded in their constituent neurons, we performed electrophysiological recording in rats performing the DS task. Although there was no firing pattern unique to either core or shell, the reward-predictive cue elicited more frequent and larger magnitude responses in the NAc core than in the shell. Conversely, more NAc shell neurons selectively responded to the nonrewarded stimulus. These quantitative differences might account for the different behavioral patterns that require either core or shell. Neurons with similar firing patterns could also have different effects on behavior due to their distinct projection targets.

Isolating event-related neuronal responses by deconvolution.

Although many studies in neuroscience are based on comparing neuronal responses to single, isolated sensory or motor events, multiple events frequently occur in close temporal proximity in freely moving animals. This often obscures the precise temporal correlation between each event and the relevant brain activity. By simulating neuronal responses in multi-event tasks, we show that perievent time histograms (PETHs) greatly distort the underlying true responses. We propose a multi-event deconvolution method that can separate the contribution of each event to the overall neuronal activity. The improvements over PETH in analyzing real data are demonstrated using simulated data and a sample electrophysiological recording obtained from rats in a task involving responses to a reward predictive cue.

Stress and addiction: glucocorticoid receptor in dopaminoceptive neurons facilitates cocaine seeking.

The glucocorticoid receptor is a ubiquitous transcription factor mediating adaptation to environmental challenges and stress. Selective Nr3c1 (the glucocorticoid receptor gene) ablation in mouse dopaminoceptive neurons expressing dopamine receptor 1a, but not in dopamine-releasing neurons, markedly decreased the motivation of mice to self-administer cocaine, dopamine cell firing and the control exerted by dopaminoceptive neurons on dopamine cell firing activity. In contrast, anxiety was unaffected, indicating that glucocorticoid receptors modify a number of behavioral disorders through different neuronal populations.

Basolateral amygdala neurons facilitate reward-seeking behavior by exciting nucleus accumbens neurons.

Both the nucleus accumbens (NAc) and basolateral amygdala (BLA) contribute to learned behavioral choice. Neurons in both structures that encode reward-predictive cues may underlie the decision to respond to such cues, but the neural circuits by which the BLA influences reward-seeking behavior have not been established. Here, we test the hypothesis that the BLA drives NAc neuronal responses to reward-predictive cues. First, using a disconnection experiment, we show that the BLA and dopamine projections to the NAc interact to promote the reward-seeking behavioral response. Next, we demonstrate that BLA neuronal responses to cues precede those of NAc neurons and that cue-evoked excitation of NAc neurons depends on BLA input. These results indicate that BLA input is required for dopamine to enhance the cue-evoked firing of NAc neurons and that this enhanced firing promotes reward-seeking behavior.

Dorsomedial prefrontal cortex contribution to behavioral and nucleus accumbens neuronal responses to incentive cues.

Cue-elicited phasic changes in firing of nucleus accumbens (NAc) neurons can facilitate reward-seeking behavior. Here, we test the hypothesis that the medial prefrontal cortex (mPFC), which sends a dense glutamatergic projection to the NAc core, contributes to NAc neuronal firing responses to reward-predictive cues. Rats trained to perform an operant response to a cue for sucrose were implanted with recording electrodes in the core of the NAc and microinjection cannulas in the dorsal mPFC (dmPFC). The cue-evoked firing of NAc neurons was reduced by bilateral injection of GABA(A) and GABA(B) agonists into the dmPFC concomitant with loss of behavioral responding to the cue. In addition, unilateral dmPFC inactivation reduced ipsilateral cue excitations and contralateral cue inhibitions. These findings indicate that cue-evoked excitations and inhibitions of NAc core neurons depend on dmPFC projections to the NAc and that these phasic changes contribute to the behavioral response to reward-predictive cues.