Frederic Ambroggi

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.

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.

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 GABAA and GABAB 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.

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.

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.

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 cocaines 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.

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.