Saleem M. Nicola

The nucleus accumbens as part of a basal ganglia action selection circuit

BackgroundThe nucleus accumbens is the ventral extent of the striatum, the main input nucleus of the basal ganglia. Recent hypotheses propose that the accumbens and its dopamine projection from the midbrain contribute to appetitive behaviors required to obtain reward. However, the specific nature of this contribution is unclear. In contrast, significant advances have been made in understanding the role of the dorsal striatum in action selection and decision making.ObjectiveIn order to develop a hypothesis of the role of nucleus accumbens dopamine in action selection, the physiology and behavioral pharmacology of the nucleus accumbens are compared to those of the dorsal striatum.HypothesesThree hypotheses concerning the role of dopamine in these structures are proposed: (1) that dopamine release in the dorsal striatum serves to facilitate the ability to respond appropriately to temporally predictable stimuli (that is, stimuli that are so predictable that animals engage in anticipatory behavior just prior to the stimulus); (2) that dopamine in the nucleus accumbens facilitates the ability to respond to temporally unpredictable stimuli (which require interruption of ongoing behavior); and (3) that accumbens neurons participate in action selection in response to such stimuli by virtue of their direct (monosynaptic inhibitory) and indirect (polysynaptic excitatory) projections to basal ganglia output nuclei.

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.

The Ventral Tegmental Area Is Required for the Behavioral and Nucleus Accumbens Neuronal Firing Responses to Incentive Cues

Reward-predictive cues exert powerful control over behavioral choice and may be a critical factor in drug addiction. Reward-seeking elicited by predictive cues is facilitated by the release of dopamine in the nucleus accumbens (NAc), yet the contribution of dopamine to the specific NAc firing patterns that underlie goal-directed behavior has remained elusive. We present evidence that subpopulations of NAc neurons that respond to predictive cues require the dopaminergic projection from the ventral tegmental area (VTA) to promote reward-seeking behavior. Rats trained to perform an operant response to a cue to obtain a sucrose reward were implanted with both multiunit recording electrodes in the NAc and microinjection cannulas in the VTA. Both the behavioral response to cues and the cue-evoked firing of NAc neurons were blocked by injection of the GABAB agonist baclofen into the VTA. An additional group of rats was trained on the same task and then implanted with microinjection cannulas in the NAc. Like VTA baclofen injection, injection of dopamine receptor antagonists into the NAc profoundly reduced cue-elicited reward seeking. Together, these results support the conclusion that both the behavioral response to the cue and the specific NAc neuronal firing that promotes the response depend on dopamine release within the NAc. Our findings suggest a neural mechanism by which the dopamine-dependent firing of NAc neurons mediates goal-directed 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 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.

Contrasting effects of dopamine and glutamate receptor antagonist injection in the nucleus accumbens suggest a neural mechanism underlying cue‐evoked goal‐directed behavior

Discriminative stimuli (DSs) inform animals that reward can be obtained contingent on the performance of a specific behavior. Such stimuli reinstate drug‐seeking behavior, evoke dopamine release in the nucleus accumbens (NAc) and excite and inhibit specific subpopulations of NAc neurons. Here we show in rats that DSs can reinstate food‐seeking behavior. In addition, we compare the effects of injecting dopamine receptor antagonists into the NAc with those of general NAc inactivation on the performance of a DS task. Selective antagonism of D1 receptors reduced responding to the DS and increased the latency to respond, whereas general inactivation of NAc neuronal activity increased the latency to respond to the DS and increased behaviors extraneous to the task, such as responding in the absence of cues and responding on the inactive lever. Based on these results and our previous findings that NAc neuronal responses to DSs are dependent on the ventral tegmental area, we propose a model for the functional role of NAc neurons in controlling behavioral responses to reward‐predictive stimuli.

Induction in the rat hippocampus of long-term potentiation (LTP) and long-term depression (LTD) in the presence of a nitric oxide synthase inhibitor

Several recent studies have suggested a critical role for nitric oxide (NO) production in hippocampal LTP and LTD. In this study we show that normal LTP and LTD can be induced in rat hippocampal slices incubated in the NO synthase inhibitor L-NG-nitroarginine (NOArg) (100 microM). A test of NMDA-stimulated cGMP production demonstrated that incubation of slices in 100 microM NOArg effectively inhibited NO synthase. Our results suggest that NO synthase activity may not be required for the generation of LTP or LTD in CA1 of rat hippocampus.

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.

Invigoration of Reward Seeking by Cue and Proximity Encoding in the Nucleus Accumbens

A key function of the nucleus accumbens is to promote vigorous reward seeking, but the corresponding neural mechanism has not been identified despite many years of research. Here, we study cued flexible approach behavior, a form of reward seeking that strongly depends on the accumbens, and we describe a robust, single-cell neural correlate of behavioral vigor in the excitatory response of accumbens neurons to reward-predictive cues. Well before locomotion begins, this cue-evoked excitation predicts both the movement initiation latency and the speed of subsequent flexible approach responses, but not those of stereotyped, inflexible responses. Moreover, the excitation simultaneously signals the subjects proximity to the approach target, a signal that appears to mediate greater response vigor on trials that begin with the subject closer to the target. These results demonstrate a neural mechanism for response invigoration whereby accumbens neuronal encoding of reward availability and target proximity together drive the onset and speed of reward-seeking locomotion.

Contrast enhancement: a physiological effect of striatal dopamine?

Dopamine functions as an important neuromodulator in the dorsal striatum and ventral striatum/nucleus accumbens. Evidence is accumulating for the idea that striatal neurons compete with each other for control over the animal’s motor resources, and that dopamine plays an important modulatory role that allows a particular subset of neurons, encoding a specific behavior, to predominate in this competition. One means by which dopamine could facilitate selection among competing neurons is to enhance the contrast between stronger and weaker excitations (or to increase the “signal to noise ratio” among neurons, where the firing of the most excited neurons is assumed to transmit signal and the firing of the least excited to transmit noise). Here, we review the electrophysiological evidence for this hypothesis and discuss potential cellular mechanisms by which dopamine-mediated contrast enhancement could occur.

Dopamine Invigorates Reward Seeking by Promoting Cue-Evoked Excitation in the Nucleus Accumbens

Approach to reward is a fundamental adaptive behavior, disruption of which is a core symptom of addiction and depression. Nucleus accumbens (NAc) dopamine is required for reward-predictive cues to activate vigorous reward seeking, but the underlying neural mechanism is unknown. Reward-predictive cues elicit both dopamine release in the NAc and excitations and inhibitions in NAc neurons. However, a direct link has not been established between dopamine receptor activation, NAc cue-evoked neuronal activity, and reward-seeking behavior. Here, we use a novel microelectrode array that enables simultaneous recording of neuronal firing and local dopamine receptor antagonist injection. We demonstrate that, in the NAc of rats performing a discriminative stimulus task for sucrose reward, blockade of either D1 or D2 receptors selectively attenuates excitation, but not inhibition, evoked by reward-predictive cues. Furthermore, we establish that this dopamine-dependent signal is necessary for reward-seeking behavior. These results demonstrate a neural mechanism by which NAc dopamine invigorates environmentally cued reward-seeking behavior.