Abrupt transitions between prefrontal neural ensemble states accompany behavioral transitions during rule learning.

One of the most intriguing aspects of adaptive behavior involves the inference of regularities and rules in ever-changing environments. Rules are often deduced through evidence-based learning which relies on the prefrontal cortex (PFC). This is a highly dynamic process, evolving trial by trial and therefore may not be adequately captured by averaging single-unit responses over numerous repetitions. Here, we employed advanced statistical techniques to visualize the trajectories of ensembles of simultaneously recorded medial PFC neurons on a trial-by-trial basis as rats deduced a novel rule in a set-shifting task. Neural populations formed clearly distinct and lasting representations of familiar and novel rules by entering unique network states. During rule acquisition, the recorded ensembles often exhibited abrupt transitions, rather than evolving continuously, in tight temporal relation to behavioral performance shifts. These results support the idea that rule learning is an evidence-based decision process, perhaps accompanied by moments of sudden insight.

Hypocretin/orexin in arousal and stress.

Multiple lines of evidence indicate that hypocretin/orexin (HCRT) participates in the regulation of arousal and arousal-related process. For example, HCRT axons and receptors are found within a variety of arousal-related systems. Moreover, when administered centrally, HCRT exerts robust wake-promoting actions. Finally, a dysregulation of HCRT neurotransmission is associated with the sleep/arousal disorder, narcolepsy. Combined, these observations suggested that HCRT might be a key transmitter system in the regulation of waking. Nonetheless, subsequent evidence indicates that HCRT may not play a prominent role in the initiation of normal waking. Instead HCRT may participate in a variety of processes such as consolidation of waking and/or coupling metabolic state with behavioral state. Additionally, substantial evidence suggests a potential involvement of HCRT in high-arousal conditions, including stress. Thus, HCRT neurotransmission is closely linked to high-arousal conditions, including stress, and HCRT administration exerts a variety of stress-like physiological and behavioral effects that are superimposed on HCRT-induced increases in arousal. Combined, this evidence suggests the hypothesis that HCRT may participate in behavioral responding under high-arousal aversive conditions. Importantly, these actions of HCRT may not be limited to stress. Like stress, appetitive conditions are associated with elevated arousal levels and a stress-like activation of various physiological systems. These and other observations suggest that HCRT may, at least in part, exert affectively neutral actions that are important under high-arousal conditions associated with elevated motivation and/or need for action.

Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers.

Orexin A/hypocretin-1 (oxA/hcrt-1) is known to be a modulator of dopamine-dependent neuronal activity and behaviors. However, the role of this system in driving motivated behaviors remains poorly understood. Here, we show that orexin/hypocretin receptor-1 (ox/hcrt-1R) signaling is important for motivation for highly salient, positive reinforcement. Blockade of ox/hcrt-1R selectively reduced work to self-administer cocaine or high fat food pellets. Moreover, oxA/hcrt-1 strengthened presynaptic glutamatergic inputs to the ventral tegmental area (VTA) only in cocaine or high fat self-administering rats. Finally, oxA/hcrt-1-mediated excitatory synaptic transmission onto VTA neurons was not potentiated following an arousing, aversive stimulus, suggesting that oxA/hcrt-1-mediated glutamatergic synaptic transmission was potentiated selectively with highly salient positive reinforcers. These experiments provide evidence for a selective role of oxA/hcrt-1 signaling in motivation for highly salient reinforcers and may represent a unique opportunity to design novel therapies that selectively reduce excessive drive to consume positive reinforcers of high salience.

Hypocretin /orexin preferentially activates caudomedial ventral tegmental area dopamine neurons.

The hypocretin/orexin (HCRT) neuropeptide system modulates behavioral state and state-dependent processes via actions on multiple neuromodulatory transmitter systems. Recent studies indicate that HCRT selectively increases dopamine (DA) neurotransmission within the prefrontal cortex (PFC) and the shell subregion of the nucleus accumbens (NAs), but not the core subregion of the nucleus accumbens (NAc). The circuitry underlying the differential actions of HCRT across distinct DA systems is unclear. The current study examined whether HCRT preferentially activates PFC- and NAs-projecting relative to NAc-projecting DA neurons within the VTA. One week after infusion of the retrograde tracer fluorogold (FG) into the medial PFC, NAc or NAs, animals received a ventricular infusion of HCRT-1. Subsequent analyses conducted across the rostral-caudal extent of the VTA determined the degree to which: (i) Fos-immunoreactivity (ir) was observed within tyrosine hydroxylase (TH)-ir neurons; (ii) TH-ir was observed within FG-ir neurons; and (iii) Fos-ir was observed within FG-ir neurons. HCRT significantly increased Fos-ir in VTA DA (TH-ir) neurons, primarily in a restricted population of small-to-medium-sized DA neurons located within the caudomedial VTA. Furthermore, within this region of the VTA, PFC- and NAs-projecting TH-ir neurons were more likely to contain Fos-ir than were NAc-projecting TH-ir neurons. These results provide novel evidence that HCRT selectively activates PFC- and NAs-projecting DA neurons within the VTA, and suggest a potential role for HCRT in PFC- and NAs-dependent cognitive and/or affective processes. Moreover, these and other observations suggest that the dysregulation of HCRT-DA interactions could contribute to cognitive/affective dysfunction associated with a variety of behavioral disorders.

Hypocretin/orexin selectively increases dopamine efflux within the prefrontal cortex: involvement of the ventral tegmental area.

Hypocretins (HCRTs) modulate a variety of behavioral and physiological processes, in part via interactions with multiple ascending modulatory systems. Further, HCRT efferents from the lateral hypothalamus innervate midbrain dopamine (DA) nuclei, and DA cell bodies express HCRT receptors. Combined, these observations suggest that HCRT may influence behavioral state and/or state-dependent processes via modulation of DA neurotransmission. The current studies used in vivo microdialysis in the unanesthetized rat to first characterize the effect of intracerebroventricular infusion of HCRT-1 (0.07, 0.7 nmol) on extracellular levels of DA within the prefrontal cortex (PFC) and nucleus accumbens (Acc). Electroencephalographic/electromyographic measures of sleep-wake state were collected along with select behavioral measures (eg locomotor activity, grooming). HCRT-1 dose-dependently increased PFC dialysate DA levels, and these increases were closely correlated with increases in time spent awake. In contrast, Acc DA levels were unaffected. Additional studies examined whether HCRT-1 acts directly within the ventral tegmental area (VTA) to selectively increase PFC DA efflux and modulate behavioral state. Unilateral infusion of HCRT-1 (0.1, 1.0 nmol) within the VTA increased PFC, but not Acc, DA levels. Importantly, intra-VTA infusion of HCRT-1 increased the time spent awake and grooming. Moreover, HCRT-induced increases in both time spent awake and time spent grooming were significantly correlated with post-infusion PFC DA levels. The current observations predict a prominent modulatory influence of HCRT on PFC-dependent cognitive and affective processes that results, in part, from actions within the VTA. Additionally, these observations suggest that the activation of VTA DA neurons contributes to the behavioral state-modulatory actions of HCRT.

A 6-hydroxydopamine lesion of the mesostriatal dopamine system decreases the expression of corticotropin releasing hormone and neurotensin mRNAs in the amygdala and bed nucleus of the stria terminalis.

The mesostriatal dopamine (DA) system is known to play a vital role in extrapyramidal motor responses, and animals with a unilateral 6-hydroxydopamine (6-OHDA) lesion of this system have proved useful in studying the behavioral and neurobiological effects of DA depletion. Less is known about the role of this system in modulating emotional responses, although a number of lines of evidence suggest that dopamine influences emotional behavior. During the course of a study involving rats that had a unilateral 6-OHDA lesion, we discovered a hemispheric asymmetry in the levels of corticotropin releasing hormone (CRH) mRNA in the central nucleus of the amygdala (CEA). The present study was performed in order to determine (1) if the lesion resulted in a decrease in CRH mRNA, and/or if there was upregulation on the intact side, (2) if a similar imbalance in CRH mRNA was observed in other brain regions and (3) if levels of other neuropeptide mRNAs were affected by the lesion. Adult male Sprague-Dawley rats were left unoperated or were pretreated with desipramine and then injected unilaterally with 6-OHDA into the medial forebrain bundle to lesion the ascending mesostriatal DA neurons. Animals were killed 15-31 days following surgery and brain sections processed for CRH, neurotensin and enkephalin mRNAs by in situ hybridization. Levels of CRH and neurotensin mRNAs were decreased on the lesioned side in the CEA and oval nucleus of the BST (BSTov) relative to the intact side and to unoperated controls. Levels of enkephalin mRNA in these regions were not affected by the lesion. These effects appeared specific, because the lesion did not alter CRH mRNA expression in the ventral BST, paraventricular nucleus of the hypothalamus or cortex or neurotensin mRNA expression in the CA1 region of the hippocampus. In contrast, and consistent with previous reports, levels of neurotensin and enkephalin mRNAs were upregulated on the lesioned side of the striatum. This study provides evidence that the mesostriatal DA system regulates CRH and neurotensin mRNA in the BSTov and CEA, suggesting that dopamine may be an important modulator of CRH and neurotensin function within these nuclei. Although the precise mechanisms are not clear, and the involvement of noradrenergic systems cannot be precluded, data are consistent with the idea that dopamine, released in response to a stressful experience for example, interacts with CRH and neurotensin in the extended amygdala to affect emotional responsiveness.