The lateral hypothalamus to lateral habenula projection, but not the ventral pallidum to lateral habenula projection, regulates voluntary ethanol consumption

Highlights

• Lesioning the stria medullaris increases voluntary ethanol consumption.

• Disconnection of the lateral hypothalamus to lateral habenula projection increases voluntary ethanol consumption.

• Disconnection of the ventral pallidum to lateral habenula projection does not alter ethanol-directed behaviors.

Abstract

The lateral habenula (LHb) is an epithalamic brain region implicated in aversive processing via negative modulation of midbrain dopamine (DA) and serotonin (5-HT) systems. Given the role of the LHb in inhibiting DA and 5-HT systems, it is thought to be involved in various psychiatric pathologies, including drug addiction. In support, it has been shown that LHb plays a critical role in cocaine- and ethanol-related behaviors, most likely by mediating drug-induced aversive conditioning. In our previous work, we showed that LHb lesions increased voluntary ethanol consumption and operant ethanol self-administration and blocked yohimbine-induced reinstatement of ethanol self-administration. LHb lesions also attenuated ethanol-induced conditioned taste aversion suggesting that a mechanism for the increased intake of ethanol may be reduced aversion learning. However, whether afferents to the LHb are required for mediating effects of the LHb on these behaviors remained to be investigated. Our present results show that lesioning the fiber bundle carrying afferent inputs to the LHb, the stria medullaris (SM), increases voluntary ethanol consumption, suggesting that afferent structures projecting to the LHb are important for mediating ethanol-directed behaviors. We then chose two afferent structures as the focus of our investigation. We specifically studied the role of the inputs from the lateral hypothalamus (LH) and ventral pallidum (VP) to the LHb in ethanol-directed behaviors. Our results show that the LH-LHb projection is necessary for regulating voluntary ethanol consumption. These results are an important first step towards understanding the functional role of afferents to LHb with regard to ethanol consumption.

Introduction

The lateral habenula (LHb) is an epithalamic brain structure that plays an important role in aversion-driven learning and behavior [1]. Neurons within the LHb show increased and decreased firing in response to aversive and rewarding stimuli, respectively [2], [3]. The LHb modulates consumption of ethanol and cocaine, as well as drug-induced aversive conditioning [4], [5], [6]. LHb lesions increase voluntary ethanol consumption in an intermittent-ethanol access (IEA) paradigm and reduce ethanol-induced conditioned taste aversion (CTA) [4]. Further, increased firing in LHb neurons is important for expression of ethanol-induced CTA [7]. LHb lesions also block yohimbine-induced reinstatement of cocaine- and ethanol-seeking, suggesting that LHb modulates stress-induced drug-seeking [4], [8]. While these experiments demonstrate a role for the LHb in mediating drug-related behaviors, whether afferent input to the LHb is also required has not been established.

The LHb receives major afferents from limbic forebrain, basal ganglia and cortical structures through the stria medullaris (SM) [9], [10]. While there are several candidate structures that may provide relevant inputs to the LHb for ethanol-directed behaviors, including orbitofrontal cortex [11], ventral tegmental area [12], entopeduncular nucleus [13], we chose to focus on the lateral hypothalamus (LH) and ventral pallidum (VP) [9], [14], [15]. Inputs from these brain regions to the LHb are candidate pathways mediating ethanol-directed behaviors, as both the LH and VP have been implicated in regulating appetitive and consummatory behaviors. The LH regulates many reward-related behaviors [16], [17], including ethanol consumption [18], [19], [20]. For example, administration of D1 agonists and D2 antagonists into the LH increases ethanol intake, whereas administration of D1 antagonists, D2 agonists, or opioid agonists into LH reduces ethanol intake [18], [19]. Further, recent evidence shows that optogenetic inhibition of the LH-LHb produces real-time preference and acutely increases consumption of a palatable liquid [21]. Similarly, the VP regulates ethanol consumption and ethanol-seeking [22], [23], [24] and is crucial for ethanol reinforcement [25] and reinstatement of drug-seeking [26], [27]. Opioid signaling in the VP has been implicated in these effects, as mu opioid receptor signaling in the VP decreases ethanol intake [24]. Together this evidence suggests that LH-LHb and VP-LHb pathways may regulate ethanol-directed behaviors.

In the present study, we first sought to determine whether afferents to the LHb are required for ethanol-directed behaviors, and then to understand the specific role of afferents from the LH and the VP to the LHb in these behaviors. We first lesioned the SM, interrupting the major source of afferents to the LHb, and examined voluntary ethanol consumption using the IEA paradigm. Bilateral SM lesion resulted in significantly higher ethanol intake during IEA compared to that measured in control rats. To begin identifying the specific afferent brain regions mediating this effect, we next studied the role of LH and VP afferents to the LHb in ethanol-directed behaviors. In separate experiments, we used a disconnection procedure to interrupt communication between these afferent structures and the LHb and investigated voluntary ethanol consumption, operant ethanol self-administration, and yohimbine-induced reinstatement of ethanol self-administration. We also investigated alterations in CTA and taste preference as possible mechanisms underlying the increase in ethanol consumption as we did in Haack, Sheth et al., 2014 [4]. Our results suggest that the LH-LHb projection plays a significant role in regulating voluntary ethanol consumption, whereas the VP-LHb projection does not.