Neurons in the ventral striatopallidal complex modulate lateral hypothalamic orexin/hypocretin neuron activity: Implications for reward-seeking

Abstract

Feeding is at once both a basic biological need and a function set in a complex system of competing motivational drivers. Orexin/hypocretin neurons are located exclusively within the lateral hypothalamus (LH) and are commonly implicated in feeding, arousal, and motivated behavior, although largely based on studies employing long-term systemic manipulations. Here we show how orexin neurons in freely behaving mice respond in real time to food presentations, and how this response is modulated by differences in metabolic state and salience. Orexin neurons increased activity during approach to food, and this activity declined to baseline at the start of consummatory behavior. Furthermore, the activity of orexin neurons on approach was enhanced by manipulations of metabolic state, and increased food salience. We investigated the nucleus accumbens shell (NAcSh) as a candidate afferent region to inhibit LH orexin neurons following approach, and using projection and cell type-specific electrophysiology, demonstrated that the NAcSh forms both direct and indirect inhibitory projections to LH orexin cells. Together these findings reveal that the activity of orexin neurons is associated with food approach rather than consumption, is modulated by motivationally relevant factors, and that the NAcSh-LH pathway is capable of suppressing orexin cell recruitment.Keywords orexin, hypocretin, lateral hypothalamus, nucleus accumbens, feeding, approach NAcSh projections to the LH control food consummatory and approach behavioursWe posited that the NAcSh could be an afferent structure that modulates LH orexin cell activity with respect to food approach and consumption. In support, activation of terminals in the LH that originate from the NAcSh inhibited food and alcohol seeking (Gibson et al., 2018;O'Connor et al., 2015). To confirm that activation of NAcSh terminals in the LH would suppress food consumption in the orexin-Cre mice and our behavioral model we injected AAV-ChR2-YFP or AAV-YFP into the NAcSh, and implanted fiber optic cannulae above the LH (Fig. 2A). The AAV-Chrimson-tdTomato construct was also used instead of ChR2 in some animals, and results were pooled (see Fig. 2). Optogenetic stimulation produced a significant disruption of feeding, measured as a reduced latency to terminate feeding (Fig. 2B). ChR2-YFP and Chrimson mice also displayed a significant increase in locomotor activity ( Fig. 2C). Together these data confirm that optogenetic activation of NAcSh LH terminals can disrupt consummatory actions, like previous reports (Gibson et al., 2018;O'Connor et al., 2015). ChR2-assisted circuit mapping of NAcSh inputs to LH orexin neuronsActivation of orexin neurons was highest during food approach, and optogenetic stimulation of NAcSh terminals in the LH disrupted consummatory actions. Therefore, we asked whether NAcSh terminals might influence LH orexin cells. To address this question, we prepared Vgat-Cre mice with NAcSh-directed injections of AAV5-DIO-ChR2-YFP, and AAV8-h-orexin-tdTomato into the LH to visualize orexin ...

Orexin-1 receptor signaling within the lateral hypothalamus, but not bed nucleus of the stria terminalis, mediates context-induced relapse to alcohol seeking

“…Systemic SB-334867 also reduces yohimbine-(stress)-induced reinstatement of alcohol-seeking (Richards et al, 2008). In line with this, our results also extend recent studies where the orexin system has been associated with the motivation to approach a reward, rather than the actual consumption of the reward (Mitchell et al, 2020).…”

Orexins (hypocretins): The intersection between homeostatic and hedonic feeding

“…Similarly, Mitchell et al (2020) report that during the approach to food, orexin activity significantly increased but then reverted to baseline level when food consumption started. Furthermore, they suggest that termination of this orexin activity may be mediated by direct and indirect inhibitory signals from the nucleus accumbens to orexin neurons in the lateral hypothalamus (Mitchell et al 2020). Together, this raises the possibility that orexin signalling is more crucial for mediating appetitive behaviour rather than the consumption itself.…”

“…Another study, using fibre photometry, found that upon physical contact with food, the activity of orexin neurons rapidly reduced, regardless of the taste, textures and caloric content (Gonzalez et al 2016). Similarly, Mitchell et al (2020) report that during the approach to food, orexin activity significantly increased but then reverted to baseline level when food consumption started. Furthermore, they suggest that termination of this orexin activity may be mediated by direct and indirect inhibitory signals from the nucleus accumbens to orexin neurons in the lateral hypothalamus (Mitchell et al 2020).…”

“…Mitchell et al ( 2020) further examined the real-time responses of orexin neurons upon food presentation using fibre photometry and showed that orexin cells produced significantly higher calcium signals when mice approached a chocolate pellet as compared to standard food suggesting that the salience/palatability of food can enhance orexin neuron activity to promote appetitive behaviour (Mitchell et al, 2020).…”

“…Therefore, the metabolic state and the palatability of the food serve to enhance the activation of orexin neurons to promote eating. Indeed, a recent study using in vivo calcium recording showed that orexin cell activity was higher in sated rats approaching a palatable chocolate pellet and in food-restricted rats approaching standard food as compared to ad libitum fed rats approaching standard food (Mitchell et al 2020).…”