4.3. Ventral pallidum (VP)
The VP has received less attention than the VTA and the NAcc, but also plays an important role in reward and reinforcement. The VP is the primary output structure for mesolimbic reward circuitry. It is heavily innervated by the GABAergic medium spiny neurons in the NAcc (Creed et al. 2016; Ho and Berridge 2013; Kupchik et al. 2015; Root et al. 2015), and projects back to the VTA and to several areas involved in the regulation of movement (Root et al. 2015; Zahm 2000). Due to these connectivity patterns, the VP is thought to be a primary hub where motivational output from the NAcc is translated into appetitive behavior (Smith et al. 2009); however, there is also evidence for bi-directional communication between the NAcc and VP, as cue responses in the VP sometimes precede and drive those in the NAcc (Chang et al. 2018; Richard et al. 2016).
The VP is a heterogeneous structure, with rostral-caudal differences in cell morphology and connectivity patterns (Kupchik and Kalivas 2013; Root et al. 2015; Zahm 2000). For example, there are topographic differences in projection patterns, with the anterior VP receiving projections from the NAcc shell and the posterior VP receiving projections from the NAcc core (Kupchik et al. 2015; Root et al. 2015). The functional differences between anterior and posterior regions are not well understood; however, some studies have found that they play different roles in modulating reward-related behavior (Root et al. 2010; Root et al. 2013), and have even been shown to have opposite effects on hedonic responses to food reward (Smith and Berridge 2007; Smith et al. 2009).
Several studies have shown that neurons in the caudal VP respond to food cues, with the magnitude of the response reflecting the strength of the cue’s motivational impact (Avila and Lin 2014a, b; Smith et al. 2011; Tachibana and Hikosaka 2012; Tindell et al. 2005; Tindell et al. 2006). The VP has also been shown to specifically encode the incentive value of a cue in a way that can be experimentally dissociated from reward prediction (Smith et al. 2011; Tindell et al. 2005; Zhang et al. 2009). For example, chemogenetic inactivation of the VP can impair the acquisition (but not expression) of sign-tracking behavior, while leaving goal-tracking unaffected (Chang et al. 2015). Importantly, the VP is the only structure where differences in single-unit neural activity have been documented between STs and GTs. In two previous studies, STs have shown sustained changes in neural activity during exposure to the lever cue that are greater, in terms of proportion of responsive cells and the magnitude of responses, than that of GTs (Ahrens et al. 2016a; Ahrens et al. 2018). The heightened VP activity in STs was specifically evoked by the lever cue. When the same animals were trained with a tone cue that predicted identical reward, but did not support the attribution of incentive salience, the tone did not elicit the robust changes in neural activity that were seen with the lever. Therefore, not only does the VP reflects individual differences in motivational tendencies, it tracks dynamic changes in incentive value of cues as they change from trial to trial within a single animal (Ahrens et al. 2018).
Few studies have specifically focused on the role of the VP during sleep; however, the VP has been examined as part of the larger basal forebrain region, which has been shown to play a very important role in mediating both sleep and waking states (Jones 2017; Yang et al. 2017). The basal forebrain describes a large area that encompasses the VP in addition to other subcortical structures, such as the medial septum, bed nucleus of the stria terminalis, substantia innominata, magnocellular preoptic nucleus, and extended amygdala (Yang et al. 2017). The basal forebrain contains a mix of cholinergic, glutamatergic, and GABAergic cells that co-express different calcium-binding proteins. Among these cell types four different functional activity patterns have been identified. The most common type (~50%) are cortically-projecting cells that show maximal firing during waking and REM sleep, but not NREM sleep (Jones 2017), and when optogenetically stimulated produces a rapid desynchronization of EEG and an increase in wakefulness (Irmak and de Lecea 2014; Xu et al. 2015). The cholinergic neurons almost exclusively fall in this wake-promoting category (Lee et al. 2005), as do most glutamatergic neurons and some parvalbumin-positive GABAergic neurons (Hassani et al. 2009). A second type (~20%) are sleep-active, meaning they respond more during NREM sleep than during active brain states. Most these neurons are somatostatin-positive GABAergic neurons, with some glutamatergic neurons, and they project primarily to the prefrontal cortex (Hassani et al. 2009; Xu et al. 2015). The third type is relatively infrequent (~10%) and are glutamatergic neurons that respond maximally during waking. The fourth type (~20%) is maximally responsive during REM sleep, but not waking. These are a mix of GABAergic and glutamatergic cells that project primarily to the posterior hypothalamus (Jones 2017). Although basal forebrain neurons have been well characterized in the context of sleep and wakefulness, it is not known whether there are individual differences in the composition or function of these different cell types. It is also not known whether the VP itself shares all of the same characteristics as this larger basal forebrain region. Finally, further research is needed to determine what role the VP plays (if any) on the ability of sleep to alter reward seeking behavior.