4.6. Paraventricular nucleus of the thalamus (PVT).
The PVT is a thalamic midline structure with numerous connections to cortical, limbic, and motor structures (Kelley et al. 2005; Li and Kirouac 2012), including dense projections to the NAcc, prelimbic and infralimbic cortices, and amygdala (Vertes and Hoover 2008). Recent studies have found that the PVT may be one of the key structures mediating incentive versus predictive cue responses seen in STs and GTs. Under normal conditions the PVT appears to suppress the attribution of incentive salience to cues and plays a role in preventing GTs from expressing attraction to cues. For example, disruption of PVT activity has been shown to increase sign-tracking behavior and decrease goal-tracking behavior, causing rats previously identified as GTs to switch to sign-tracking (Haight et al. 2015). Furthermore, disruption of the PVT increases cue-induced reinstatement of drug seeking in GTs to the level normally seen in STs (Kuhn et al. 2017). A recent dual-labeling study (c-fos and flourogold) found that in both STs and GTs a food-paired cue activated the projection from the prelimbic cortex to the PVT, suggesting that this pathway mediates the predictive value of the cue, which both STs and GTs experience equally. However, in STs, the cues also activated subcortical pathways from the hypothalamus and amygdala to the PVT, as well as projections from the PVT to the ventral striatum, suggesting that these connections are involved in processing the incentive value of a cue. Therefore, the prelimbic-to-PVT pathway is hypothesized to be part of an inhibitory mechanism by which GTs exert greater cortical “top-down” control over motivated behavior and react primarily to the predictive value of a cue. The lack of this inhibition causes STs to act more on “bottom-up” emotional impulses driven by subcortical circuitry (Haight et al. 2017).
In addition to its prominent role in incentive motivation, the PVT is also ideally situated to play an important role in modulating sleep-wake states. The PVT receives synaptic inputs from, and projects back to, the suprachiasmatic nucleus (SCN), which is the master clock that regulates circadian rhythms in mammals (Alamilla et al. 2015; Colavito et al. 2015; Moga et al. 1995; Peng and Bentivoglio 2004; Vertes and Hoover 2008). Through its dense projections to limbic areas, the PVT can relay information about circadian rhythms from the SCN to the NAcc, amygdala, infralimbic and prelimbic cortices (Vertes and Hoover 2008). In addition, axon terminals of SCN fibers terminate on PVT neurons projecting to the amygdala (Peng and Bentivoglio 2004). Many of these connections are reciprocal, and since the PVT projects back to the SCN it can mediate the ability of behavioral arousal and attentive states to alter circadian rhythms. For example, inputs from the PVT can shift membrane potential in SCN neurons and make them more responsive to external light cues transmitted through the retinohypothalamic tract (Alamilla et al. 2015). Therefore, the PVT is in an ideal position to relay information about circadian timing from the SCN to brain regions involved in motivation aspects of behavior, and to also provide regulatory feedback to the SCN.
There is a bidirectional relationship between circadian rhythms and reward-related behavior, and given that circadian rhythms play such an integral role in regulating sleep, it is likely that individual traits related to circadian mechanisms play a role in the interaction between sleep and substance abuse (DePoy et al. 2017). Polymorphisms in circadian clock genes (including per1 and per2) have been shown to increase alcohol consumption in rodents (Dong et al. 2011; Spanagel et al. 2005), and in humans have been associated with cocaine addiction and reduced dopamine D2 receptor expression in the striatum (Shumay et al. 2012). The link between circadian rhythms and addictive behavior is complicated by the fact that exposure to alcohol, drugs of abuse, and food reward in some cases, can cause disruption or entrainment of circadian timing (Hasler et al. 2012; Webb 2017). Therefore, as with other aspects of sleep, it is not yet known which features of circadian rhythms represent underlying predisposing traits, and which results from drug exposure or environmental factors.