4.1. Ventral tegmental area (VTA) and nucleus accumbens
(NAcc)
Dopamine activity in the pathway from the VTA to the NAcc is well known
to be a crucial mediator of reward and reinforcement. However, there is
debate about the exact role that dopamine plays in reward; whether it
encodes hedonic pleasure and euphoria, reward-prediction, or
motivational salience (Berridge 2007). There is a compelling argument
that dopamine specifically encodes the state of incentive motivation,
much of which comes from evidence that dopamine signaling is important
for sign-tracking but not goal-tracking behavior (Berridge 2007; Flagel
et al. 2011; Flagel and Robinson 2017). For example, reward-paired cues
elicit greater dopamine release in the NAcc in STs than GTs (Flagel et
al. 2011) and STs have greater surface expression of the DA transporter
in the NAcc than GTs (Singer et al. 2016b). Although disruption of
activity in the NAcc-shell does not impair sign-tracking acquisition
(Chang and Holland 2013; Chang et al. 2018), disruption of activity in
the NAcc-core will reduce approach to the lever in STs, but not approach
to the food cup in GTs (Chang et al. 2012b; Flagel et al. 2011; Fraser
and Janak 2017; Saunders and Robinson 2012). Thus, it appears that cues
must be attributed with incentive salience to engage dopamine-mediated
reward circuitry, and that the predictive value of cues is not
sufficient (Flagel et al. 2011; Yager et al. 2015).
Key structures in the mesolimbic system are also activated during sleep
and play a vital role in the reprocessing and encoding of memories with
high emotional or motivational content (Oishi and Lazarus 2017;
Perogamvros and Schwartz 2012; Perogamvros et al. 2013). There has been
some debate about the role of the VTA in sleep (Oishi and Lazarus 2017)
since early electrophysiological studies found that VTA dopamine neurons
did not change firing rates across sleep-wake states (Miller et al.
1983). However, in more recent studies, single unit recordings have
shown that burst firing patterns in the VTA, but not mean firing rates,
differ between REM sleep, NREM sleep, and wakefulness, with burst firing
observed during REM sleep that is similar to activity patterns seen
during the consumption of food reward (Dahan et al. 2007). Consequently,
dopamine concentrations in the NAcc are higher during waking and REM
sleep compared to NREM sleep (Eban-Rothschild et al. 2016; Lena et al.
2005). In addition, it is well known that stimulant drugs that increase
dopamine concentrations are powerful promoters of wakefulness (Boutrel
and Koob 2004). There is also recent evidence that VTA dopaminergic
neurons are directly involved in promoting wakefulness in response to
environmental stimuli. Optogenetic or chemogenetic activation of VTA
neurons initiates and maintains wakefulness despite high homeostatic
sleep pressure, and this effect is primarily mediated by projections to
the NAcc (Eban-Rothschild et al. 2016; Oishi et al. 2017). Finally,
there is evidence that mesolimbic dopamine activity also plays an
important role in the generation of dreams (Feld et al. 2014), and it
has been suggested that the dopaminergic forebrain pathway plays a
larger role in dreaming than the cholinergic brain stem mechanisms that
trigger REM sleep (Solms 2000). Since the same pathway from the VTA to
the NAcc is critically involved in both the attribution of incentive
salience to cues and the regulation of sleep-wake states, it is likely
that individual differences between STs and GTs will also be expressed
as differences in dopaminergic control of sleep and wakefulness.