Nicotinic receptors in the ventral tegmental area promote uncertainty-seeking

Abstract

Cholinergic neurotransmission affects decision-making, notably through the modulation of perceptual processing in the cortex. In addition, acetylcholine acts on value-based decisions through as yet unknown mechanisms. We found that nicotinic acetylcholine receptors (nAChRs) expressed in the ventral tegmental area (VTA) are involved in the translation of expected uncertainty into motivational value. We developed a multi-armed bandit task for mice with three locations, each associated with a different reward probability. We found that mice lacking the nAChR β2 subunit showed less uncertainty-seeking than their wild-type counterparts. Using model-based analysis, we found that reward uncertainty motivated wild-type mice, but not mice lacking the nAChR β2 subunit. Selective re-expression of the β2 subunit in the VTA was sufficient to restore spontaneous bursting activity in dopamine neurons and uncertainty-seeking. Our results reveal an unanticipated role for subcortical nAChRs in motivation induced by expected uncertainty and provide a parsimonious account for a wealth of behaviors related to nAChRs in the VTA expressing the β2 subunit.

Manipulating midbrain dopamine neurons and reward-related behaviors with light-controllable nicotinic acetylcholine receptors

“…They are also present on DAergic terminals in the Nucleus Accumbens (NAc) and the prefrontal cortex (Grady et al, 2007; Changeux, 2010). Genetic and pharmacological manipulations have implicated VTA nAChRs in tuning the activity of DA neurons and in mediating the addictive properties of nicotine (Mameli-Engvall et al, 2006; Maskos et al, 2005; Morel et al, 2014; Naudé et al, 2016; Picciotto et al, 1998; Tapper et al, 2004; Tolu et al, 2013). However, understanding the mechanism by which ACh and nicotine participate in these activities requires to comprehend the spatio-temporal dynamics of nAChRs activation.…”

Nicotinic receptors in mouse prefrontal cortex modulate ultraslow fluctuations related to conscious processing

“…Many studies in both animal models and humans have shown that nicotinic acetylcholine receptors (nAChRs) are of particular importance for cognitive functions, reward, aging, and for pathologies like Alzheimer's Disease (11). For example, deletion of the α7 and β2 nAChR subunits in mice impairs behaviors, such as exploration and attention (12)(13)(14)(15)(16). Importantly, lesions of the prelimbic cortex (PrLC) in WT mice cause deficits in social behavior, similar to those observed in β2 knock-out (KO) mice, whereas re-expression of the β2 subunit in the PrLC of β2 KO mice rescues their social interaction (4).…”

Nicotine and alcohol: the role of midbrain dopaminergic neurons in drug reinforcement

“…In particular, lesions of the LDTg and PPTg decrease the firing rate and the bursting activity of VTA DA neurons (Blaha et al., ). In anesthetized mice, deletion of the β2nAChRs subunit gene – β2KO mice (Picciotto et al., ) – induces a loss of VTA DA bursting activity, associated with an alteration of exploratory behavior and uncertainty processing (Mameli‐Engvall et al., ; Avale et al., ; Maubourguet et al., ; Naudé et al., ). The viral re‐expression of β2 nAChRs in both VTA DA and GABA neurons are required to restore spontaneous VTA DA neuron bursting activity (Maskos et al., ; Tolu et al., ).…”

“…Smoking and impulsivity form a bidirectional relationship; increased impulsivity is associated with increased smoking vulnerability and increased nicotine dependence (Kale et al., ). A recent study described the role of VTA β2*nAChRs in uncertainty seeking behaviors (Naudé et al., ). As nicotine exposure alters the endogenous function of β2*nAChRs in the VTA, it is expected that nicotine would affect uncertainty seeking processes and overall decision making (Naudé et al., ).…”