Dysfunction of ventrolateral striatal dopamine receptor type 2-expressing medium spiny neurons impairs instrumental motivation

Abstract

Impaired motivation is present in a variety of neurological disorders, suggesting that decreased motivation is caused by broad dysfunction of the nervous system across a variety of circuits. Based on evidence that impaired motivation is a major symptom in the early stages of Huntington's disease, when dopamine receptor type 2-expressing striatal medium spiny neurons (D2-MSNs) are particularly affected, we hypothesize that degeneration of these neurons would be a key node regulating motivational status. Using a progressive, time-controllable, diphtheria toxin-mediated cell ablation/dysfunction technique, we find that loss-of-function of D2-MSNs within ventrolateral striatum (VLS) is sufficient to reduce goal-directed behaviours without impairing reward preference or spontaneous behaviour. Moreover, optogenetic inhibition and ablation of VLS D2-MSNs causes, respectively, transient and chronic reductions of goal-directed behaviours. Our data demonstrate that the circuitry containing VLS D2-MSNs control motivated behaviours and that VLS D2-MSN loss-of-function is a possible cause of motivation deficits in neurodegenerative diseases.

Ventrolateral Striatal Medium Spiny Neurons Positively Regulate Food-Incentive, Goal-Directed Behavior Independently of D1 and D2 Selectivity

“…This view has been extended to studies on the ventral striatum (VS), especially on the nucleus accumbens (NAc; the rostral VS) in a series of drug-seeking behavioral studies (Hikida et al, 2010;Lobo et al, 2010;Stefanik et al, 2013). Such an extension was supported in part by anatomical similarity; in the VS, D1-MSNs project to the ventral tegmental area (ventral mesencephalon [VM]) directly and D2-MSNs project the ventral pallidum (VP), a relay nucleus to the VM.…”

“…D2-ArchT mice (Drd2-tTA::tetO-ArchT-EGFP double-transgenic mice) were obtained by crossing between Drd2-tTA mice and tetO-ArchT-EGFP mice (Tsunematsu et al, 2013). D1-YC mice (Pde10a2-tTA::tetO-YCnano50; Adora2a-Cre triple-transgenic mice) were obtained by crossing between Pde10a2-tTA mice (Sano et al, 2008), tetO-YCnano50 mice, and Adora2a-Cre mice (Durieux et al, 2009) (see Fig. 1).…”

“…To sufficiently express the Ca 2ϩ indicator in the targeted cell population, we took advantage of an improved tetracycline-controllable gene induction system (KENGE-tet system, e.g., tetO-YCnano50 mice) (Tanaka et al, 2012). To express YCnano50 selectively in D2-MSNs, we generated Drd2-tTA:: tetO-YCnano50 double-transgenic mice (D2-YC; Fig.…”

Acute stress enhances associative learning via dopamine signaling in the ventral lateral striatum

“…Studies examining the role of ventral striatal dopamine in appetitive behavior have primarily focused on the VMS 26,37,46-49 . However, recent findings indicate that dopaminoceptive VLS spiny projection neurons regulate aspects of rewardseeking 35,40,41 . Our results demonstrate that dopamine in the VLS regulates conditioned responding in later training sessions in unstressed animals.…”

“…3D). Dopamine release to the US decayed with training (session effect F(2.5, 43.9)=8.02, p=.0005; Fig 3E) Increasing evidence highlights that the ventral lateral striatum (VLS) contributes to reward-related behaviors 35,40,41 . Furthermore, aversive experience increases excitatory transmission to dopamine neurons projecting to the VLS 42 .…”