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

Abstract

The ventral striatum is involved in motivated behavior. Akin to the dorsal striatum, the ventral striatum contains two parallel pathways: the striatomesencephalic pathway consisting of dopamine receptor Type 1-expressing medium spiny neurons (D1-MSNs) and the striatopallidal pathway consisting of D2-MSNs. These two genetically identified pathways are thought to encode opposing functions in motivated behavior. It has also been reported that D1/D2 genetic selectivity is not attributed to the anatomical discrimination of two pathways. We wanted to determine whether D1-and D2-MSNs in the ventral striatum functioned in an opposing manner as previous observations claimed, and whether D1/D2 selectivity corresponded to a functional segregation in motivated behavior of mice. To address this question, we focused on the lateral portion of ventral striatum as a region implicated in food-incentive, goal-directed behavior, and recorded D1 or D2-MSN activity by using a gene-encoded ratiometric Ca 2ϩ indicator and by constructing a fiberphotometry system, and manipulated their activities via optogenetic inhibition during ongoing behaviors. We observed concurrent event-related compound Ca 2ϩ elevations in ventrolateral D1-and D2-MSNs, especially at trial start cue-related and first lever press-related times. D1 or D2 selective optogenetic inhibition just after the trial start cue resulted in a reduction of goal-directed behavior, indicating a shared coding of motivated behavior by both populations at this time. Only D1-selective inhibition just after the first lever press resulted in the reduction of behavior, indicating D1-MSN-specific coding at that specific time. Our data did not support opposing encoding by both populations in food-incentive, goal-directed behavior.

Striatal Local Circuitry: A New Framework for Lateral Inhibition

“…Fiber photometry recordings of SPNs in the NAc and dorsal striatum also showed large transients of calcium concentrations time locked to cues and specific behaviors during behavioral tasks (Calipari et al, 2016; Cui et al, 2014; Natsubori et al, 2017; Zalocusky et al, 2016), suggestive of population synchrony during actions, though again not necessarily due to cells in close proximity. Moreover, deep brain calcium imaging, which provides a wide field of view, shows clusters of SPNs that display synchronized calcium transients during free locomotion.…”

“…Extending this idea to the ventral striatum, optogenetic inhibition of either iSPN or dSPNs in the NAc after trial start cue in an operant food task reduced motivated responding on the task (Natsubori et al, 2017), and inhibiting synaptic transmission from either iSPNs or dSPNs prevents the acute locomotor response to cocaine and methamphetamine, a behavior known to involve the NAc (Hikida et al, 2010). These studies provide evidence that both dSPNs and iSPNs are more active during actions than at rest, and activity in both SPN subtypes is needed for driving normal motivated behavior.…”

“…In addition, fiber photometry recordings to examine the activity of dSPNs and iSPNs in the NAc during an operant food responding task show that both SPN subtypes are more active after a trial start cue and reward delivery than at rest (Natsubori et al, 2017). Furthermore photometry recordings in the NAc during a risky decision task have demonstrated that iSPN activity is highest following a risky choice that led to no reward and that this activity predicts future “safe” choices (Zalocusky et al, 2016).…”

“…An important question then is how to reconcile the findings from optogenetic stimulation experiments suggesting that iSPN activation inhibits movement (Kravitz et al, 2010) with those from calcium dynamics showing iSPN activation during action initiation and behavior (Barbera et al, 2016; Cui et al, 2014; Natsubori et al, 2017). The most parsimonious explanation is that during behavior, dSPNs facilitate the desired behavior, while iSPNs act simultaneously to inhibit all other competing undesirable behaviors (see more in section 3).…”

Cross-talk between the epigenome and neural circuits in drug addiction

“…Further, these increased responses to drug-associated contextual cues by D1 MSNs were still present after a 2-week withdrawal period, suggesting that the changes in the population activity were stable and long-lasting (Calipari et al, 2016). This is particularly interesting because recent work with food self-administration has shown that both D1 and D2 MSN activity is stimulated, suggesting that something is fundamentally different about the encoding of food and drug rewards (Natsubori et al, 2017). …”