In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward

Abstract

The reinforcing and rewarding properties of cocaine are attributed to its ability to increase dopaminergic transmission in nucleus accumbens (NAc). This action reinforces drug taking and seeking and leads to potent and long-lasting associations between the rewarding effects of the drug and the cues associated with its availability. The inability to extinguish these associations is a key factor contributing to relapse. Dopamine produces these effects by controlling the activity of two subpopulations of NAc medium spiny neurons (MSNs) that are defined by their predominant expression of either dopamine D1 or D2 receptors. Previous work has demonstrated that optogenetically stimulating D1 MSNs promotes reward, whereas stimulating D2 MSNs produces aversion. However, we still lack a clear understanding of how the endogenous activity of these cell types is affected by cocaine and encodes information that drives drug-associated behaviors. Using fiber photometry calcium imaging we define D1 MSNs as the specific population of cells in NAc that encodes information about drug associations and elucidate the temporal profile with which D1 activity is increased to drive drug seeking in response to contextual cues. Chronic cocaine exposure dysregulates these D1 signals to both prevent extinction and facilitate reinstatement of drug seeking to drive relapse. Directly manipulating these D1 signals using designer receptors exclusively activated by designer drugs prevents contextual associations. Together, these data elucidate the responses of D1-and D2-type MSNs in NAc to acute cocaine and during the formation of context-reward associations and define how prior cocaine exposure selectively dysregulates D1 signaling to drive relapse.cocaine | reward | medium spiny neuron | calcium imaging | associative learning D rug seeking associated with addiction is mediated in part by strong associations between the rewarding effects of drugs and the environment within which they are administered (1). The nucleus accumbens (NAc) is a key neural substrate of contextreward associations because it mediates multiple aspects of this process, including learning, selecting, and executing goal-oriented behaviors (2-5). Over time, contextual cues in the absence of drug can elicit neural responses that resemble that of the drug itself and trigger drug craving and seeking, resulting in relapse in drugaddicted individuals (1). Furthermore, an inability to extinguish previously formed associations is thought to contribute to pathological drug seeking that persists despite periods of abstinence (6-9). Thus, identifying the specific neuronal populations that drive these behaviors, and determining therapeutic strategies to manipulate the cell populations to promote extinction of these associations, would be advantageous to improving treatment outcomes in drug-addicted individuals.Increased activity of the mesolimbic dopamine system is a central mechanism underlying the reinforcing and rewarding actions of drugs of abuse, including cocaine, as well as the comp...

Activation of GABAergic Neurons in the Nucleus Accumbens Mediates the Expression of Cocaine-Associated Memory

“…19) Moreover, chemogenetic inhibition of D1R-MSNs, but not D2R-MSNs, before the posttest blocks the expression of cocaine CPP. 20) Thus, although we expressed hM4Di in all vGAT-positive GABAergic neurons in the NAc, these findings suggest the involvement of subpopulations of MSNs in the expression of cocaine CPP. However, it should be noted that recent studies have shown that silencing NAc GABAergic parvalbumin (PV) interneurons blocks CPP induced by amphetamine, 21) while optogenetic activation of NAc PV interneurons produces aversion.…”

Making the Case for ‘Power Abuse Disorder' as a Nosologic Entity

“…However, a crude summary seems permissible: dopamine in the accumbens is currently thought to serve at least 2 functions: (1) baseline dopamine and slow, that is, minute-to-minute, changes in accumbal dopamine (tonic DA release) seem to correlate with motivational vigor, reward rate, motivational vigor, and deprivation, whereas (2) fast, that is, second-to-second, changes in DA dopamine (phasic release) encode reward intensity/value as demonstrated by combinations of the most recent techniques [51,52,53,54]. …”

Clues on the coding of reward cues by the nucleus accumbens

“…No such correlation was found between the preference and the magnitude of the reduction of signals in D2-expressing neurons. Calipari et al (1) wisely interpret these results as evidence that high activation of D1-expressing neurons in the nucleus accumbens is largely responsible for coding the cocaine-context association. The study goes on to show that a history of cocaine exposure impairs the extinction of the preference, and it also enhances the magnitude of the preceding calcium signals in D1-expressing neurons.…”

“…The study by Calipari et al in PNAS provides a glimpse into the in vivo pattern of neuronal activation in the mouse nucleus accumbens during the acquisition and expression of learned reward-context associations (1). The nucleus accumbens sits in the ventral part of the mouse striatum, and is required for reward-motivated learning.…”

“…However, recording the activity of the striatal neurons in a cell-specific manner has been very difficult. To this end, Calipari et al (1) introduce the genetically coded calcium indicator GCaMP6 selectively in D1-or D2-expressing neurons of the nucleus accumbens, and use fiber photometry to monitor the calcium signals generated in this cell-specific fashion during the acquisition of condition place preference for cocaine. It is important to stress that although each detected calcium signal is generated by the firing of one or more action potentials in the neuron, not every action potential appears to lead to a detectable calcium signal.…”