Dynamic processing of hunger and thirst by common mesolimbic neural ensembles

Abstract

The nucleus accumbens (NAc) is a canonical reward center that regulates feeding and drinking but it is not known whether these behaviors are mediated by same or different neurons. We employed two-photon calcium imaging in awake, behaving mice and found that during the appetitive phase, both hunger and thirst are sensed by a nearly identical population of individual D1 and D2 neurons in the NAc that respond monophasically to food cues in fasted animals and water cues in dehydrated animals. During the consummatory phase, we identified three distinct neuronal clusters that are temporally correlated with action initiation, consumption, and cessation shared by feeding and drinking. These dynamic clusters also show a nearly complete overlap of individual D1 neurons and extensive overlap among D2 neurons. Modulating D1 and D2 neural activities revealed analogous effects on feeding versus drinking behaviors. In aggregate, these data show that a highly overlapping set of D1 and D2 neurons in NAc detect food and water reward and elicit concordant responses to hunger and thirst. These studies establish a general role of this mesolimbic pathway in mediating instinctive behaviors by controlling motivation-associated variables rather than conferring behavioral specificity.

Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need

“…2a). In these studies, the response of D1 and D2 neurons to food and water consumption after a period of deprivation were similar to our previous report ( 14 ).…”

“…Two days after the last drug injection (i.e., on day 7), mice were fasted (or dehydrated) and allowed to consume food (or water), while the same D1 or D2 neurons were imaged. In a previous study, we found that during refeeding three distinct clusters are activated during the consummatory phase correlating with meal initiation, continued feeding, and meal cessation ( 14 ). Here, we found that during cocaine withdrawal these three D1 neuronal clusters were entirely disordered with significantly reduced variances.…”

“…The NAc houses two key subregions, the core and shell, which exhibit unique cell-type composition, circuit projections, and functions in motivation and learning ( 3 ). Here, we specifically focus on the NAc core subregion based on its well-established role in coordinating motivated behavior and our prior report demonstrating convergent representations of hunger and thirst in this subregion ( 7, 14 ). We stereotaxically delivered an inhibitory DREADD, AAV5-hsyn-hM4Di-mCherry, or a control AAV5-hsyn-mCherry bilaterally to the NAc, and three weeks later assessed food and water intake after combined treatment with clozapine N-oxide (CNO) plus cocaine, morphine, or saline (Fig.…”

“…We directly tracked NAc D1 and D2 neuronal activity at single-cell resolution using GRIN lens-based two-photon calcium imaging in headbar-fixed, treadmill-running mice (Fig. S4a, b), as we have recently described ( 14 ). We designed a series of experiments in which we first recorded individual neuronal responses during feeding and drinking after food or water deprivation, then before and after administration of drugs of abuse for 5 consecutive days, and followed by imaging the same sets of neuronal responses to food and water during drug withdrawal (Summarized in Fig.…”

“…The distinct augmentation of neural responses induced by chronic exposure to cocaine vs. morphine identifies drug-specific pathological changes in D1 and D2 neuronal subtypes within the NAc. Furthermore, this shift in ensemble dynamics, potentially reflective of real-time plasticity, was not observed throughout serial testing with natural rewards ( 14 ). Thus, drugs of abuse increasingly modulate ensemble structure and dynamics of D1 and D2 neurons, which is not observed in the case of natural rewards, and indicates a progressive alteration of the activity of the associated basal motivation circuits.…”