Prelimbic neuron calcium activity predicts perceived hedonic value across drinking solutions and ethanol dependent states in mice
Authors: Rinker Jennifer A. , Hoffman Michaela , Knapp Jason , Wukitsch Thomas J. , Kutlu M. Gunes , Calipari Erin S. , McMahan Christopher S. , Baker G. Hamilton , Woodward John J. , Mulholland Patrick J. 
Published: April 2023

The medial prefrontal cortex (mPFC) is part of the mesocorticolimbic reward circuitry and integrates information about both salience and valence of stimuli, including drugs and alcohol. While the mPFC has been implicated in regulating aspects of alcohol seeking and consumption, our understanding of how cortical outputs encode motivation to consume is still limited. Here we used fiber photometry to measure calcium activity in putative pyramidal glutamatergic projection neurons in the prelimbic (PrL) mPFC in response to consumption of solutions with varying reinforcing value, i.e., water (nondeprived), ethanol (20% v/v) or sucrose (1% w/v). A similar but distinct pattern of activity emerged across the three solutions during the peri-consummatory phase, such that PrL calcium activity ramped immediately preceding bouts for water, ethanol and sucrose, and scaled with presumed reinforcing value, i.e., water<ethanol<sucrose. Thus, PrL neurons modulate their activity in response to anticipation of drinking bouts, and the population GCaMP6f signal appears to track the hedonic value of different drinking solutions. Further, machine learning of population activity of PrL neurons in anticipation of fluid consumption was sufficient to predict both fluid consumption and distinguish between type of reinforcer consumed. To determine if this signal was indeed encoding valence, we adulterated the ethanol solution with quinine and in non-dependent mice, the calcium signal surrounding drinking bouts was reduced, paralleling the decrease in voluntary quinine-adulterated ethanol drinking. This effect was not present in dependent mice, suggestive of reduced sensitivity to the aversive qualities of quinine or increased sensitivity of reinforcing value of the ethanol solution. Using fiber photometry, we also show that the global population of PrL glutamatergic neurons display sustained GCaMP6f “up-states” that last tens to hundreds of seconds. Drinking bouts frequently occurred during these sustained up-states. Although the PrL→NAcore projection is thought to drive reward-guided behavior, the GCaMP6f signal surrounding ethanol drinking bouts was similar to the signal for water. Overall, our results demonstrate a functional signature in PrL neurons that aligns with the valence of different rewarding solutions compared to home cage water drinking. In summary, these results suggest that PrL neurons encode the hedonic value of rewarding solutions, and population activity in anticipation of ethanol drinking is disrupted by induction of ethanol dependence.

Significance statement

The PrL mPFC has been implicated in mediating aspects of alcohol consumption and seeking, but how and whether the PrL encodes aspects of reward differentially is not clear. Here we show that the PrL shows similar but distinguishable glutamatergic population level calcium activity patterns in response to anticipation of solutions with presumed variance in hedonic value (water, ethanol and sucrose). Contrary to our presumption, PrL→NAcore did not differently encode ethanol drinking compared to water, but ethanol dependence was sufficient to disrupt normal modulation of calcium activity in response to reward devaluation. We present evidence of PrL signatures that track presumed hedonic value, that is disrupted by ethanol dependence.