A novel multidimensional reinforcement task in mice elucidates sex-specific behavioral strategies

Abstract

A large body of work has focused on understanding stimulus-driven behavior, sex differences in these processes, and the neural circuits underlying them. Many preclinical mouse models present rewarding or aversive stimuli in isolation, ignoring that ethologically, reward seeking requires the consideration of potential aversive outcomes. In addition, the context (or reinforcement schedule under) in which stimuli are encountered can engender different behavioral responses to the same stimulus. Thus, delineating neural control of behavior requires a dissociation between stimulus valence and stimulus-driven behavior. We developed the Multidimensional Cue Outcome Action Task (MCOAT) to dissociate motivated action from cue learning and valence in mice. First, mice acquire positive and negative reinforcement in the presence of discrete discriminative stimuli. Next, discriminative stimuli are presented concurrently allowing for parsing innate behavioral strategies based on reward seeking and avoidance. Lastly, responding in the face of punishment is assessed, thus examining how positive and negative outcomes are relatively valued. First, we identified sex-specific behavioral strategies, showing that females prioritize avoidance of negative outcomes over seeking positive, while males have the opposite strategy. Next, we show that chemogenetically inhibiting D1 medium spiny neurons (MSNs) in the nucleus accumbens-a population that has been linked to reward-driven behavior-reduces positive and increases negative reinforcement learning rates. Thus, D1 MSNs modulate stimulus processing, rather than motivated responses or the reinforcement process itself. Together, the MCOAT has broad utility for understanding complex behaviors as well as the definition of the discrete information encoded within cellular populations.

Dopamine release in the nucleus accumbens core signals perceived saliency

“…To disentangle multiple task parameters (e.g., valence, action initiation, prediction 33 ), we used the recently developed multidimensional cue outcome action task (MCOAT) 34 in combination with the genetically encoded dopamine sensor, dLight1.1, 35 to record in vivo dopamine dynamics in the NAc core (Figures S1A-S1D). We trained mice in a positive reinforcement task, in which an auditory cue predicted that an operant response would result in the delivery of sucrose (positive reinforcement) (Figures 1A and 1B).…”

“…Our previous studies showed the order of the positive and negative reinforcement training did not change the behavioral performance. 34 A second auditory discriminative stimulus (S d,shock ) -either tone or white noise, counterbalanced across animals and trial types -was presented at the beginning of each trial following a variable ITI as described above. In each trial the discriminative stimulus was presented for 30 s after which a series of 20 footshocks (1mA, 0.5 s duration) was delivered with a 15 s inter-stimulus interval.…”

Cues conditioned to withdrawal and negative reinforcement: Neglected but key motivational elements driving opioid addiction

“…Few rodent studies to date have examined sex differences in opioid taking or reinstatement. In a study investigating non–addiction-related reinforcement processes, female mice were biased toward negative reinforcement relative to positive reinforcement, in which females responded more to avoid an aversive shock than to receive a sucrose reward and were more sensitive to punishment than males ( 70 ). Female rodents more rapidly acquired morphine and heroin self-administration ( 22 , 71 , 72 ), self-administered more intravenous heroin ( 22 ) and fentanyl vapor ( 23 ) in long-access self-administration sessions, consumed more oral oxycodone during self-administration ( 73 , 74 ), and had higher motivation for fentanyl ( 75 ) than males.…”

From Circuits to Chromatin: The Emerging Role of Epigenetics in Mental Health

“…As many have reported previously, in rodents, females are more motivated to self-administer both natural reinforcers and cocaine, suggesting that females may be more vulnerable to the reinforcing properties of drugs, especially stimulants (Becker et al, 2017). Further, differences in motivation for natural reinforcers suggest key differences between males and females at baseline that could interact with drug-induced plasticity to alter the trajectory of cocaine-induced changes within the brain (Kutlu et al, 2020). To investigate this sexual dichotomy, E.S.C.…”