Serotonin 1B receptor effects on response inhibition are independent of inhibitory learning.

Impulsivity is defined in terms of deficits in instrumental response inhibition, when the inability to withhold an action produces a negative outcome. However, there are many behavioral and cognitive constructs which theoretically could contribute to disordered impulsivity, including Pavlovian responding, which few studies have considered in this context. In the present set of studies, we examine Pavlovian inhibitory learning and excitatory responding in a mouse model for dysregulated impulsivity, specifically, mice lacking the serotonin 1B receptor (5-HT1BR). Consistent with previous results, we show that these mice display increased impulsivity as measured by premature responding in the operant 5-choice serial reaction time test. In a Pavlovian conditioned inhibition paradigm, they also show a decreased ability to withhold responding, but importantly have an intact ability to learn inhibitory associations. In a Pavlovian appetitive conditioning experiment, 5-HT1BR knockout mice show normal responding under a positive contingency schedule, however, they display increased responding to cues presented on an independent schedule from reinforcement in a zero contingency schedule. Interestingly this difference does not occur when the cues are explicitly unpaired in a negative contingency schedule, nor during a 25% reinforcement schedule. Overall, while our results show that the deficits in operant response inhibition in mice lacking 5-HT1BR are likely not due to Pavlovian inhibitory or excitatory learning, it is relevant to consider associative learning in the context of dysregulated impulsive behavior.

Acute, but not longer-term, exposure to environmental enrichment attenuates Pavlovian cue-evoked conditioned approach and Fos expression in the prefrontal cortex in mice.

Exposure to environmental enrichment can modify the impact of motivationally relevant stimuli. For instance, previous studies in rats have found that even a brief, acute (~1 day), but not chronic, exposure to environmentally enriched (EE) housing attenuates instrumental lever pressing for sucrose-associated cues in a conditioned reinforcement setup. Moreover, acute EE reduces corticoaccumbens activity, as measured by decreases in expression of the neuronal activity marker "Fos." Currently, it is not known whether acute EE also reduces sucrose seeking and corticoaccumbens activity elicited by non-contingent or "forced" exposure to sucrose cues, which more closely resembles cue exposure encountered in daily life. We therefore measured the effects of acute/intermittent (1 day or 6 day of EE prior to test day) versus chronic (EE throughout conditioning lasting until test day) EE on the ability of a Pavlovian sucrose cue to elicit sucrose seeking (conditioned approach) and Fos expression in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), and nucleus accumbens (NAc) in mice. One day, but not 6 day or chronic EE , reduced sucrose seeking and Fos in the deep layers of the dorsal mPFC. By contrast, 1 day, 6 day, and chronic EE all reduced Fos in the shallow layers of the OFC. None of the EE manipulations modulated NAc Fos expression. We reveal how EE reduces behavioral reactivity to sucrose cues by reducing activity in select prefrontal cortical brain areas. Our work further demonstrates the robustness of EE in its ability to modulate various forms of reward-seeking across species.