Department of Psychology (Scarborough), University of Toronto, Toronto, Ontario, M1C 1A4, Canada.
Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, M5S 3G5 Canada.
J Neurosci. 2022 May 4;42(18):3811-3822. doi: 10.1523/JNEUROSCI.2175-21.2022. Epub 2022 Mar 29.
The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been associated with the expression of adaptive and maladaptive behavior elicited by fear-related and drug-associated cues. However, reported effects of mPFC manipulations on cue-elicited natural reward-seeking and inhibition thereof have been varied, with few studies examining cortico-striatal contributions in tasks that require adaptive responding to cues signaling reward and punishment within the same session. The current study aimed to better elucidate the role of mPFC and NAc subdivisions, and their functional connectivity in cue-elicited adaptive responding using a novel discriminative cue responding task. Male Long-Evans rats learned to lever-press on a VR5 schedule for a discriminative cue signaling reward, and to avoid pressing the same lever in the presence of another cue signaling punishment. Postacquisition, prelimbic (PL) and infralimbic (IL) areas of the mPFC, NAc core, shell, PL-core, or IL-shell circuits were pharmacologically or chemogenetically inhibited while animals performed under (1) nonreinforced (extinction) conditions, where the appetitive and aversive cues were presented in alternating trials alone or as a compound stimulus; and (2) reinforced conditions, whereby cued responding was accompanied by associated outcomes. PL and IL inactivation attenuated nonreinforced and reinforced goal-directed cue responding, whereas NAc core and shell inactivation impaired nonreinforced responding for the appetitive, but not aversive cue. Furthermore, PL-core and IL-shell inhibition disinhibited nonreinforced but not reinforced cue responding. Our findings implicate the mPFC as a site of confluence of motivationally significant cues and outcomes, and in the regulation of nonreinforced cue responding via downstream NAc targets. The ability to discriminate and respond appropriately to environmental cues that signal availability of reward or punishment is essential for survival. The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been implicated in adaptive and maladaptive behavior elicited by fear-related and drug-associated cues. However, less is known about the role they play in orchestrating adaptive responses to natural reward and punishment cues within the same behavioral task. Here, using a novel discriminative cue responding task combined with pharmacological or chemogenetic inhibition of mPFC, NAc and mPFC-NAc circuits, we report that mPFC is critically involved in responding to changing cued response-outcomes, both when the responses are reinforced, and nonreinforced. Furthermore, the mPFC coordinates nonreinforced discriminative cue responding by suppressing inappropriate responding via downstream NAc targets.
内侧前额叶皮层（mPFC）和伏隔核（NAc）与恐惧相关和药物相关线索引起的适应性和不良行为的表达有关。然而，mPFC 操作对线索诱发的自然奖赏寻求及其抑制的影响报告各不相同，很少有研究在需要对同一会话中奖励和惩罚信号的线索做出适应性反应的任务中检查皮质纹状体的贡献。本研究旨在使用一种新的辨别线索反应任务，更好地阐明 mPFC 和 NAc 细分以及它们在线索诱发的适应性反应中的功能连接的作用。雄性长耳大鼠学会在 VR5 时间表上按压杠杆以获得信号奖励的辨别线索，并在另一个信号惩罚的线索存在时避免按压同一杠杆。习得后，在动物执行以下任务时，通过药理学或化学遗传抑制 mPFC 的前额叶（PL）和下边缘（IL）区域、NAc 核心、壳、PL-核心或 IL-壳回路：（1）非强化（消退）条件，其中奖赏和厌恶线索单独或作为复合刺激在交替试验中呈现；（2）强化条件，其中线索反应伴随着相关结果。PL 和 IL 失活减弱了非强化和强化的目标导向线索反应，而 NAc 核心和壳失活削弱了对奖赏线索的非强化反应，但对厌恶线索没有影响。此外，PL-核心和 IL-壳抑制抑制了非强化但不强化的线索反应。我们的发现表明，mPFC 是与动机相关的重要线索和结果的融合点，并通过下游 NAc 靶标调节非强化线索反应。区分和适当地对信号奖励或惩罚的环境线索做出反应的能力对于生存至关重要。内侧前额叶皮层（mPFC）和伏隔核（NAc）与恐惧相关和药物相关线索引起的适应性和不良行为有关。然而，关于它们在协调同一行为任务中对自然奖赏和惩罚线索的适应性反应中所起的作用，我们知之甚少。在这里，我们使用一种新的辨别线索反应任务，结合药理学或化学遗传抑制 mPFC、NAc 和 mPFC-NAc 回路，报告 mPFC 对改变的线索反应结果的反应至关重要，无论是在强化还是非强化的情况下。此外，mPFC 通过抑制下游 NAc 靶标来协调非强化的辨别线索反应，从而抑制不适当的反应。
