Peters Kate Z, Pedan Zuzana, Agbude Romarua, Woods Emily C, Steele Oliver G, Suto Nobuyoshi, Kinghorn Scott B, Tsaponina Olga, Koya Eisuke
Sussex Neuroscience, School of Psychology, University of Sussex, Falmer, UK.
Brighton and Sussex Medical School, University of Sussex, Falmer, UK.
Neuropsychopharmacology. 2025 Jun 6. doi: 10.1038/s41386-025-02142-y.
Cues associated with food, such as fast-food advertising, can provoke food cravings and may lead to unhealthy overeating. Environmental enrichment (EE) that enhances cognitive and physical stimulation can reduce cue-evoked sucrose seeking in mice and recruitment of sucrose cue-reactive neurons or 'neuronal ensembles' in the prelimbic cortex (PL), which regulates appetitive behaviors. Hence, EE provides us with a behavioral model and neuronal targets to identify 'anti-craving' relevant mechanisms. Here, we investigated in the PL how EE modulated neuronal excitability and activity patterns in cue-reactive neuronal populations. Chemogenetic inhibition of cue-reactive neurons in PL blocked cue-evoked sucrose seeking, thereby confirming the function of these neurons in sucrose cue memory. EE boosted the baseline excitability of 'originally', or before EE exposure, cue-reactive, excitatory pyramidal cells in PL. Furthermore, their sucrose cue-specificity was lost - resulting in their persistent activation and non-cue selective activation or 'excitatory overdrive'. Furthermore, EE reduced recruitment of cue-reactive, inhibitory interneurons reflecting 'inhibitory underdrive'. Taken together, impaired neuronal food cue processing due to simultaneous prefrontal cortical excitatory 'overdrive' and inhibitory 'underdrive' likely underlies EE's anti-craving action, thereby serving as potential neurophysiological targets to develop novel medications that help control food cravings.
与食物相关的线索，如快餐广告，会引发对食物的渴望，并可能导致不健康的暴饮暴食。环境丰富化（EE）可增强认知和身体刺激，能减少小鼠对线索诱发的蔗糖觅求，并减少前边缘皮层（PL）中蔗糖线索反应性神经元或“神经元集群”的募集，而该皮层调节着食欲行为。因此，EE为我们提供了一个行为模型和神经元靶点，以识别“抗渴望”相关机制。在此，我们研究了在PL中EE如何调节线索反应性神经元群体的神经元兴奋性和活动模式。对PL中线索反应性神经元进行化学遗传学抑制可阻断线索诱发的蔗糖觅求，从而证实了这些神经元在蔗糖线索记忆中的功能。EE提高了PL中“原本”（即EE暴露前）线索反应性兴奋性锥体细胞的基线兴奋性。此外，它们的蔗糖线索特异性丧失，导致其持续激活以及非线索选择性激活或“兴奋性过载”。此外，EE减少了线索反应性抑制性中间神经元的募集，这反映出“抑制不足”。综上所述，由于前额叶皮层同时出现兴奋性“过载”和抑制性“不足”而导致的神经元对食物线索处理受损，可能是EE抗渴望作用的基础，从而可作为开发有助于控制食物渴望的新型药物的潜在神经生理学靶点。
