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Suppression of Corticostriatal Circuit Activity Improves Cognitive Flexibility and Prevents Body Weight Loss in Activity-Based Anorexia in Rats
Biological Psychiatry ( IF 9.6 ) Pub Date : 2020-07-02 , DOI: 10.1016/j.biopsych.2020.06.022
Laura K Milton 1 , Paul N Mirabella 1 , Erika Greaves 2 , David C Spanswick 3 , Maarten van den Buuse 4 , Brian J Oldfield 1 , Claire J Foldi 1
Affiliation  

Background

The ability to adapt behavior to changing environmental circumstances, or cognitive flexibility, is impaired in multiple psychiatric conditions, including anorexia nervosa (AN). Exaggerated prefrontal cortical activity likely underpins the inflexible thinking and rigid behaviors exhibited by patients with AN. A better understanding of the neural basis of cognitive flexibility is necessary to enable treatment approaches that may target impaired executive control.

Methods

Utilizing the activity-based anorexia (ABA) model and touchscreen operant learning paradigms, we investigated the neurobiological link between pathological weight loss and cognitive flexibility. We used pathway-specific chemogenetics to selectively modulate activity in neurons of the medial prefrontal cortex (mPFC) projecting to the nucleus accumbens shell (AcbSh) in female Sprague Dawley rats.

Results

DREADD (designer receptor exclusively activated by designer drugs)-based inhibition of the mPFC-AcbSh pathway prevented weight loss in ABA and improved flexibility during early reversal learning by reducing perseverative responding. Modulation of activity within the mPFC-AcbSh pathway had no effect on running, locomotor activity, or feeding under ad libitum conditions, indicating the specific involvement of this circuit in conditions of dysregulated reward.

Conclusions

Parallel attenuation of weight loss in ABA and improvement of cognitive flexibility following suppression of mPFC-AcbSh activity align with the relationship between disrupted prefrontal function and cognitive rigidity in AN patients. The identification of a neurobiological correlate between cognitive flexibility and pathological weight loss provides a unique insight into the executive control of feeding behavior. It also highlights the utility of the ABA model for understanding the biological bases of cognitive deficits in AN and provides context for new treatment strategies.



中文翻译:

抑制皮质纹状体回路活动可提高认知灵活性并防止大鼠活动性厌食症的体重减轻

背景

在多种精神疾病(包括神经性厌食症 (AN))中,使行为适应不断变化的环境环境的能力或认知灵活性受到损害。过度的前额叶皮质活动可能是 AN 患者表现出的僵化思维和僵化行为的基础。更好地了解认知灵活性的神经基础对于启用可能针对受损执行控制的治疗方法是必要的。

方法

利用基于活动的厌食 (ABA) 模型和触摸屏操作学习范式,我们研究了病理性体重减轻与认知灵活性之间的神经生物学联系。我们使用通路特异性化学遗传学选择性地调节投射到雌性 Sprague Dawley 大鼠伏隔核壳 (AcbSh) 的内侧前额叶皮层 (mPFC) 神经元的活动。

结果

DREADD(由设计药物专门激活的设计受体)基于 mPFC-AcbSh 通路的抑制阻止了 ABA 的体重减轻,并通过减少持续反应来提高早期逆转学习期间的灵活性。mPFC-AcbSh 通路内的活动调节对跑步、运动活动或在随意条件下的进食没有影响,表明该电路在奖励失调的条件下的具体参与。

结论

抑制 mPFC-AcbSh 活性后 ABA 体重减轻的平行衰减和认知灵活性的改善与 AN 患者的前额叶功能破坏和认知僵硬之间的关系一致。识别认知灵活性和病理性体重减轻之间的神经生物学相关性提供了对进食行为执行控制的独特见解。它还强调了 ABA 模型在理解 AN 认知缺陷的生物学基础方面的效用,并为新的治疗策略提供了背景。

更新日期:2020-07-02
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