Perry Sarah, Sharalla Paul S, Sarubin Dylan R, Li Xuan, Roesch Matthew R, Brockett Adam T
Department of Psychology, University of Maryland, College Park, MD, USA.
Program in Neuroscience and Cognitive Science, College Park, MD, USA.
Neuropsychopharmacology. 2025 Aug 3. doi: 10.1038/s41386-025-02181-5.
The balance between impulsive prepotent behavior and inhibition is a crucial aspect of self-control, and disruptions to this balance are observed in aging and various neuropsychiatric conditions, such as addiction. Both the insula and histone deacetylases (HDACs), a family of epigenetic enzymes, are implicated in these disruptions, with HDAC inhibitors showing therapeutic potential. However, the role of single neuron activity in the insula in relation to cognitive control and how this activity is affected by HDAC modulation in behaving animals remains unclear. In this study, we focus on HDAC5, a class II HDAC that regulates gene transcription and shuttles between the nucleus and cytoplasm in response to neuronal activity. We investigate how overexpression of nuclear-localized HDAC5 in the anterior insula influences cognitive control and associated neural processes in rats performing a STOP-change task. This task contrasts frequent prepotent responding (GO trials) with infrequent response inhibition and behavioral redirection (STOP-change trials). Our results show that HDAC5 overexpression altered neural activity linked to executive control signals in the anterior insula, leading to faster prepotent responses and a reduced capacity for behavioral inhibition (i.e., increased motor impulsivity). Additionally, while insula firing was influenced by trial history (i.e., previous trial rewarded or not), HDAC5 overexpression did not affect this feature. These findings suggest that increased HDAC5 activity impair cognitive control, and targeting HDAC5 in this region may offer a promising therapeutic approach for enhancing executive control and mitigating impulsivity-related cognitive, emotional, and social impairments.
冲动性优势行为与抑制之间的平衡是自我控制的关键方面，在衰老和各种神经精神疾病（如成瘾）中可观察到这种平衡的破坏。脑岛和组蛋白脱乙酰酶（HDACs，一类表观遗传酶）都与这些破坏有关，HDAC抑制剂显示出治疗潜力。然而，脑岛中单个神经元活动在认知控制方面的作用以及在行为动物中这种活动如何受到HDAC调节的影响仍不清楚。在本研究中，我们聚焦于HDAC5，一种II类HDAC，它调节基因转录并响应神经元活动在细胞核和细胞质之间穿梭。我们研究在前脑岛中过表达核定位的HDAC5如何影响执行“停止 - 改变”任务的大鼠的认知控制及相关神经过程。该任务将频繁的优势反应（“执行”试验）与不频繁的反应抑制和行为重定向（“停止 - 改变”试验）进行对比。我们的结果表明，HDAC5过表达改变了与前脑岛执行控制信号相关的神经活动，导致更快的优势反应和行为抑制能力降低（即运动冲动性增加）。此外，虽然脑岛放电受试验历史（即先前试验是否有奖励）影响，但HDAC5过表达并未影响这一特征。这些发现表明，HDAC5活性增加会损害认知控制，针对该区域的HDAC5可能为增强执行控制和减轻与冲动性相关的认知、情感和社会障碍提供一种有前景的治疗方法。
