Central amygdala HDAC6 contributes to visceral hypersensitivity and affective comorbidities in IBS-like rats

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder characterized by visceral hypersensitivity and prominent affective symptoms, yet molecular regulators that coordinate these dimensions remain poorly defined. Histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase implicated in neuronal plasticity and inflammatory signaling, has been linked to pain-related conditions, but its relevance to IBS is unclear. Here, we used optogenetics to selectively stimulate projection terminals from the parabrachial nucleus (PBN) or basolateral amygdala (BLA) within the central amygdala (CeA). Activation of PBN-CeA terminals exacerbated visceral hypersensitivity and anxiety-like behaviors, whereas activation of BLA-CeA terminals alleviated these phenotypes. Notably, pro-nociceptive PBN-CeA stimulation increased HDAC6 expression, while the anti-nociceptive BLA-CeA stimulation decreased it. To probe downstream pathways, we combined bioinformatic analyses with intracranial pharmacological intervention and found that intra-CeA infusion of the highly selective HDAC6 Inhibitor ACY-738 alleviated visceral pain and negative affect-like behaviors in IBS-like rats. These behavioral improvements were accompanied by reduced synaptic and neuroimmune alterations in the CeA and decreased phosphorylation of p38 MAPK and ERK1/2. Importantly, ACY-738 also attenuated the exacerbation of pain and negative affect induced by pro-nociceptive PBN-CeA stimulation. Together, these findings suggest that CeA HDAC6 contributes to circuit state-associated alterations underlying pain-affect comorbidity and may serve as a potential therapeutic target in IBS.