HDAC6 Inhibition Alleviates Anesthesia and Surgery-Induced Less Medial Prefrontal-Dorsal Hippocampus Connectivity and Cognitive Impairment in Aged Rats

To investigate the underlying mechanisms of postoperative cognitive dysfunction and the impairment of medial prefrontal cortex-hippocampus connectivity. Postoperative cognitive dysfunction frequently affects elderly following surgery. The role of inter-brain-region connectivity abnormality after anesthesia and surgery on postoperative cognitive dysfunction development remains unclear. Medial prefrontal cortex-hippocampus connectivity of aged and adult rats was evaluated by injecting neurotracer biotinylated dextranamine (BDA) into bilateral hippocampus 3 days before partial hepatectomy, and biotinylated dextranamine positive cells of medial prefrontal cortex 2 days after hepatectomy were counted. HDAC6 shRNA was injected into medial prefrontal cortex and hippocampus bilaterally before hepatectomy or an HDAC6 activity inhibitor Tubastatin A was administered systemically after hepatectomy. Neuroinflammation and HDAC6 down-target ac-tubulin in medial prefrontal cortex and hippocampus were detected. Learning and memory of rats were evaluated by Barnes Maze task during 2–5 days after surgery and delayed matching-to-place water maze task during 10–23 days after surgery. Compared to the age-matched normal controls, anesthesia and surgery significantly decreased BDA-positive neurons in medial prefrontal cortex of aged rats, but not young adult rats. Local HDAC6 knockdown and systemic HDAC6 inhibition both increased BDA-positive neurons number of medial prefrontal cortex, alleviated learning and memory impairment in the Barnes Maze task and water maze task, decreased HDAC6 expression, inflammatory cytokines, astrocyte and microglial activation, and increased ac-tubulin expression in aged rats which received surgery. Our data indicated that anesthesia and surgery impaired medial prefrontal cortex-hippocampus connectivity and cognition which was associated with HDAC6 overexpression.