Abstract
Postoperative delirium is a frequent and debilitating complication, especially amongst high risk procedures such as orthopedic surgery, and its pathogenesis remains unclear. Inattention is often reported in the clinical diagnosis of delirium, however limited attempts have been made to study this cognitive domain in preclinical models. Here we implemented the 5-choice serial reaction time task (5-CSRTT) to evaluate attention in a clinically relevant mouse model following orthopedic surgery. The 5-CSRTT showed a time-dependent impairment in the number of responses made by the mice acutely after orthopedic surgery, with maximum impairment at 24 h and returning to pre-surgical performance by day 5. Similarly, the latency to the response was also delayed during this time period but returned to pre-surgical levels within several days. While correct responses decreased following surgery, the accuracy of the response (e.g., selection of the correct nose-poke) remained relatively unchanged. In a separate cohort we evaluated neuroinflammation and blood-brain barrier (BBB) dysfunction using clarified brain tissue with light-sheet microscopy. CLARITY revealed significant changes in microglial morphology and impaired astrocytic-tight junction interactions using high-resolution 3D reconstructions of the neurovascular unit. Deposition of IgG, fibrinogen, and autophagy markers (TFEB and LAMP1) were also altered in the hippocampus 24 h after surgery. Together, these results provide translational evidence for the role of peripheral surgery contributing to delirium-like behavior and disrupted neuroimmunity in adult mice.
Highlights
Postoperative delirium is a common complication characterized by acute cognitive impairments featuring disorganized thinking, fluctuating levels of consciousness, altered arousal levels, and inattention [1]
Orthopedic surgery is a common intervention across every age group that can frequently contribute to cognitive impairments, emotional disturbances, and pain in a significant proportion of patients [6]
We have developed a mouse model of tibial fracture and repair to study the impact of orthopedic surgery on the central nervous system (CNS) and to interrogate the pathogenesis of perioperative neurocognitive disorders [10]
Summary
Postoperative delirium is a common complication characterized by acute cognitive impairments featuring disorganized thinking, fluctuating levels of consciousness, altered arousal levels, and inattention [1]. Neuroinflammation has emerged as an active driver in the pathogenesis of multiple neurological conditions, including neuropsychiatric, neurodegenerative, and perioperative disorders [13, 14] Following surgical procedures such as orthopedic surgery, pro-inflammatory cytokines have been detected in the cerebrospinal fluid of patients developing postoperative delirium [15, 16]. CLARITY provides a unique approach to preserve cellular integrity through the formation of a tissue-hydrogel mesh that enables deeper optical imaging This technology can elucidate complex 3D structures and cellular architectures of relevance to both tissue physiology and pathology, including the diagnosis of clinical conditions [19,20,21]. We implemented a CLARITY protocol combined with light sheet microscopy to enable visualization and 3D rendering of pathological features associated with postoperative complications focusing on neuroinflammation and endothelial dysfunction
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
