Basal sleep differences correlate with anxious phenotypes in mice: establishing an animal model for post-anesthetic cognitive impairments
Alp Altunkaya, Kim Michelle Mengel, Alina Elisabeth Kreitmaier, Catharina Hedenig, Matthias Kreuzer, Gerhard Rammes, Gerhard Schneider, Thomas Fenzl
Rechts der Isar Hastanesi Münih Teknik Üniversitesi
Giriş: Postoperative delirium (POD), ranging from mild cognitive impairments to chronic deficits or death, is relevant in up to 80% of patients after surgery under general anesthesia (GA) [1]. The systemic-mechanistic relationship between clinically relevant preoperative anxiety (POA) and POD, though frequently reported, remains largely unknown [2]. Identifying a preoperative-anxious phenotype and associated sleep impairments holds potential to establish predictive parameters for POD. These discoveries may further elucidate the neuronal mechanisms underlying these phenomena.
Gereç ve Yöntem: 42 C57BL/6N male mice (16-weeks-old) were used. Chronic electroencephalogram (EEG) and electromyogram (EMG) recordings assessed basal sleep/wake behavior. Following baseline recordings, a cued fear-conditioning (FC, Fig.2A) was performed (120s acclimation, 30s of auditory stimulus (10kHz, 75dB/octave), 2s with 0.6mA electrical foot-shock, repetition-rate=5), followed by fear retrieval after 24h (RET, Fig.2B) for anxiety phenotype classification. See Fig.1 for experimental timeline.
Bulgular: Statistical separation of high-anxiety (HA) and low-anxiety (LA) phenotypes was shown using "freezing" during RET using k-means clustering (Fig.3A). In retrospective observation prior to FC, all HA mice showed multiple temporal sleep architecture changes (WAKE latency, p=0.0154, AUC=0.26 [0.12;0.41] (Fig.3B), vigilance state proportions, p=0.0049, AUC=0.77 [0.58;0.94] (Fig.3C) and transitions, p=0.034, AUC=0.29 [0.13;0.47] (Fig.3D)), together with a clear increase in intensity in the theta band (5-8Hz, peak power: 4% vs. 3.5%, peak AUC=0.79 [0.61;0.91]), (Fig.4).
Tartışma ve Sonuç: Our results enable the classification of naïve animals into LA and HA mice using prognostic EEG parameters and establish an animal model for POA, based on their intrinsic predisposition to individual anxiety levels. We are currently testing potential cognitive impairments in predictive HA and LA animals after experimental GA exposure in the standardized Water-Cross-Maze test, thereby extending our POA animal model to a POA/POD animal model. This model will allow us to investigate GA-dependent physiological processes and morphological conditions systemically in vivo, that potentially lead to postoperative cognitive impairments.
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