Disrupted prefrontal neuronal oscillations and morphology induced by sleep deprivation in young APP/PS1 transgenic AD mice
Introduction
Sleep disturbance is a common and debilitating symptom of Alzheimer's disease (AD), and recent evidence has highlighted a bidirectional relationship between sleep and AD (Dufort-Gervais et al., 2019; Ju et al., 2014; Tabuchi et al., 2015a; Wang and Holtzman, 2020). As sleep appears to be critical for the maintenance of neurological homeostasis, sleep deprivation (SD) or sleep loss could lead to the development of various neurological disorders such as AD. Millions of young people regularly obtain insufficient sleep (Hublin et al., 2001; Zitting et al., 2018) and given the harmful effects of SD on brain function (McHill et al., 2018; Vecsey et al., 2009), an understanding of the cellular and molecular mechanism that is sensitive to sleep curtailment in early-stage AD is clearly of clinical importance.
Recent studies investigating early diagnosis to prevent AD progression has focused on its prodromal stage known as mild cognitive impairment (MCI) (Galluzzi et al., 2013; Nestor et al., 2004). However, the mechanism underlying the progression from MCI to AD is not well documented. A potential mechanism linked with this disease development incriminates abnormal prefrontal cortex (PFC) activity. The PFC govern many higher-order executive tasks such as learning (Antzoulatos and Miller, 2011), memory (Warden and Miller, 2010), cognitive flexibility (Gruber et al., 2010), and emotional processing (Koush et al., 2019; Parfitt et al., 2017; Woodruff et al., 2018). Aberrant prefrontal activity, such as impaired executive functioning and working memory, is reported in AD patients (Satler and Tomaz, 2011; Stopford et al., 2012). Moreover, studies suggest the PFC mediated higher-order executive tasks are sensitive to sleep curtailment (Chuah et al., 2006; Winters et al., 2011; Wu et al., 2006); however, underlying mechanism remain largely unknown.
A crucial mechanism of the neural signatures underlying higher-order executive tasks is communication between selective brain regions. It is known that theta (4–7.5 Hz) and gamma (30−100 Hz) oscillations in the PFC are strongly associated with higher cognitive function and sensory processes (Goldman-Rakic, 1995; Iaccarino et al., 2016). Theta oscillations are important for the learning ability, formation, and retrieval of spatial memory (Hasselmo, 2005). Gamma oscillations synchronize information transfer between various brain structures by systematically timing the population activity of neuronal ensembles (Kaiser and Lutzenberger, 2003; Klein et al., 2016). Altered brain oscillatory activity is prevalent in AD (van Deursen et al., 2008) and neuronal hyperexcitability, marked by enhanced firing rates, near plaques (Busche et al., 2008; Minkeviciene et al., 2009). Moreover, various reports suggest altered oscillations and connectivity in sleep-deprived brain (Bosch et al., 2013; Cajochen et al., 1999; Gao et al., 2015; Gujar et al., 2010; Olbrich et al., 2014; Samann et al., 2010). Given that sleep is important for synaptic renormalization and ensures homeostatic changes in the brain (Born and Feld, 2012), it is of great importance to investigate the impact of sleep loss on brain oscillations in early-stage AD.
In this study, we attempted to explore the impact of SD on cellular and molecular signatures of PFC in young APP/PS1 transgenic AD mice. We used female 3∼4 months-old APP/PS1 transgenic AD mice - an age at which these AD mice do not show amyloid plaques or cognitive deficits (Oberg et al., 2008). We found that SD caused alteration in the delta, theta and high-gamma oscillations, accompanied by an imbalance between excitatory/inhibitory postsynaptic receptor levels and increased calcium/calmodulin-dependent protein kinase II (CaMKII) levels in the PFC of AD mice. Moreover, we discovered that SD caused dendritic morphological abnormalities and a reduction in cyclic AMP response element binding protein (CREB) signaling in the PFC of AD mice. This study, for the first time, identifies early electrophysiological, molecular, and morphological changes in PFC of young AD mice associated with insufficient sleep.
Section snippets
Animal housing and study groups
Amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice derived from the B6C3-Tg (APPswe, PSEN1dE9) 85Dbo/J strain (JAX 004462), which expresses a chimeric mouse/human APP gene (APPswe) and human mutant PS1 (DeltaE9), were maintained at the animal house facility of the School of Life Sciences, South China Normal University. Female APPswe/PS1ΔE9 and their WT littermate mice were used in this study. The mice were maintained at South China Normal University according to SPF
Altered delta, theta and gamma oscillation in the PFC of sleep-deprived WT and AD mice
An exciting feature of the brain is the generation of oscillations through the synchronized activity of neuronal network (Aron and Yankner, 2016; Bartos et al., 2007). To test the impact of SD on PFC oscillations, we conducted in vivo extracellular recording in the PFC of WT and AD mice. Oscillatory traces for all groups of animals are shown in Fig. 2A-D. The absolute power spectrum density (PSD) was computed in six a priori defined frequency bands: delta (0.5−4 Hz), theta (4–7.5 Hz), alpha
Discussion
A considerable number of young people obtain inadequate sleep every day because of suboptimal work habits, socio-economic stress, around the clock lifestyle, and sleep disorders. It has been reported that individuals with sleep deficiency perform poorly at learning and memory tasks (Mednick et al., 2002) and exhibit emotional disturbances (Kamphuis et al., 2017; Novati et al., 2008). Similarly, recent research on humans confirmed that SD causes a young human brain to display the properties of
Author contributions
Sidra Tabassum conducted western blotting experiments and analysis, statistical analyses, experimental design, and manuscript writing. Afzal Misrani carried out western blotting experiments, extracellular recordings, statistical analyses, figure generation, and manuscript writing. Sumaiya Tabassum contributed to Golgi cox staining and data analysis. Adeel Ahmed contributed to extracellular recordings and analysis. Li Yang provided suggestions on experimental design and manuscript. Cheng Long
Declaration of Competing Interest
The authors declare no conflicts of interest.
Acknowledgments
The present study was supported by grants from the National Natural Science Foundation of China [31871170, 31771219, 31970915], the Guangdong Grant 'Key Technologies for Treatment of Brain Disorders' [2018B030332001], the Guangdong Natural Science Foundation for Major Cultivation Project (2018B030336001) and the Major Industry-university-research Collaborative Innovation Project of Guangzhou [201604046016].
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These authors contributed equally