Circuit mechanism underlying fragmented sleep and memory deficits in 16p11.2 deletion mouse model of autism
Ashley Choi,
Bowon Kim,
Eleanor Labriola,
Alyssa Wiest,
Yingqi Wang,
Jennifer Smith,
Hyunsoo Shin,
Xi Jin,
Isabella An,
Jiso Hong,
Hanna Antila,
Steven Thomas,
Janardhan P. Bhattarai,
Kevin Beier,
Minghong Ma,
Franz Weber,
Shinjae Chung
Affiliations
Ashley Choi
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Bowon Kim
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Eleanor Labriola
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Alyssa Wiest
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Yingqi Wang
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Jennifer Smith
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Hyunsoo Shin
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Xi Jin
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Isabella An
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Jiso Hong
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Hanna Antila
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Steven Thomas
Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Janardhan P. Bhattarai
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Kevin Beier
Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, Irvine, CA 92617, USA
Minghong Ma
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Franz Weber
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Shinjae Chung
Department of Neuroscience, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
Summary: Sleep disturbances are prevalent in children with autism spectrum disorder (ASD). Strikingly, sleep problems are positively correlated with the severity of ASD symptoms, such as memory impairment. However, the neural mechanisms underlying sleep disturbances and cognitive deficits in ASD are largely unexplored. Here, we show that non-rapid eye movement sleep (NREMs) is fragmented in the 16p11.2 deletion mouse model of ASD. The degree of sleep fragmentation is reflected in an increased number of calcium transients in the activity of locus coeruleus noradrenergic (LC-NE) neurons during NREMs. In contrast, optogenetic inhibition of LC-NE neurons and pharmacological blockade of noradrenergic transmission using clonidine consolidate sleep. Furthermore, inhibiting LC-NE neurons restores memory. Finally, rabies-mediated screening of presynaptic neurons reveals altered connectivity of LC-NE neurons with sleep- and memory-regulatory regions in 16p11.2 deletion mice. Our findings identify a crucial role of the LC-NE system in regulating sleep stability and memory in ASD.
