Molecular Biology and Genetics of Sleep

Chiara Cirelli, M.D., Ph.D. Department of Psychiatry

University of Wisconsin/Madison

Molecular biology studies (transcriptomics) Genetic studies

Molecular biology Studies (transcriptomics)

Genetic studies

Molecular changes: microarray analysis

sleep sleep

Molecular changes: microarray analysis

sleep sleep

10-15,000 mRNAs analyzed

state-dependent expression in 1-5% of all

present probes

wake and sleep genes belong to different

functional categories

Functional categories of sleep and wake genes

Cirelli, Nature Review Neuroscience 2009

Molecular state-dependent changes

energy metabolism

cellular stress response

synaptic potentiation

Waking

Sleep

Genes involved in synaptic potentiation are upregulated during wake

Cirelli et al. Science 1996, J Neurosci 2000, Neuron 2004

6h of sleep 6h of waking

P-CREB

rat cerebral cx

Cirelli et al, J Neurosci 2000, Neuron 2004; Hanlon E, unpublished

Genes involved in synaptic potentiation are upregulated during wake

Other plasticity-related genes upregulated in wake: NGFI-A, Homer, Narp, CamKII, Arc

6h of sleep 6h of waking

BDNF

rat cerebral cx

GluR1-AMPA receptors are the best established molecular markers of synaptic strength

Decrease in synaptic strength in vivo / LTD in vitro

Monocular deprivation and visual cx (Heynen et al., Nature Neurosci 2003)

Increase in synaptic strength in vivo / LTP in vitro

Fear conditioning and amygdala (Rumpel et al. Science 2005) Avoidance learning and hippocampus (Whitlock et al. Science 2006) Emotional memory and hippocampus (Hu et al. Cell 2007)

P-S845 P-S845 P-S831 GluR1

Increased expression of synaptic GluR1 during wake

Vyazovskiy et al., Nature Neurosci 2008

Synapto- neurosomes

SD S W

Molecular state-dependent changes

energy metabolism

cellular stress response

synaptic potentiation

Waking

Sleep