A causal role for brain-derived neurotrophic factor in the homeostatic regulation of sleep.
Slow-wave activity (SWA), the EEG power between 0.5 and 4 Hz during non-rapid eye movement (NREM) sleep, is one of the best characterized markers of sleep need, because it increases as a function of preceding waking duration and decreases during sleep, but the underlying mechanisms remain unknown. We hypothesized that SWA is high at sleep onset because it reflects the occurrence, during the previous waking period, of widespread synaptic potentiation in cortical and subcortical areas. Consistent with this hypothesis, we recently showed that the more rats explore, the stronger is the cortical expression of BDNF during wakefulness, and the larger is the increase in SWA during the subsequent sleep period. There is compelling evidence that BDNF plays a causal role in synaptic potentiation, and exogenous application of BDNF in vivo is sufficient to induce long-term increases in synaptic strength. We therefore performed cortical unilateral microinjections of BDNF in awake rats and measured SWA during the subsequent sleep period. SWA during NREM sleep was higher in the injected hemisphere relative to the contralateral one. The effect was reversible within 2 h, and did not occur during wakefulness or rapid eye movement sleep. Asymmetries in NREM SWA did not occur after vehicle injections. Furthermore, microinjections, during wakefulness, of a polyclonal anti-BDNF antibody or K252a, an inhibitor of BDNF TrkB receptors, led to a local SWA decrease during the following sleep period. These effects were also reversible and specific for NREM sleep. These results show a causal link between BDNF expression during wakefulness and subsequent sleep regulation.
Faraguna
Ugo
U
Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin 53719, USA.
Vyazovskiy
Vladyslav V
VV
Nelson
Aaron B
AB
Tononi
Giulio
G
Cirelli
Chiara
C
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D002227:Carbazoles / Q000008:administration & dosage / Q000494:pharmacology; D004569:Electroencephalography; D005625:Frontal Lobe; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D026121:Indole Alkaloids / Q000008:administration & dosage / Q000494:pharmacology; D007267:Injections; D008297:Male; D008845:Microinjections; D051381:Rats; D011921:Rats, Inbred WKY; D020813:Receptor, trkB / Q000037:antagonists & inhibitors; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D000906:Antibodies; D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D026121:Indole Alkaloids; C049985:staurosporine aglycone; D020813:Receptor, trkB