Increased sleep time and intensity quantified as low-frequency brain electrical activity after sleep loss demonstrate that sleep need is homeostatically regulated, yet the underlying molecular mechanisms remain elusive. We here demonstrate that metabotropic glutamate receptors of subtype 5 (mGluR5) contribute to the molecular machinery governing sleep-wake homeostasis. Using positron emission tomography, magnetic resonance spectroscopy, and electroencephalography in humans, we find that increased mGluR5 availability after sleep loss tightly correlates with behavioral and electroencephalographic biomarkers of elevated sleep need. These changes are associated with altered cortical myo-inositol and glycine levels, suggesting sleep loss-induced modifications downstream of mGluR5 signaling. Knock-out mice without functional mGluR5 exhibit severe dysregulation of sleep-wake homeostasis, including lack of recovery sleep and impaired behavioral adjustment to a novel task after sleep deprivation. The data suggest that mGluR5 contribute to the brain's coping mechanisms with sleep deprivation and point to a novel target to improve disturbed wakefulness and sleep.

The parietal mechanisms for online control of hand trajectory were studied by combining single-cell recording and reversible inactivation of superior parietal area 5 (PE/PEc; SPL) of monkeys while these made reaches and saccades to visual targets, when the target position changed unexpectedly. Neural activity was modulated by hand position, speed, and movement direction, and by preand/or postsaccadic signals. After bilateral muscimol injection, an increase in the hand reaction-and movement-time toward both the first and second targets was observed. This caused an increase in the time necessary for the trajectory correction, and therefore an elongation of the hand-path toward the first target location. Furthermore, hand trajectories were different in shape than control ones. An elongation of the eye reaction time to both first and second targets was also observed, which could partially explain the deficit of planning and correction of hand movement. These results identify the superior parietal lobule as a crucial node in the online control of hand and eye movement and highlight the role of the eye impairment in the emergence of the reaching disorder so far regarded as the hallmark of optic ataxia.

Prolonged wakefulness leads to a homeostatic response manifested in increased amplitude and number of electroencephalogram (EEG) slow waves during recovery sleep. Cortical networks show a slow oscillation when the excitatory inputs are reduced (during slow wave sleep, anesthesia), or absent (in vitro preparations). It was recently shown that a homeostatic response to electrical stimulation can be induced in cortical cultures. Here we used cortical cultures grown on microelectrode arrays and stimulated them with a cocktail of waking neuromodulators. We found that recovery from stimulation resulted in a dose-dependent homeostatic response. Specifically, the inter-burst intervals decreased, the burst duration increased, the network showed higher cross-correlation and strong phasic synchronized burst activity. Spectral power below <1.75 Hz significantly increased and the increase was related to steeper slopes of bursts. Computer simulation suggested that a small number of clustered neurons could potently drive the behavior of the network both at baseline and during recovery. Thus, this in vitro model appears valuable for dissecting network mechanisms of sleep homeostasis.

The time course of neural variability was studied in three nodes of the parieto-frontal system: the dorsal premotor cortex (PMd, area 6), primary motor cortex (MI, area 4), and posterior parietal cortex (PPC, area 5) while monkeys made either direct reaches to visual targets or changed reach direction in response to an unexpected change of target location. These areas are crucial nodes in the distributed control of reaching and their lesion impairs trajectory formation and correction under different circumstances. During unperturbed reaches, neural variability declined before the onset of hand movement in both frontal and parietal cortex. When the original motor intention suddenly changed, neural variability displayed a complex and area-specific modulation because the perturbation of the motor state was signaled earlier in PMd than in MI and PPC. The comparison of perturbed versus unperturbed reaches revealed that, in the time between the onset of correction signal and trajectory change, identical hand movements were associated with different, therefore contextdependent, patterns of neural variability induced by the instruction to change hand movement direction. In PMd, neural variability was higher before the initiation of hand reach than before its correction, thus providing a neural underpinning to the phenomenon that it takes less time to correct than to initiate hand movement. Furthermore, neural variability was an excellent predictor of slow and fast reach corrections because it was lower during the latter than the former. We conclude that the analysis of neural variability can be an important tool for the study of complex forms of motor cognition.

Increased sleep time and intensity quantified as low-frequency brain electrical activity after sleep loss demonstrate that sleep need is homeostatically regulated, yet the underlying molecular mechanisms remain elusive. We here demonstrate that metabotropic glutamate receptors of subtype 5 (mGluR5) contribute to the molecular machinery governing sleep-wake homeostasis. Using positron emission tomography, magnetic resonance spectroscopy, and electroencephalography in humans, we find that increased mGluR5 availability after sleep loss tightly correlates with behavioral and electroencephalographic biomarkers of elevated sleep need. These changes are associated with altered cortical myo-inositol and glycine levels, suggesting sleep loss-induced modifications downstream of mGluR5 signaling. Knock-out mice without functional mGluR5 exhibit severe dysregulation of sleep-wake homeostasis, including lack of recovery sleep and impaired behavioral adjustment to a novel task after sleep deprivation. The data suggest that mGluR5 contribute to the brain's coping mechanisms with sleep deprivation and point to a novel target to improve disturbed wakefulness and sleep.