Hypoxic damage to the prefrontal cortex (PFC) has been implicated in the frontal lobe dysfunction found in various neuropsychiatric disorders. The underlying subcortical mechanisms, however, have not been well explored. In this study, we induced a PFC-specific hypoxia-like damage by cobalt-wire implantation to demonstrate that the role of the mediodorsal thalamus (MD) is critical for the development of frontal lobe dysfunction, including frontal lobe-specific seizures and abnormal hyperactivity. Before the onset of these abnormalities, the cross talk between the MD and PFC nuclei at theta frequencies was enhanced. During the theta frequency interactions, burst spikes, known to depend on T-type Ca 2ϩ channels, were increased in MD neurons. In vivo knockout or knockdown of the T-type Ca 2ϩ channel gene (Ca V 3.1) in the MD substantially reduced the theta frequency MD-PFC cross talk, frontal lobe-specific seizures, and locomotor hyperactivity in this model. These results suggest a two-step model of prefrontal dysfunction in which the response to a hypoxic lesion in the PFC results in abnormal thalamocortical feedback driven by thalamic T-type Ca 2ϩ channels, which, in turn, leads to the onset of neurological and behavioral abnormalities. This study provides valuable insights into preventing the development of neuropsychiatric disorders arising from irreversible PFC damage.
Drowsiness is an awake state with increased sleep drive, yet the neural correlates and underlying mechanisms remains unclear. Here, we established a mouse model of drowsiness, where mice are fasted for 1 day and then allowed to overeat high-fat food (to promote sleep) while positioned in an open-field box (to promote vigilance). They fall into a long-lasting drowsy state, as reflected by repeated and open-eyed nodding of the head while in a standing position. Simultaneous recording of electroencephalogram (EEG) and neck electromyogram (EMG) readouts revealed that this drowsy state including nodding state had multiple stages in terms of the relationship between the level of vigilance and head movement: delta oscillations decreased in power prior to the head-nodding period and increased during the non-nodding period. Cav3.1-knockout mice, which have reduced delta oscillations, showed frequent head nodding with reduced duration of nodding episodes compared to wild-type mice. This suggests that the balance of drive is tilted in favor of wakefulness, likely due to their previously proposed decrease in sleep-promoting functions. Our findings indicate that delta oscillations play a dominant role in controlling vigilance dynamics during sleep/wake competition and that our novel mouse model may be useful for studying drowsiness and related neurological disorders.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0377-4) contains supplementary material, which is available to authorized users.
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