A brainstem-to-mediodorsal thalamic pathway mediates sound-induced arousal from slow-wave sleep.

Auditory-induced arousal is a defense mechanism of animals against potential dangers. Although the thalamus is the neural substrate that relays sensory information to the cortex, its function is reduced during slow-wave sleep (SWS), also known as deep sleep. Despite this, animals are capable of waking up in response to external sensory stimuli, suggesting the existence of neural circuits that are involved in this response. Here, we report that kainate-class-type ionotropic glutamate receptor subunit 4 (GRIK4)-positive mediodorsal (MD) thalamic neurons act as a neural substrate for arousals from SWS. These neurons become active during arousal from SWS and their photoactivation can induce arousal from SWS. Moreover, we show that these neurons are influenced by glutamatergic neurons in the brainstem, the activity of which increases during auditory-induced arousals. These results suggest that this brainstem-MD pathway can mediate wakefulness from SWS.

Thalamic T-type Ca²+ channels mediate frontal lobe dysfunctions caused by a hypoxia-like damage in the prefrontal cortex.

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(2+) channels, were increased in MD neurons. In vivo knockout or knockdown of the T-type Ca(2+) 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(2+) 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.