LAUSR

The thalamus is the gate of the cerebral cortex, the ultimate target for the neural networks controlling behavioral states and cognitive functions. According to the reticular theory initially proposed by Moruzzi and Magoun, excitatory inputs from large reticular zones of the brainstem via widespread intraand extra-thalamocortical systems finally activate the cerebral cortex to cause generalized cortical activation and wakefulness [1]. This theory proposes a central relay role to the thalamus for cortical activation as supported by early studies using neurodegeneration techniques and by the elegant work of Steriade’s group and other investigators illustrating the electrophysiological mechanisms of the thalamocortical system at the cellular level during wakefulness, rapid eye-movement sleep (REMs) and non-REM sleep (NREMs) [2]. Yet, more selective lesion studies conducted between 1960 and the 2000s by many research teams have questioned the importance of the thalamus because these thalamic lesions do not result in loss of cortical activation and wakefulness [3]. Moreover, the identification of other wake-promoting systems, such as those of the hypothalamic hypocretin (Hcrt) and histamine neurons [4], has diverted attention from the thalamus to other structures and thus ‘‘dilute’’ its importance. Recently, the use of innovative approaches such as optogenetics and chemogenetics combined with transgenic animal models has demonstrated the effects of cell-type-specific and real-time activation and/or inactivation of selective cellular targets along with their pathways. Thus, the time appears opportune to assess whether the previous lesion methods involved large-scale damage of all thalamic cells, leading therefore to biased conclusions on the thalamic control of wakefulness. It is in this context that Ren et al. studied the role of a distinct thalamic structure, the paraventricular thalamus (PVT) in the paramedian region of the thalamus in the wake-control neural network [5]. Indeed, the complex thalamic nuclei involved in sleep-wake control have distinct afferent and efferent connections and participate in various brain functions [6]. Yet, which specific nuclei and circuitry are key in controlling wakefulness remain to be assessed. In this study, the authors first found a markedly greater number of c-fos-immunoreactive neurons in the PVT than in the other paramedian thalamic nuclei after wake-enhancement in the mouse. Using in vivo fiber photometry and multichannel electrophysiological recordings, they further found that the PVT glutamatergic (Glu) neurons were more active during wakefulness than during sleep. Moreover, the firing of these neurons increased in anticipation of cortical activation and behavioral arousal but decreased prior to sleep onset. These neurons, therefore, have the discharge pattern of a brain arousal system. Then, the authors questioned the importance of the PVT in wakefulness. On the one hand, when the PVTGlu neurons were chemogenetically inhibited in the early dark phase, NREMs with a high EEG delta power (2–4 Hz) increased markedly. In addition, lesioning PVTGlu neurons by diphtheria toxin A or ibotenic acid equally caused a decrease in wakefulness and an increase in NREMs accompanied by an enhanced EEG delta power. When PVTGlu neurons were optogenetically activated during & Yi-Ping Hou [email protected]