Glutamatergic Neurons in the Preoptic Hypothalamus Promote Wakefulness, Destabilize NREM Sleep, Suppress REM Sleep, and Regulate Cortical Dynamics.

Clinical and experimental data from the last nine decades indicate that the preoptic area of the hypothalamus is a critical node in a brain network that controls sleep onset and homeostasis. By contrast, we recently reported that a group of glutamatergic neurons in the lateral and medial preoptic area increases wakefulness, challenging the long-standing notion in sleep neurobiology that the preoptic area is exclusively somnogenic. However, the precise role of these subcortical neurons in the control of behavioral state transitions and cortical dynamics remains unknown. Therefore, in this study, we used conditional expression of excitatory hM3Dq receptors in these preoptic glutamatergic (Vglut2+) neurons and show that their activation initiates wakefulness, decreases non-rapid eye movement (NREM) sleep, and causes a persistent suppression of rapid eye movement (REM) sleep. We also demonstrate, for the first time, that activation of these preoptic glutamatergic neurons causes a high degree of NREM sleep fragmentation, promotes state instability with frequent arousals from sleep, decreases body temperature, and shifts cortical dynamics (including oscillations, connectivity, and complexity) to a more wake-like state. We conclude that a subset of preoptic glutamatergic neurons can initiate, but not maintain, arousals from sleep, and their inactivation may be required for NREM stability and REM sleep generation. Further, these data provide novel empirical evidence supporting the hypothesis that the preoptic area causally contributes to the regulation of both sleep and wakefulness.SIGNIFICANCE STATEMENT Historically, the preoptic area of the hypothalamus has been considered a key site for sleep generation. However, emerging modeling and empirical data suggest that this region might play a dual role in sleep-wake control. We demonstrate that chemogenetic stimulation of preoptic glutamatergic neurons produces brief arousals that fragment sleep, persistently suppresses REM sleep, causes hypothermia, and shifts EEG patterns toward a "lighter" NREM sleep state. We propose that preoptic glutamatergic neurons can initiate, but not maintain, arousal from sleep and gate REM sleep generation, possibly to block REM-like intrusions during NREM-to-wake transitions. In contrast to the long-standing notion in sleep neurobiology that the preoptic area is exclusively somnogenic, we provide further evidence that preoptic neurons also generate wakefulness.

Causal role for sleep-dependent reactivation of learning-activated sensory ensembles for fear memory consolidation.

Learning-activated engram neurons play a critical role in memory recall. An untested hypothesis is that these same neurons play an instructive role in offline memory consolidation. Here we show that a visually-cued fear memory is consolidated during post-conditioning sleep in mice. We then use TRAP (targeted recombination in active populations) to genetically label or optogenetically manipulate primary visual cortex (V1) neurons responsive to the visual cue. Following fear conditioning, mice respond to activation of this visual engram population in a manner similar to visual presentation of fear cues. Cue-responsive neurons are selectively reactivated in V1 during post-conditioning sleep. Mimicking visual engram reactivation optogenetically leads to increased representation of the visual cue in V1. Optogenetic inhibition of the engram population during post-conditioning sleep disrupts consolidation of fear memory. We conclude that selective sleep-associated reactivation of learning-activated sensory populations serves as a necessary instructive mechanism for memory consolidation.

Visual search inverts the classic Stroop asymmetry.

The Stroop effect is typically much larger than the reverse Stroop effect. One explanation for this asymmetry asserts that interference between the attended feature and an incongruent unattended feature depends on which feature is more strongly associated with the processing typically needed to complete the task. Accordingly, because identification of the target's color or the target word (as in the traditional Stroop paradigm) is more strongly associated with verbal processing than visual processing, the target's meaning should interfere with identification of the target's color (Stroop) more than vice versa (reverse Stroop). In contrast, localization is more strongly associated with visual processing, so strength-of-association predicts that the target's color should interfere with localizing the target word (reverse Stroop) more than vice versa (Stroop). Experiments 1 and 2 supported the strength-of-association account: compared to Stroop, the reverse Stroop effect was smaller for an identification task, but larger for a localization task. Because overall responses were slower for the reverse Stroop condition than the Stroop condition in Experiment 2, we entertained two alternative explanations for the reverse Stroop effect being larger than the Stroop effect. Experiments 3 and 4 showed that the larger reverse Stroop effect could not have been due to scaling, and Experiment 5 showed that it could not have been due to covert translation. Taken together, these experiments demonstrate the role of strength of association in generating the classic Stroop asymmetry, and pave the way for future exploration of the reverse Stroop effect using localization tasks.