Thalamoreticular circuitry is central to sensory processing, attention, and sleep, and is implicated in numerous brain disorders, but the cellular and synaptic mechanisms remain intractable. Therefore, we developed the first detailed microcircuit model of mouse thalamus and thalamic reticular nucleus that captures morphological and biophysical properties of ~14,000 neurons connected via ~6M synapses, and recreates biological synaptic and gap junction connectivity. Realistic spontaneous and evoked activity during wakefulness and sleep emerge allowing dissection of cellular and synaptic contributions. Computer simulations suggest that reticular inhibition shapes thalamic responses and cortex can drive frequency-selective thalamic enhancement during wakefulness, whereas in sleep, reticular inhibition and cortical UP-states can trigger thalamic bursts and spindles. Gap junctions and short-term synaptic plasticity underlie spindle properties such as waxing and waning, and neuromodulation influences the occurrence of spindles. The model is openly available to support testing hypotheses of thalamoreticular circuitry in normal brain function and in disease.
Understanding the neural mechanisms underlying sleep state transitions is a fundamental goal of neurobiology and important for the development of new treatments for insomnia and other sleep disorders. Yet, brain circuits controlling this process remain poorly understood. Here we identify a population of sleep-active glutamatergic neurons in the ventrolateral medulla (VLM) that project to the preoptic area (POA), a prominent sleep-promoting region, in mice. Microendoscopic calcium imaging demonstrate that these VLM glutamatergic neurons display increased activity during the transitions from wakefulness to Non-Rapid Eye Movement (NREM) sleep. Chemogenetic silencing of POA-projecting VLM neurons suppresses NREM sleep, whereas chemogenetic activation of these neurons promotes NREM sleep. Moreover, we show that optogenetic activation of VLM glutamatergic neurons or their projections in the POA initiates NREM sleep in awake mice. Together, our findings uncover an excitatory brainstem-hypothalamic circuit that controls the wake-sleep transitions.
Voltage-gated sodium channel (NaV) activity underlies electrical signaling, synaptic release, circuit function, and, ultimately, behavior. Molecular tools that enable precise control of NaV subpopulations make possible temporal regulation of neuronal activity and cellular communication. To rapidly modulate NaV currents, we have rendered a potent NaV inhibitor, saxitoxin, transiently inert through chemical protection with a novel nitrobenzyl-derived photocleavable group. Light-induced uncaging of the photocaged toxin, STX-bpc, effects rapid inhibitor release and focal NaV block. We demonstrate the efficacy of this reagent for manipulating action potentials in mammalian neurons and brain slice and for altering locomotor behavior in larval zebrafish. Photo-uncaging of STX-bpc is a non-invasive, effective method for reversible, spatiotemporally precise tuning of NaV currents, application of which requires no genetic manipulation of the biological sample.
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