SummaryTo interpret visual-motion events, the underlying computation must involve internal reference to the motion status of the observer’s head. We show here that layer 6 (L6) principal neurons in mouse primary visual cortex (V1) receive a diffuse, vestibular-mediated synaptic input that signals the angular velocity of horizontal rotation. Behavioral and theoretical experiments indicate that these inputs, distributed over a network of 100 L6 neurons, provide both a reliable estimate and, therefore, physiological separation of head-velocity signals. During head rotation in the presence of visual stimuli, L6 neurons exhibit postsynaptic responses that approximate the arithmetic sum of the vestibular and visual-motion response. Functional input mapping reveals that these internal motion signals arrive into L6 via a direct projection from the retrosplenial cortex. We therefore propose that visual-motion processing in V1 L6 is multisensory and contextually dependent on the motion status of the animal’s head.

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Damage to the lateral hypothalamus (LH) causes profound physical inactivity in mammals. Several molecularly distinct types of LH neurons have been identified, including orexin cells and glutamic acid decarboxylase 65 (GAD65) cells, but their interplay in orchestrating physical activity is not fully understood. Here, using optogenetic circuit analysis and cell type-specific deep-brain recordings in behaving mice, we show that orexin cell activation rapidly recruits GAD65 LH neurons. We demonstrate that internally initiated GAD65 LH cell bursts precede and accompany spontaneous running bouts, that selective chemogenetic silencing of natural GAD65 LH cell activity depresses voluntary locomotion, and that GAD65 LH cell overactivation leads to hyperlocomotion. These results thus identify a molecularly distinct, orexin-activated LH submodule that governs physical activity in mice.T he lateral hypothalamus (LH) is thought to provide an essential drive for diverse vital behaviors, including locomotion. Peri-LH lesions in mammals disrupt context-appropriate physical activity, and are associated with the human disorder encephalitis lethargica, which has been noted to make humans "sit motionless. . .all day" (1-6). The LH is not a homogeneous entity, but contains many molecularly distinct classes of neurons that are thought to have different physiological roles (7). However, the interrelations of distinct LH cell classes in computing and driving context-appropriate physical activity are not fully understood.For example, LH neurons expressing orexins/hypocretins (8, 9) become activated in diverse stressful contexts, including acute auditory stimulation, hypoglycemia, hypercapnia, and physical capture (3, 9-13). Orexin LH cell activity may thus represent an important input variable for computing context-appropriate locomotor outputs (3,14), and orexin peptides have been proposed to increase arousal and locomotion by actions on extrahypothalamic projections to areas such as the locus coeruleus (15, 16). However, hypoactivity phenotypes caused by orexin LH cell deletion are milder than the hypoactivity phenotypes caused by broader LH lesions (1-3, 5, 12, 13, 17-19), whereas melanin-concentrating hormone LH (MCH LH ) cell deletion causes hyperactivity, implying that MCH LH cells suppress locomotion (20). These findings suggest that additional drivers of physical activity may exist in the LH.It was recently found that LH neurons expressing glutamic acid decarboxylase 65 (GAD65) are distinct from orexin and MCH neurons (21). We hypothesized that these cells may be a source of natural LH signals underlying normal levels of physical activity. Here, we investigate this hypothesis by using a combination of cell type-specific manipulation and recording techniques. We find that GAD65 LH cells operate as a stress-and orexin-activated LH module whose physiological activity is essential for normal locomotion, and whose hyperactivity causes hyperlocomotion. ResultsOrexin and Stress Rapidly Recruit GAD65 LH Neurons. To examine whether orex...

Orexins (also called hypocretins) are hypothalamic neuropeptides that carry out essential functions in the central nervous system; however, little is known about their release and range of action in vivo owing to the limited resolution of current detection technologies. Here we developed a genetically encoded orexin sensor (OxLight1) based on the engineering of circularly permutated green fluorescent protein into the human type-2 orexin receptor. In mice OxLight1 detects optogenetically evoked release of endogenous orexins in vivo with high sensitivity. Photometry recordings of OxLight1 in mice show rapid orexin release associated with spontaneous running behavior, acute stress and sleep-to-wake transitions in different brain areas. Moreover, two-photon imaging of OxLight1 reveals orexin release in layer 2/3 of the mouse somatosensory cortex during emergence from anesthesia. Thus, OxLight1 enables sensitive and direct optical detection of orexin neuropeptides with high spatiotemporal resolution in living animals.