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Activation of GABAergic neurons in the ventral medulla can reliably induce REM sleep and prolong the duration of REM episodes in mice. Control of REM sleep Previous attempts to understand the contribution of specific brain regions to the promotion and maintenance of rapid eye movement (REM) sleep, the type of sleep during which most instances of dreaming occur, have mainly relied on transection or lesion-based studies. Here, Yang Dan and colleagues use optogenetics to demonstrate that activation of GABAergic neurons in the ventral medulla can reliably induce REM sleep and prolong the duration of REM episodes in mice. The ability to control REM sleep at a high temporal precision, as demonstrated in this study, should provide a useful tool for the study of its functions. Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with vivid dreams 1 , 2 , 3 . Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation 2 , and the neural circuits in the pons have since been studied extensively 4 , 5 , 6 , 7 , 8 . The medulla also contains neurons that are active during REM sleep 9 , 10 , 11 , 12 , 13 , but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic (γ-aminobutyric-acid-releasing) pathway originating from the ventral medulla powerfully promotes REM sleep in mice. Optogenetic activation of ventral medulla GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. Optrode recordings from channelrhodopsin-2-tagged ventral medulla GABAergic neurons showed that they were most active during REM sleep (REM max ), and during wakefulness they were preferentially active during eating and grooming. Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate ventral medulla neuron populations. Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, which are probably mediated in part by inhibition of REM-suppressing GABAergic neurons in the ventrolateral periaqueductal grey. These results identify a key component of the pontomedullary network controlling REM sleep. The capability to induce REM sleep on command may offer a powerful tool for investigating its functions.

Survival in threatening situations depends on the selection and rapid execution of an appropriate active or passive defensive response, yet the underlying brain circuitry is not understood. Here we use circuit-based optogenetic, in vivo and in vitro electrophysiological, and neuroanatomical tracing methods to define midbrain periaqueductal grey circuits for specific defensive behaviours. We identify an inhibitory pathway from the central nucleus of the amygdala to the ventrolateral periaqueductal grey that produces freezing by disinhibition of ventrolateral periaqueductal grey excitatory outputs to pre-motor targets in the magnocellular nucleus of the medulla. In addition, we provide evidence for anatomical and functional interaction of this freezing pathway with long-range and local circuits mediating flight. Our data define the neuronal circuitry underlying the execution of freezing, an evolutionarily conserved defensive behaviour, which is expressed by many species including fish, rodents and primates. In humans, dysregulation of this ‘survival circuit’ has been implicated in anxiety-related disorders. A combination of optogenetic, electrophysiological and neuroanatomical tracing methods defines midbrain periaqueductal grey circuits for specific defensive behaviours. Brain circuits choosing the response to threat A mouse perceiving a threat has a choice between two principal means of defence: active flight or a passive 'freeze'. Andreas Lüthi and colleagues have used a combination of optogenetic, electrophysiological and neuroanatomical tracing to identify the neural circuits underlying the control of these different strategies. They identify a pathway from the amygdala to the periaqueductal grey that not only mediates freezing, but also interacts with circuits mediating flight. Freezing is an evolutionarily conserved behaviour in many species, including fish, rodents and primates. In humans, dysregulation of this 'survival circuit' has been implicated in anxiety-related disorders.

Various environmental stressors, such as extreme temperatures (hot and cold), pathogens, predators and insufficient food, can threaten life. Remarkable progress has recently been made in understanding the central circuit mechanisms of physiological responses to such stressors. A hypothalamomedullary neural pathway from the dorsomedial hypothalamus (DMH) to the rostral medullary raphe region (rMR) regulates sympathetic outflows to effector organs for homeostasis. Thermal and infection stress inputs to the preoptic area dynamically alter the DMH → rMR transmission to elicit thermoregulatory, febrile and cardiovascular responses. Psychological stress signalling from a ventromedial prefrontal cortical area to the DMH drives sympathetic and behavioural responses for stress coping, representing a psychosomatic connection from the corticolimbic emotion circuit to the autonomic and somatic motor systems. Under starvation stress, medullary reticular neurons activated by hunger signalling from the hypothalamus suppress thermogenic drive from the rMR for energy saving and prime mastication to promote food intake. This Perspective presents a combined neural network for environmental stress responses, providing insights into the central circuit mechanism for the integrative regulation of systemic organs.Environmental stressors, including extreme ambient temperature, the presence of pathogens or predators, and a lack of food, can profoundly influence animal behaviour. In this Perspective, Nakamura, Nakamura and Kataoka present a hypothalamomedullary network model for physiological responses to various environmental stressors.

The brainstem is a key centre in the control of body movements. Although the precise nature of brainstem cell types and circuits that are central to full-body locomotion are becoming known 1 – 5 , efforts to understand the neuronal underpinnings of skilled forelimb movements have focused predominantly on supra-brainstem centres and the spinal cord 6 – 12 . Here we define the logic of a functional map for skilled forelimb movements within the lateral rostral medulla (latRM) of the brainstem. Using in vivo electrophysiology in freely moving mice, we reveal a neuronal code with tuning of latRM populations to distinct forelimb actions. These include reaching and food handling, both of which are impaired by perturbation of excitatory latRM neurons. Through the combinatorial use of genetics and viral tracing, we demonstrate that excitatory latRM neurons segregate into distinct populations by axonal target, and act through the differential recruitment of intra-brainstem and spinal circuits. Investigating the behavioural potential of projection-stratified latRM populations, we find that the optogenetic stimulation of these populations can elicit diverse forelimb movements, with each behaviour stably expressed by individual mice. In summary, projection-stratified brainstem populations encode action phases and together serve as putative building blocks for regulating key features of complex forelimb movements, identifying substrates of the brainstem for skilled forelimb behaviours. This study reveals a functional map for skilled forelimb movements within the lateral rostral medulla of the brainstem on the basis of the identification of specific neuronal populations by axonal targets.

In the brain, compact clusters of neuron cell bodies, termed nuclei, are essential for maintaining parameters of host physiology within a narrow range optimal for health. Neurons residing in the brainstem dorsal motor nucleus (DMN) project in the vagus nerve to communicate with the lungs, liver, gastrointestinal tract, and other organs. Vagus nerve-mediated reflexes also control immune system responses to infection and injury by inhibiting the production of tumor necrosis factor (TNF) and other cytokines in the spleen, although the function of DMN neurons in regulating TNF release is not known. Here, optogenetics and functional mapping reveal cholinergic neurons in the DMN, which project to the celiacsuperior mesenteric ganglia, significantly increase splenic nerve activity and inhibit TNF production. Efferent vagus nerve fibers terminating in the celiac-superior mesenteric ganglia form varicose-like structures surrounding individual nerve cell bodies innervating the spleen. Selective optogenetic activation of DMN cholinergic neurons or electrical activation of the cervical vagus nerve evokes action potentials in the splenic nerve. Pharmacological blockade and surgical transection of the vagus nerve inhibit vagus nerve-evoked splenic nerve responses. These results indicate that cholinergic neurons residing in the brainstem DMN control TNF production, revealing a role for brainstem coordination of immunity.

Whisking and sniffing are predominant aspects of exploratory behaviour in rodents. Yet the neural mechanisms that generate and coordinate these and other orofacial motor patterns remain largely uncharacterized. Here we use anatomical, behavioural, electrophysiological and pharmacological tools to show that whisking and sniffing are coordinated by respiratory centres in the ventral medulla. We delineate a distinct region in the ventral medulla that provides rhythmic input to the facial motor neurons that drive protraction of the vibrissae. Neuronal output from this region is reset at each inspiration by direct input from the pre-Bötzinger complex, such that high-frequency sniffing has a one-to-one relationship with whisking, whereas basal respiration is accompanied by intervening whisks that occur between breaths. We conjecture that the respiratory nuclei, which project to other premotor regions for oral and facial control, function as a master clock for behaviours that coordinate with breathing. Motor patterns underlying the rodent exploratory behaviours whisking and sniffing are coordinated by respiratory centres in the ventral medulla; a distinct region in the ventral medulla provides rhythmic input to the facial motor neurons that drive scanning by the vibrissae, and input from the pre-Bötzinger complex coordinates whisking with sniffing and basal breathing. A master clock for oral and facial control Rodents explore their environment by rhythmically sniffing and sweeping their whiskers. The coordination of these behaviours is central to their effectiveness, and this study highlights the neural systems involved. David Kleinfeld and colleagues identify a region in the ventral medulla that drives rhythmic whisking, and find that neurons in this area are controlled by input from nuclei that mediate breathing patterns. Breathing pattern generators may serve as a master clock not just for whisking, but for other breath-coordinated behaviours as well.

The sympathetic and parasympathetic nervous systems regulate the activities of internal organs 1 , but the molecular and functional diversity of their constituent neurons and circuits remains largely unknown. Here we use retrograde neuronal tracing, single-cell RNA sequencing, optogenetics and physiological experiments to dissect the cardiac parasympathetic control circuit in mice. We show that cardiac-innervating neurons in the brainstem nucleus ambiguus (Amb) are comprised of two molecularly, anatomically and functionally distinct subtypes. The first, which we call ambiguus cardiovascular (ACV) neurons (approximately 35 neurons per Amb), define the classical cardiac parasympathetic circuit. They selectively innervate a subset of cardiac parasympathetic ganglion neurons and mediate the baroreceptor reflex, slowing heart rate and atrioventricular node conduction in response to increased blood pressure. The other, ambiguus cardiopulmonary (ACP) neurons (approximately 15 neurons per Amb) innervate cardiac ganglion neurons intermingled with and functionally indistinguishable from those innervated by ACV neurons. ACP neurons also innervate most or all lung parasympathetic ganglion neurons—clonal labelling shows that individual ACP neurons innervate both organs. ACP neurons mediate the dive reflex, the simultaneous bradycardia and bronchoconstriction that follows water immersion. Thus, parasympathetic control of the heart is organized into two parallel circuits, one that selectively controls cardiac function (ACV circuit) and another that coordinates cardiac and pulmonary function (ACP circuit). This new understanding of cardiac control has implications for treating cardiac and pulmonary diseases and for elucidating the control and coordination circuits of other organs. In mouse, two distinct types of neurons from the brainstem nucleus ambiguus, one that innervates the heart and another that innervates both the heart and lung, collectively control cardiac function and coordinate cardiac and pulmonary function.

Using a combination of targeted activation and optogenetic-based mapping in mice, this study demonstrates that sleep-active GABAergic neurons in the medullary parafacial zone promote slow wave sleep and cortical slow wave activity and uncovers functional circuit connections linking these neurons with the cortex. Work in animals and humans has suggested the existence of a slow wave sleep (SWS)-promoting/electroencephalogram (EEG)-synchronizing center in the mammalian lower brainstem. Although sleep-active GABAergic neurons in the medullary parafacial zone (PZ) are needed for normal SWS, it remains unclear whether these neurons can initiate and maintain SWS or EEG slow-wave activity (SWA) in behaving mice. We used genetically targeted activation and optogenetically based mapping to examine the downstream circuitry engaged by SWS-promoting PZ neurons, and we found that this circuit uniquely and potently initiated SWS and EEG SWA, regardless of the time of day. PZ neurons monosynaptically innervated and released synaptic GABA onto parabrachial neurons, which in turn projected to and released synaptic glutamate onto cortically projecting neurons of the magnocellular basal forebrain; thus, there is a circuit substrate through which GABAergic PZ neurons can potently trigger SWS and modulate the cortical EEG.

The preBötzinger Complex (preBötC), a medullary network critical for breathing, relies on excitatory interneurons to generate the inspiratory rhythm. Yet, half of preBötC neurons are inhibitory, and the role of inhibition in rhythmogenesis remains controversial. Using optogenetics and electrophysiology in vitro and in vivo, we demonstrate that the intrinsic excitability of excitatory neurons is reduced following large depolarizing inspiratory bursts. This refractory period limits the preBötC to very slow breathing frequencies. Inhibition integrated within the network is required to prevent overexcitation of preBötC neurons, thereby regulating the refractory period and allowing rapid breathing. In vivo, sensory feedback inhibition also regulates the refractory period, and in slowly breathing mice with sensory feedback removed, activity of inhibitory, but not excitatory, neurons restores breathing to physiological frequencies. We conclude that excitation and inhibition are interdependent for the breathing rhythm, because inhibition permits physiological preBötC bursting by controlling refractory properties of excitatory neurons. Excitatory neurons in the preBötzinger Complex generate bursting activity responsible for breathing, but these alone cannot generate physiological breathing frequencies. Here the authors show how inhibition regulates refractory properties of excitatory neurons to allow dynamic breathing rhythms.

Acute painful stimuli applied to one body site reduce pain at other sites. The circuit basis of this “pain-inhibits-pain” phenomenon, also known as diffuse noxious inhibitory control (DNIC) in animals or conditioned pain modulation (CPM) in humans, is largely unknown. Using anatomical and optogenetic circuit tracing, we identified a population of descending inhibitory neurons of the rostral ventromedial medulla (RVM) that densely and bilaterally innervate the spinal cord along its rostrocaudal axis. Activating these neurons reduced heat and cold sensitivity widely in healthy mice and caused similarly wide-spread antihyperalgesia in chronic pain models, while their silencing evoked mechanical allodynia and spontaneous pain-like behaviors. Noxious stimuli activated subsets of these neurons in the lateral paragigantocellularis nucleus (LPGi), which inhibited nociception upon chemogenetic reactivation. Spinally projecting inhibitory RVM neurons are hence ideally positioned to function as circuit elements of DNIC and CPM, while their dysfunction may contribute to wide-spread chronic pain syndromes. In this study, the authors identify inhibitory brainstem neurons that innervate the entire spinal cord as parts of a descending pain-inhibits-pain circuit. Their activation causes body-wide analgesia, while silencing induces pain in response to innocuous stimuli.