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The loss of orexin neurons in humans is associated with the sleep disorder narcolepsy, which is characterized by excessive daytime sleepiness and cataplexy. Mice lacking orexin peptides, orexin neurons, or orexin receptors recapitulate human narcolepsy phenotypes, further highlighting a critical role for orexin signaling in the maintenance of wakefulness. Despite the known role of orexin neurons in narcolepsy, the precise neural mechanisms downstream of these neurons remain unknown. We found that targeted restoration of orexin receptor expression in the dorsal raphe (DR) and in the locus coeruleus (LC) of mice lacking orexin receptors inhibited cataplexy-like episodes and pathological fragmentation of wakefulness (i.e., sleepiness), respectively. The suppression of cataplexy-like episodes correlated with the number of serotonergic neurons restored with orexin receptor expression in the DR, while the consolidation of fragmented wakefulness correlated with the number of noradrenergic neurons restored in the LC. Furthermore, pharmacogenetic activation of these neurons using designer receptor exclusively activated by designer drug (DREADD) technology ameliorated narcolepsy in mice lacking orexin neurons. These results suggest that DR serotonergic and LC noradrenergic neurons play differential roles in orexin neuron-dependent regulation of sleep/wakefulness and highlight a pharmacogenetic approach for the amelioration of narcolepsy.

Connections between neurons can be mapped by acquiring and analysing electron microscopic brain images. In recent years, this approach has been applied to chunks of brains to reconstruct local connectivity maps that are highly informative 1 – 6 , but nevertheless inadequate for understanding brain function more globally. Here we present a neuronal wiring diagram of a whole brain containing 5 × 10 7 chemical synapses 7 between 139,255 neurons reconstructed from an adult female Drosophila melanogaster 8 , 9 . The resource also incorporates annotations of cell classes and types, nerves, hemilineages and predictions of neurotransmitter identities 10 – 12 . Data products are available for download, programmatic access and interactive browsing and have been made interoperable with other fly data resources. We derive a projectome—a map of projections between regions—from the connectome and report on tracing of synaptic pathways and the analysis of information flow from inputs (sensory and ascending neurons) to outputs (motor, endocrine and descending neurons) across both hemispheres and between the central brain and the optic lobes. Tracing from a subset of photoreceptors to descending motor pathways illustrates how structure can uncover putative circuit mechanisms underlying sensorimotor behaviours. The technologies and open ecosystem reported here set the stage for future large-scale connectome projects in other species. FlyWire presents a neuronal wiring diagram of the whole fly brain with annotations for cell types, classes, nerves, hemilineages and predicted neurotransmitters, with data products and an open ecosystem to facilitate exploration and browsing.

Activity in the motor cortex predicts movements, seconds before they are initiated. This preparatory activity has been observed across cortical layers, including in descending pyramidal tract neurons in layer 5. A key question is how preparatory activity is maintained without causing movement, and is ultimately converted to a motor command to trigger appropriate movements. Here, using single-cell transcriptional profiling and axonal reconstructions, we identify two types of pyramidal tract neuron. Both types project to several targets in the basal ganglia and brainstem. One type projects to thalamic regions that connect back to motor cortex; populations of these neurons produced early preparatory activity that persisted until the movement was initiated. The second type projects to motor centres in the medulla and mainly produced late preparatory activity and motor commands. These results indicate that two types of motor cortex output neurons have specialized roles in motor control. Transcriptional profiling and axonal reconstructions identify two types of pyramidal tract neuron in the motor cortex: one type projects to thalamic regions and produces early and persistent preparatory activity, and the other type projects to motor centres in the medulla and produces motor commands.

A graphdiyne-based artificial synapse (GAS), exhibiting intrinsic short-term plasticity, has been proposed to mimic biological signal transmission behavior. The impulse response of the GAS has been reduced to several millivolts with competitive femtowatt-level consumption, exceeding the biological level by orders of magnitude. Most importantly, the GAS is capable of parallelly processing signals transmitted from multiple pre-neurons and therefore realizing dynamic logic and spatiotemporal rules. It is also found that the GAS is thermally stable (at 353 K) and environmentally stable (in a relative humidity up to 35%). Our artificial efferent nerve, connecting the GAS with artificial muscles, has been demonstrated to complete the information integration of pre-neurons and the information output of motor neurons, which is advantageous for coalescing multiple sensory feedbacks and reacting to events. Our synaptic element has potential applications in bioinspired peripheral nervous systems of soft electronics, neurorobotics, and biohybrid systems of brain–computer interfaces. Constructing artificial sensorimotor systems for robotic applications calls for development of synaptic connections for complicated information processing. Wei et al. propose a graphdiyne-based artificial synapse capable of parallel processing signals and utilize it in an artificial mechanoreceptor system.

Key Points The mammalian neocortex is an extremely complex, highly organized, six-layered structure that contains hundreds of different neuronal cell types. Within the neocortex, distinct populations of projection neurons are located in different cortical layers and areas, have unique morphological features, express different complements of transcription factors, and ultimately serve different functions. Projection neurons are glutamatergic neurons characterized by a typical pyramidal morphology, and function to transmit information both between different regions of the cortex and to other regions of the brain. During development, they are generated from progenitors of the neocortical germinal zone, which includes the ventricular zone (VZ) and, as neurogenesis proceeds, an additional proliferative zone known as the subventricular zone (SVZ). Different types of progenitors contribute to cortical neurogenesis. These include radial glial progenitors located in the VZ as well as progenitors undergoing division away from the ventricular surface, which have been termed 'intermediate progenitors'. The lineage relationship between different progenitors and the type of projection neuron progeny that they generate are largely not understood. Upon induction of the telencephalon by gradients of extracellular signalling molecules, genes including empty spiracles homologue 2 ( Emx2 ), paired box 6 ( Pax6 ), LIM homeobox 2 ( Lhx2 ) and forkhead box G1 ( Foxg1 ) have crucial roles in specifying the progenitors that give rise to neocortical projection neurons. Together, these genes establish the neocortical progenitor domain by repressing dorsal midline ( Lhx2 and Foxg1 ) and ventral ( Emx2 and Pax6 ) fates. Recently, tremendous advances have been made in the identification of laminar- and subtype-specific markers. In this review we provide a comprehensive list of laminar-specific genes with information regarding their expression domains. For many of the layer-specific genes that have been identified, subtype specificity is starting to be defined, and some have been already described as being expressed in one specific neuronal type within a layer or across layers. It is not clear whether the same markers can be used to identify progenitors of each neuronal subtype, or whether such lineage-committed progenitors even exist. Among the different types of cortical projection neuron, subcerebral projection neurons are an ideal model population for studying subtype-specific fate specification in the neocortex. The most well-studied subtype of subcerebral projection neuron is corticospinal motor neurons (CSMNs). During the last several years the identification of a large number of subcerebral- and CSMN-specific genes has activated and enabled an expanding effort to decipher the programmes controlling CSMN development. Although a comprehensive understanding of the part played by additional subcerebral-specific genes still awaits substantial experimental work in vivo , on the basis of the data available thus far, a possible model for the generation of subcerebral projection neurons can be put forward that requires sequential steps of progressive differentiation. Recent experimental data indicate that cortical progenitors might be more plastic than previously suspected, even late in neurogenesis, if manipulated by the appropriate control molecules. An increasing number of genes have been identified that control the specification and development of projection neuron subtypes in the neocortex. Macklis and colleagues review recent progress in understanding their function and discuss the implications for progenitor plasticity. In recent years, tremendous progress has been made in understanding the mechanisms underlying the specification of projection neurons within the mammalian neocortex. New experimental approaches have made it possible to identify progenitors and study the lineage relationships of different neocortical projection neurons. An expanding set of genes with layer and neuronal subtype specificity have been identified within the neocortex, and their function during projection neuron development is starting to be elucidated. Here, we assess recent data regarding the nature of neocortical progenitors, review the roles of individual genes in projection neuron specification and discuss the implications for progenitor plasticity.

Primary pain and touch sensory neurons not only detect internal and external sensory stimuli, but also receive inputs from other neurons. However, the neuronal derived inputs for primary neurons have not been systematically identified. Using a monosynaptic rabies viruses-based transneuronal tracing method combined with sensory-specific Cre-drivers, we found that sensory neurons receive intraganglion, intraspinal, and supraspinal inputs, the latter of which are mainly derived from the rostroventral medulla (RVM). The viral-traced central neurons were largely inhibitory but also consisted of some glutamatergic neurons in the spinal cord and serotonergic neurons in the RVM. The majority of RVM-derived descending inputs were dual GABAergic and enkephalinergic (opioidergic). These inputs projected through the dorsolateral funiculus and primarily innervated layers I, II, and V of the dorsal horn, where pain-sensory afferents terminate. Silencing or activation of the dual GABA/enkephalinergic RVM neurons in adult animals substantially increased or decreased behavioral sensitivity, respectively, to heat and mechanical stimuli. These results are consistent with the fact that both GABA and enkephalin can exert presynaptic inhibition of the sensory afferents. Taken together, this work provides a systematic view of and a set of tools for examining peri- and extrasynaptic regulations of pain-afferent transmission.

The function of the inner ear critically depends on mechanoelectrically transducing hair cells and their afferent and efferent innervation. The first part of this review presents data on the evolution and development of polarized vertebrate hair cells that generate a sensitive axis for mechanical stimulation, an essential part of the function of hair cells. Beyond the cellular level, a coordinated alignment of polarized hair cells across a sensory epithelium, a phenomenon called planar cell polarity (PCP), is essential for the organ's function. The coordinated alignment of hair cells leads to hair cell orientation patterns that are characteristic of the different sensory epithelia of the vertebrate inner ear. Here, we review the developmental mechanisms that potentially generate molecular and morphological asymmetries necessary for the control of PCP. In the second part, this review concentrates on the evolution, development and function of the enigmatic efferent neurons terminating on hair cells. We present evidence suggestive of efferents being derived from motoneurons and synapsing predominantly onto a unique but ancient cholinergic receptor. A review of functional data shows that the plesiomorphic role of the efferent system likely was to globally shut down and protect the peripheral sensors, be they vestibular, lateral line or auditory hair cells, from desensitization and damage during situations of self-induced sensory overload. The addition of a dedicated auditory papilla in land vertebrates appears to have favored the separation of vestibular and auditory efferents and specializations for more sophisticated and more diverse functions.

Key Points Brainstem vagovagal neurocircuits modulate the functions of the upper gastrointestinal tract Neuronal communications between vagal sensory (nucleus tractus solitarius, NTS) and motor (dorsal motor nucleus of the vagus, DMV) nuclei are highly specialized and probably specific for function and target organ NTS–DMV synaptic contacts are not static but undergo plastic changes to ensure that vagally regulated gastrointestinal functions respond appropriately to ever-changing physiological conditions or derangements Gastrointestinal peptides influence vagovagal circuits via actions on both vagal afferent fibres and brainstem nuclei Neurodegenerative alterations of the vagal neurocircuitry induce marked impairments of gastrointestinal functions Upper gastrointestinal tract function is regulated by vagovagal neurocircuits, comprising brainstem nuclei that integrate visceral sensory information and provide vagal motor output. Here, Travagli and Anselmi describe the organization of these neurocircuits and their plasticity in response to stressors. The influence of gastrointestinal peptides on vagovagal neurons is also discussed. A large body of research has been dedicated to the effects of gastrointestinal peptides on vagal afferent fibres, yet multiple lines of evidence indicate that gastrointestinal peptides also modulate brainstem vagal neurocircuitry, and that this modulation has a fundamental role in the physiology and pathophysiology of the upper gastrointestinal tract. In fact, brainstem vagovagal neurocircuits comprise highly plastic neurons and synapses connecting afferent vagal fibres, second order neurons of the nucleus tractus solitarius (NTS), and efferent fibres originating in the dorsal motor nucleus of the vagus (DMV). Neuronal communication between the NTS and DMV is regulated by the presence of a variety of inputs, both from within the brainstem itself as well as from higher centres, which utilize an array of neurotransmitters and neuromodulators. Because of the circumventricular nature of these brainstem areas, circulating hormones can also modulate the vagal output to the upper gastrointestinal tract. This Review summarizes the organization and function of vagovagal reflex control of the upper gastrointestinal tract, presents data on the plasticity within these neurocircuits after stress, and discusses the gastrointestinal dysfunctions observed in Parkinson disease as examples of physiological adjustment and maladaptation of these reflexes.

There has been accumulating evidence for a regionalized organization of the cerebellum, which was mostly deduced from anatomical mapping of axonal projections of cerebellar afferents. A likewise regionalization of the cerebellar output has been suggested from lesion studies and dye-tracer experiments, but its physiological targets as well as the functional relevance of such an output regionalization are less clear. Ideally, such functional regionalization should be proven noninvasively in vivo. We here provide evidence for such a regionalization of the output from the cerebellar cortex by genetically encoded transneuronal mapping of efferent circuits of zebrafish Purkinje neurons. These identified circuits correspond to distinct regionalized Purkinje cell activity patterns in freely behaving zebrafish larvae during the performance of cerebellar-dependent behaviors. Furthermore, optogenetic interrogation of selected Purkinje cell regions during animal behavior confirms the functional regionalization of Purkinje cell efferents and reveals their contribution to behavior control as well as their function in controlling lateralized behavioral output. Our findings reveal how brain compartments serve to fulfill a multitude of functions by dedicating specialized efferent circuits to distinct behavioral tasks.

Lateral olivocochlear (LOC) efferent neurons modulate auditory nerve fiber (ANF) activity using a large repertoire of neurotransmitters, including dopamine (DA) and acetylcholine (ACh). Little is known about how individual neurotransmitter systems are differentially utilized in response to the ever-changing acoustic environment. Here we present quantitative evidence in rodents that the dopaminergic LOC input to ANFs is dynamically regulated according to the animal’s recent acoustic experience. Sound exposure upregulates tyrosine hydroxylase, an enzyme responsible for dopamine synthesis, in cholinergic LOC intrinsic neurons, suggesting that individual LOC neurons might at times co-release ACh and DA. We further demonstrate that dopamine down-regulates ANF firing rates by reducing both the hair cell release rate and the size of synaptic events. Collectively, our results suggest that LOC intrinsic neurons can undergo on-demand neurotransmitter re-specification to re-calibrate ANF activity, adjust the gain at hair cell/ANF synapses, and possibly to protect these synapses from noise damage. Every day, we hear sounds that might be alarming, distracting, intriguing or calming – or simply just too loud. Our hearing system responds to these acoustic changes by fine-tuning sounds before they enter the brain. For example, if a noise is too loud, the volume can be turned down by dampening the signals nerve fibers in the ear send to the brain. This is thought to reduce the damage loud sounds can cause to the sensory organ inside the ear. A set of nerve cells located at the base of the brain called the lateral olivocochlear (LOC) neurons coordinate this adjustment to different volumes and sounds. When these neurons receive information on external sounds, they signal back to the hearing organs and adjust the activity of auditory nerve fibers that communicate this information to the brain. LOC neurons use a diverse range of molecules to modify the activity of auditory nerve fibers, including the ‘feel-good’ neurotransmitter dopamine. But it is unclear what role dopamine plays in this auditory feedback loop. To find out, Wu et al. studied the hearing system of mice that had been exposed to different levels of sound. This involved imaging LOC neurons stained with a marker for dopamine and measuring the activity of nerve fibers in the inner ear. The experiments showed that LOC neurons in mice that had recently been exposed to sound were covered in an enzyme that is essential for making dopamine. The louder the sound, the more of this enzyme was present, suggesting that the amount of dopamine released depends on the volume of the sound. LOC neurons release another neurotransmitter called acetylcholine, which stimulates activity in auditory nerve fibers. Wu et al. found that dopamine and acetylcholine are released from the same group of LOC neurons. However, dopamine had the opposite effect to acetylcholine and reduced nerve activity. These findings suggest that by controlling the mixture of neurotransmitters released, LOC neurons are able to fine-tune the activity of auditory nerve fibers in response to acoustic changes. This work provides a new insight into how our hearing system is able to perceive and relay changes in the sound environment. A better understanding of this auditory feedback loop could influence the design of implant devices for people with impaired hearing.