A gene affecting the specificity of the chemosensory neurons of Drosophila

The sensilla on the proboscis and tarsi of Drosophila contain five neurons, four chemosensory and one mechanosensory. The sugar-sensitive neuron, designated S, carries independent acceptor sites for pyranose, furanose and trehalose. Two others, L1 and L2, respond to salts. The fourth neuron, W, is inhibited by salts and sugars, and is believed to mediate detection of water. We describe here a gene in which mutations alter the neurons in such a way that the S cell is excited by salts. As a result, the mutant flies are strongly attracted by NaCl at concentrations which are repellent to the wild type. To our knowledge, this is the first instance of a mutation which changes the specificity of the chemosensory neurons.     

A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans

How left/right functional asymmetry is layered on top of an anatomically symmetrical nervous system is poorly understood. In the nematode Caenorhabditis elegans, two morphologically bilateral taste receptor neurons, ASE left (ASEL) and ASE right (ASER), display a left/right asymmetrical expression pattern of putative chemoreceptor genes that correlates with a diversification of chemosensory specificities. Here we show that a previously undefined microRNA termed lsy-6 controls this neuronal left/right asymmetry of chemosensory receptor expression. lsy-6 mutants that we retrieved from a genetic screen for defects in neuronal left/right asymmetry display a loss of the ASEL-specific chemoreceptor expression profile with a concomitant gain of the ASER-specific profile. A lsy-6 reporter gene construct is expressed in less than ten neurons including ASEL, but not ASER. lsy-6 exerts its effects on ASEL through repression of cog-1, an Nkx-type homeobox gene, which contains a lsy-6 complementary site in its 3' untranslated region and that has been shown to control ASE-specific chemoreceptor expression profiles. lsy-6 is the first microRNA to our knowledge with a role in neuronal patterning, providing new insights into left/right axis formation.     

Deficient pheromone responses in mice lacking a cluster of vomeronasal receptor genes

The mammalian vomeronasal organ (VNO), a part of the olfactory system, detects pheromones--chemical signals that modulate social and reproductive behaviours. But the molecular receptors in the VNO that detect these chemosensory stimuli remain undefined. Candidate pheromone receptors are encoded by two distinct and complex superfamilies of genes, V1r and V2r (refs 3 and 4), which code for receptors with seven transmembrane domains. These genes are selectively expressed in sensory neurons of the VNO. However, there is at present no functional evidence for a role of these genes in pheromone responses. Here, using chromosome engineering technology, we delete in the germ line of mice an approximately 600-kilobase genomic region that contains a cluster of 16 intact V1r genes. These genes comprise two of the 12 described V1r gene families, and represent approximately 12% of the V1r repertoire. The mutant mice display deficits in a subset of VNO-dependent behaviours: the expression of male sexual behaviour and maternal aggression is substantially altered. Electrophysiologically, the epithelium of the VNO of such mice does not respond detectably to specific pheromonal ligands. The behavioural impairment and chemosensory deficit support a role of V1r receptors as pheromone receptors.     

A TRPV family ion channel required for hearing in Drosophila

The many types of insect ear share a common sensory element, the chordotonal organ, in which sound-induced antennal or tympanal vibrations are transmitted to ciliated sensory neurons and transduced to receptor potentials. However, the molecular identity of the transducing ion channels in chordotonal neurons, or in any auditory system, is still unknown. Drosophila that are mutant for NOMPC, a transient receptor potential (TRP) superfamily ion channel, lack receptor potentials and currents in tactile bristles but retain most of the antennal sound-evoked response, suggesting that a different channel is the primary transducer in chordotonal organs. Here we describe the Drosophila Nanchung (Nan) protein, an ion channel subunit similar to vanilloid-receptor-related (TRPV) channels of the TRP superfamily. Nan mediates hypo-osmotically activated calcium influx and cation currents in cultured cells. It is expressed in vivo exclusively in chordotonal neurons and is localized to their sensory cilia. Antennal sound-evoked potentials are completely absent in mutants lacking Nan, showing that it is an essential component of the chordotonal mechanotransducer.     

Integration of target and body-part information in the premotor cortex when planning action

To plan an action, we must first select an object to act on and the body part (or parts) to use to accomplish our intention. To plan the motor task of reaching, we specify both the target to reach for and the arm to use. In the process of planning and preparing a motor task, information about the motor target and the arm to use must be integrated before a motor program can be formulated to generate the appropriate limb movement. One of the structures in the brain that is probably involved in integrating these two sets of information is the premotor area in the cerebral cortex of primates. The lateral sector of the dorsal premotor cortex is known to receive both visual and somatosensory input, and we show here that neurons in this area gather information about both the target and the body part, while subsequent activity specifies the planned action.     

The role of Drosophila Piezo in mechanical nociception

Transduction of mechanical stimuli by receptor cells is essential for senses such as hearing, touch and pain. Ion channels have a role in neuronal mechanotransduction in invertebrates; however, functional conservation of these ion channels in mammalian mechanotransduction is not observed. For example, no mechanoreceptor potential C (NOMPC), a member of transient receptor potential (TRP) ion channel family, acts as a mechanotransducer in Drosophila melanogaster and Caenorhabditis elegans; however, it has no orthologues in mammals. Degenerin/epithelial sodium channel (DEG/ENaC) family members are mechanotransducers in C. elegans and potentially in D. melanogaster; however, a direct role of its mammalian homologues in sensing mechanical force has not been shown. Recently, Piezo1 (also known as Fam38a) and Piezo2 (also known as Fam38b) were identified as components of mechanically activated channels in mammals. The Piezo family are evolutionarily conserved transmembrane proteins. It is unknown whether they function in mechanical sensing in vivo and, if they do, which mechanosensory modalities they mediate. Here we study the physiological role of the single Piezo member in D. melanogaster (Dmpiezo; also known as CG8486). Dmpiezo expression in human cells induces mechanically activated currents, similar to its mammalian counterparts. Behavioural responses to noxious mechanical stimuli were severely reduced in Dmpiezo knockout larvae, whereas responses to another noxious stimulus or touch were not affected. Knocking down Dmpiezo in sensory neurons that mediate nociception and express the DEG/ENaC ion channel pickpocket (ppk) was sufficient to impair responses to noxious mechanical stimuli. Furthermore, expression of Dmpiezo in these same neurons rescued the phenotype of the constitutive Dmpiezo knockout larvae. Accordingly, electrophysiological recordings from ppk-positive neurons revealed a Dmpiezo-dependent, mechanically activated current. Finally, we found that Dmpiezo and ppk function in parallel pathways in ppk-positive cells, and that mechanical nociception is abolished in the absence of both channels. These data demonstrate the physiological relevance of the Piezo family in mechanotransduction in vivo, supporting a role of Piezo proteins in mechanosensory nociception.     

Functional asymmetry in Caenorhabditis elegans taste neurons and its computational role in chemotaxis

Chemotaxis in Caenorhabditis elegans, like chemotaxis in bacteria, involves a random walk biased by the time derivative of attractant concentration, but how the derivative is computed is unknown. Laser ablations have shown that the strongest deficits in chemotaxis to salts are obtained when the ASE chemosensory neurons (ASEL and ASER) are ablated, indicating that this pair has a dominant role. Although these neurons are left-right homologues anatomically, they exhibit marked asymmetries in gene expression and ion preference. Here, using optical recordings of calcium concentration in ASE neurons in intact animals, we demonstrate an additional asymmetry: ASEL is an ON-cell, stimulated by increases in NaCl concentration, whereas ASER is an OFF-cell, stimulated by decreases in NaCl concentration. Both responses are reliable yet transient, indicating that ASE neurons report changes in concentration rather than absolute levels. Recordings from synaptic and sensory transduction mutants show that the ON-OFF asymmetry is the result of intrinsic differences between ASE neurons. Unilateral activation experiments indicate that the asymmetry extends to the level of behavioural output: ASEL lengthens bouts of forward locomotion (runs) whereas ASER promotes direction changes (turns). Notably, the input and output asymmetries of ASE neurons are precisely those of a simple yet novel neuronal motif for computing the time derivative of chemosensory information, which is the fundamental computation of C. elegans chemotaxis. Evidence for ON and OFF cells in other chemosensory networks suggests that this motif may be common in animals that navigate by taste and smell.     

Activity-dependent homeostatic specification of transmitter expression in embryonic neurons

Neurotransmitters are essential for interneuronal signalling, and the specification of appropriate transmitters in differentiating neurons has been related to intrinsic neuronal identity and to extrinsic signalling proteins. Here we show that altering the distinct patterns of Ca2+ spike activity spontaneously generated by different classes of embryonic spinal neurons in vivo changes the transmitter that neurons express without affecting the expression of markers of cell identity. Regulation seems to be homeostatic: suppression of activity leads to an increased number of neurons expressing excitatory transmitters and a decreased number of neurons expressing inhibitory transmitters; the reverse occurs when activity is enhanced. The imposition of specific spike frequencies in vitro does not affect labels of cell identity but again specifies the expression of transmitters that are inappropriate for the markers they express, during an early critical period. The results identify a new role of patterned activity in development of the central nervous system.     

The homeobox gene lim-6 is required for distinct chemosensory representations in C. elegans

The ability to discriminate between different chemical stimuli is crucial for food detection, spatial orientation and other adaptive behaviours in animals. In the nematode Caenorhabditis elegans, spatial orientation in gradients of soluble chemoattractants (chemotaxis) is controlled mainly by a single pair of chemosensory neurons. These two neurons, ASEL and ASER, are left-right homologues in terms of the disposition of their somata and processes, morphology of specialized sensory endings, synaptic partners and expression profile of many genes. However, recent gene-expression studies have revealed unexpected asymmetries between ASEL and ASER. ASEL expresses the putative receptor guanylyl cyclase genes gcy-6 and gcy-7, whereas ASER expresses gcy-5 (ref. 4). In addition, only ASEL expresses the homeobox gene lim-6, an orthologue of the human LMX1 subfamily of homeobox genes. Here we show, using laser ablation of neurons and whole-cell patch-clamp electrophysiology, that the asymmetries between ASEL and ASER extend to the functional level. ASEL is primarily sensitive to sodium, whereas ASER is primarily sensitive to chloride and potassium. Furthermore, we find that lim-6 is required for this functional asymmetry and for the ability to distinguish sodium from chloride. Thus, a homeobox gene increases the representational capacity of the nervous system by establishing asymmetric functions in a bilaterally symmetrical neuron pair.     

p阶Feigenbaum映射的拟极限集及其Hausdorff维数

通过研究Feigenbaum映射分形极限集的存在条件, 证明了对任何t∈(0,1), 存在一个p阶Feigenbaum映射, 使得其拟极限集的Hausdorff维数是t, 并在广泛意义下推广了已有的相应结果.     

Cholinergic phenotype developed by noradrenergic sympathetic neurons after innervation of a novel cholinergic target in vivo

Mammalian sympathetic neurons in vivo may express either a noradrenergic or cholinergic phenotype. In view of the opposing effect of noradrenaline and acetylcholine on most autonomic target organs, the target-appropriate expression of neurotransmitter is critical. We have examined the maturation of the sympathetic innervation of rat sweat glands to define the developmental mechanisms regulating neurotransmitter choice in vivo. Eccrine sweat glands and their sympathetic innervation develop together postnatally in the rat. Early postnatal innervation expresses only noradrenergic properties, but as the glands and their innervation mature, noradrenergic properties decrease dramatically and cholinergic features appear in the same population of neurons. To investigate the role of the sweat gland in this change we have used a transplantation paradigm which allows sweat glands to be innervated by sympathetic neurons that would normally innervate noradrenergic target organs and remain noradrenergic throughout life. We observe that the sympathetic neurons that innervate the novel cholinergic target alter their neurotransmitter properties and develop a cholinergic phenotype. These results indicate that target organs are able to induce appropriate neurotransmitter traits in the neurons that innervate them.     

GABA regulates synaptic integration of newly generated neurons in the adult brain

Adult neurogenesis, the birth and integration of new neurons from adult neural stem cells, is a striking form of structural plasticity and highlights the regenerative capacity of the adult mammalian brain. Accumulating evidence suggests that neuronal activity regulates adult neurogenesis and that new neurons contribute to specific brain functions. The mechanism that regulates the integration of newly generated neurons into the pre-existing functional circuitry in the adult brain is unknown. Here we show that newborn granule cells in the dentate gyrus of the adult hippocampus are tonically activated by ambient GABA (gamma-aminobutyric acid) before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA, the major inhibitory neurotransmitter in the adult brain, initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic chloride ion content. Conversion of GABA-induced depolarization (excitation) into hyperpolarization (inhibition) in newborn neurons leads to marked defects in their synapse formation and dendritic development in vivo. Our study identifies an essential role for GABA in the synaptic integration of newly generated neurons in the adult brain, and suggests an unexpected mechanism for activity-dependent regulation of adult neurogenesis, in which newborn neurons may sense neuronal network activity through tonic and phasic GABA activation.     

Endothelins are vascular-derived axonal guidance cues for developing sympathetic neurons

During development, sympathetic neurons extend axons along a myriad of distinct trajectories, often consisting of arteries, to innervate one of a large variety of distinct final target tissues. Whether or not subsets of neurons within complex sympathetic ganglia are predetermined to innervate select end-organs is unknown. Here we demonstrate in mouse embryos that the endothelin family member Edn3 (ref. 1), acting through the endothelin receptor EdnrA (refs 2, 3), directs extension of axons of a subset of sympathetic neurons from the superior cervical ganglion to a preferred intermediate target, the external carotid artery, which serves as the gateway to select targets, including the salivary glands. These findings establish a previously unknown mechanism of axonal pathfinding involving vascular-derived endothelins, and have broad implications for endothelins as general mediators of axonal growth and guidance in the developing nervous system. Moreover, they suggest a model in which newborn sympathetic neurons distinguish and choose between distinct vascular trajectories to innervate their appropriate end organs.     

A second class of chemosensory receptors in the olfactory epithelium

The mammalian olfactory system detects chemicals sensed as odours as well as social cues that stimulate innate responses. Odorants are detected in the nasal olfactory epithelium by the odorant receptor family, whose approximately 1,000 members allow the discrimination of a myriad of odorants. Here we report the discovery of a second family of receptors in the mouse olfactory epithelium. Genes encoding these receptors, called 'trace amine-associated receptors' (TAARs), are present in human, mouse and fish. Like odorant receptors, individual mouse TAARs are expressed in unique subsets of neurons dispersed in the epithelium. Notably, at least three mouse TAARs recognize volatile amines found in urine: one detects a compound linked to stress, whereas the other two detect compounds enriched in male versus female urine-one of which is reportedly a pheromone. The evolutionary conservation of the TAAR family suggests a chemosensory function distinct from odorant receptors. Ligands identified for TAARs thus far suggest a function associated with the detection of social cues.     

Induction of visual orientation modules in auditory cortex

Modules of neurons sharing a common property are a basic organizational feature of mammalian sensory cortex. Primary visual cortex (V1) is characterized by orientation modules--groups of cells that share a preferred stimulus orientation--which are organized into a highly ordered orientation map. Here we show that in ferrets in which retinal projections are routed into the auditory pathway, visually responsive neurons in 'rewired' primary auditory cortex are also organized into orientation modules. The orientation tuning of neurons within these modules is comparable to the tuning of cells in V1 but the orientation map is less orderly. Horizontal connections in rewired cortex are more patchy and periodic than connections in normal auditory cortex, but less so than connections in V1. These data show that afferent activity has a profound influence on diverse components of cortical circuitry, including thalamocortical and local intracortical connections, which are involved in the generation of orientation tuning, and long-range horizontal connections, which are important in creating an orientation map.     

Identification of protein pheromones that promote aggressive behaviour

Mice use pheromones, compounds emitted and detected by members of the same species, as cues to regulate social behaviours such as pup suckling, aggression and mating. Neurons that detect pheromones are thought to reside in at least two separate organs within the nasal cavity: the vomeronasal organ (VNO) and the main olfactory epithelium (MOE). Each pheromone ligand is thought to activate a dedicated subset of these sensory neurons. However, the nature of the pheromone cues and the identity of the responding neurons that regulate specific social behaviours are largely unknown. Here we show, by direct activation of sensory neurons and analysis of behaviour, that at least two chemically distinct ligands are sufficient to promote male-male aggression and stimulate VNO neurons. We have purified and analysed one of these classes of ligand and found its specific aggression-promoting activity to be dependent on the presence of the protein component of the major urinary protein (MUP) complex, which is known to comprise specialized lipocalin proteins bound to small organic molecules. Using calcium imaging of dissociated vomeronasal neurons (VNs), we have determined that the MUP protein activates a sensory neuron subfamily characterized by the expression of the G-protein Galpha(o) subunit (also known as Gnao) and Vmn2r putative pheromone receptors (V2Rs). Genomic analysis indicates species-specific co-expansions of MUPs and V2Rs, as would be expected among pheromone-signalling components. Finally, we show that the aggressive behaviour induced by the MUPs occurs exclusively through VNO neuronal circuits. Our results substantiate the idea of MUP proteins as pheromone ligands that mediate male-male aggression through the accessory olfactory neural pathway.