Loss of sex discrimination and male-male aggression in mice deficient for TRP2

The mouse vomeronasal organ (VNO) is thought to mediate social behaviors and neuroendocrine changes elicited by pheromonal cues. The molecular mechanisms underlying the sensory response to pheromones and the behavioral repertoire induced through the VNO are not fully characterized. Using the tools of mouse genetics and multielectrode recording, we demonstrate that the sensory activation of VNO neurons requires TRP2, a putative ion channel of the transient receptor potential family that is expressed exclusively in these neurons. Moreover, we show that male mice deficient in TRP2 expression fail to display male-male aggression, and they initiate sexual and courtship behaviors toward both males and females. Our study suggests that, in the mouse, sensory activation of the VNO is essential for sex discrimination of conspecifics and thus ensures gender-specific behavior.     

MHC class I peptides as chemosensory signals in the vomeronasal organ

The mammalian vomeronasal organ detects social information about gender, status, and individuality. The molecular cues carrying this information remain largely unknown. Here, we show that small peptides that serve as ligands for major histocompatibility complex (MHC) class I molecules function also as sensory stimuli for a subset of vomeronasal sensory neurons located in the basal Gao- and V2R receptor-expressing zone of the vomeronasal epithelium. In behaving mice, the same peptides function as individuality signals underlying mate recognition in the context of pregnancy block. MHC peptides constitute a previously unknown family of chemosensory stimuli by which MHC genotypic diversity can influence social behavior.     

Encoding gender and individual information in the mouse vomeronasal organ

The mammalian vomeronasal organ detects complex chemical signals that convey information about gender, strain, and the social and reproductive status of an individual. How these signals are encoded is poorly understood. We developed transgenic mice expressing the calcium indicator G-CaMP2 and analyzed population responses of vomeronasal neurons to urine from individual animals. A substantial portion of cells was activated by either male or female urine, but only a small population of cells responded exclusively to gender-specific cues shared across strains and individuals. Female cues activated more cells and were subject to more complex hormonal regulations than male cues. In contrast to gender, strain and individual information was encoded by the combinatorial activation of neurons such that urine from different individuals activated distinctive cell populations.     

Encoding pheromonal signals in the accessory olfactory bulb of behaving mice

Many mammalian species rely on pheromones-semiochemicals produced by other members of the same species-to communicate social status and reproductive readiness. To assess how the central nervous system integrates the complex repertoire of pheromones, we recorded from single neurons in the accessory olfactory bulb, a nucleus that processes pheromonal signals, of male mice engaged in natural behaviors. Neuronal firing was robustly modulated by physical contact with male and female conspecifics, with individual neurons activated selectively by specific combinations of the sex and strain of conspecifics. We infer that mammals encode social and reproductive information by integrating vomeronasal sensory activity specific to sex and genetic makeup.     

Amygdaloid nucleus: new afferent input from the vomeronasal organ

Terminal degeneration stained by the Fink-Heimer technique was found in the medial and cortical amygdaloid nuclei in a discrete zone after lesions were inflicted in the accessory olfactory bulb but not after lesions were made in the main olfactory bulb in the rabbit. Since the accessory olfactory bulb receives the endings of the vomeronasal nerve, the mediocortical complex of the amygdala is the central projection area for the vomeronasal sensory organ. The vomeronasal organ is seen as having new potential significance in sexual and feeding behavior because the cortical amygdaloid nucleus projects to the anterior, medial hypothalamus and the ventromedial nucleus.     

Activity-dependent enhancement of presynaptic inhibition in Aplysia sensory neurons

Tail shock produces transient presynaptic inhibition and longer lasting presynaptic facilitation of the siphon sensory neurons in Aplysia. The facilitation undergoes activity-dependent enhancement that is thought to contribute to classical conditioning of the gill- and siphon-withdrawal reflex. Inhibition of the sensory neurons has now also been shown to undergo activity-dependent enhancement when action potential activity in the sensory neurons is paired with inhibitory transmitter. This effect appears to involve an amplification of the same cellular mechanisms that are involved in normal presynaptic inhibition. These results suggest that activity-dependent enhancement may be a general type of associative cellular mechanism.     

Postnatal refinement of peripheral olfactory projections

Axonal projections from the olfactory epithelium to the olfactory bulb are organized into glomeruli according to the expressed odorant receptor. Using gene-targeted mice, we show that glomerular maturation proceeds along different time courses for two similar receptors and requires sensory input during distinct sensitive periods. During early development, some glomeruli are innervated by axons of neurons that do not express the same receptor. These heterogeneous glomeruli normally disappear with age, but they persist in adults deprived of sensory input by unilateral and permanent naris closure. Persistence may be due, in part, to prolonged survival of olfactory sensory neurons.     

Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin

Environmental temperature is thought to be directly sensed by neurons through their projections in the skin. A subset of the mammalian transient receptor potential (TRP) family of ion channels has been implicated in this process. These "thermoTRPs" are activated at distinct temperature thresholds and are typically expressed in sensory neurons. TRPV3 is activated by heat (>33 degrees C) and, unlike most thermoTRPs, is expressed in mouse keratinocytes. We found that TRPV3 null mice have strong deficits in responses to innocuous and noxious heat but not in other sensory modalities; hence, TRPV3 has a specific role in thermosensation. The natural compound camphor, which modulates sensations of warmth in humans, proved to be a specific activator of TRPV3. Camphor activated cultured primary keratinocytes but not sensory neurons, and this activity was abolished in TRPV3 null mice. Therefore, heat-activated receptors in keratinocytes are important for mammalian thermosensation.     

Neuroscience. More to seeing than meets the eye

A single event may elicit several different sensory stimuli such as vision, sound, and touch. But how does the brain know which of the many different stimuli arriving in the sensory cortex of the brain are connected? In her Perspective, de Gelder discusses new findings showing that when a touch is applied on the same side of the body as a visual cue, vision is enhanced (Macaluso et al.). She explains that this effect is due to neurons projecting from the somatosensory (touch) area of the sensory cortex back to the visual cortex. These neurons keep the visual cortex informed about tactile stimuli elicited at the same time as the visual stimuli.     

The connectome of a decision-making neural network

In order to understand the nervous system, it is necessary to know the synaptic connections between the neurons, yet to date, only the wiring diagram of the adult hermaphrodite of the nematode Caenorhabditis elegans has been determined. Here, we present the wiring diagram of the posterior nervous system of the C. elegans adult male, reconstructed from serial electron micrograph sections. This region of the male nervous system contains the sexually dimorphic circuits for mating. The synaptic connections, both chemical and gap junctional, form a neural network with four striking features: multiple, parallel, short synaptic pathways directly connecting sensory neurons to end organs; recurrent and reciprocal connectivity among sensory neurons; modular substructure; and interneurons acting in feedforward loops. These features help to explain how the network robustly and rapidly selects and executes the steps of a behavioral program on the basis of the inputs from multiple sensory neurons.     

Control of larval development by chemosensory neurons in Caenorhabditis elegans

Larval development of the nematode Caenorhabditis elegans is controlled by the activities of four classes of chemosensory neurons. The choice between normal development and development into a specialized larval form called a dauer larva is regulated by competing environmental stimuli: food and a dauer pheromone. When the neuron classes ADF, ASG, ASI, and ASJ are killed, animals develop as dauer larvae regardless of environmental conditions. These neurons might sense food or dauer pheromone, or both, to initiate the specialized differentiation of many cell types that occurs during dauer formation. Entry into and exit from the dauer stage are primarily controlled by different chemosensory neurons. The analysis of mutants defective in dauer formation indicates that the chemosensory neurons are active in the absence of sensory inputs and that dauer pheromone inhibits the ability of these neurons to generate a signal necessary for normal development.     

Song replay during sleep and computational rules for sensorimotor vocal learning

Songbirds learn a correspondence between vocal-motor output and auditory feedback during development. For neurons in a motor cortex analog of adult zebra finches, we show that the timing and structure of activity elicited by the playback of song during sleep matches activity during daytime singing. The motor activity leads syllables, and the matching sensory response depends on a sequence of typically up to three of the preceding syllables. Thus, sensorimotor correspondence is reflected in temporally precise activity patterns of single neurons that use long sensory memories to predict syllable sequences. Additionally, "spontaneous" activity of these neurons during sleep matches their sensorimotor activity, a form of song "replay." These data suggest a model whereby sensorimotor correspondences are stored during singing but do not modify behavior, and off-line comparison (e.g., during sleep) of rehearsed motor output and predicted sensory feedback is used to adaptively shape motor output.     

The cell and molecular basis of mechanical, cold, and inflammatory pain

Peripheral pain pathways are activated by a range of stimuli. We used diphtheria toxin to kill all mouse postmitotic sensory neurons expressing the sodium channel Nav1.8. Mice showed normal motor activity and low-threshold mechanical and acute noxious heat responses but did not respond to noxious mechanical pressure or cold. They also showed a loss of enhanced pain responses and spontaneous pain behavior upon treatment with inflammatory insults. In contrast, nerve injury led to heightened pain sensitivity to thermal and mechanical stimuli indistinguishable from that seen with normal littermates. Pain behavior correlates well with central input from sensory neurons measured electrophysiologically in vivo. These data demonstrate that Na(v)1.8-expressing neurons are essential for mechanical, cold, and inflammatory pain but not for neuropathic pain or heat sensing.     

Somatosensory responses of bulboreticular units in awake cat: relation to escape-producing stimuli

In awake, unrestrained cats, bulboreticular neurons respond after electrical stimulation of cutaneous nerve with increasing discharge as stimulus intensity is raised to levels eliciting escape behavior. These cells discharge most vigorously to noxious natural somatic stimuli and are not driven by other sensory modalities. Electrical stimulation through the recording microelectrode also elicits escape, which further suggests bulboreticular participation in pain sensory mechanisms.     

Fast trap jaws and giant neurons in the ant odontomachus

Ants of the ponerine genus Odontomachus use a trap jaw mechanism when hunting fast prey. When particular trigger hairs, located on the inner edge of the mandibles, are touched by prey, the jaws close extremely rapidly and trap the target. This trap jaw response lasts only 0.33 to 1 millisecond. Electrophysiological recordings demonstrated that the trigger hairs function as mechanoreceptors. Associated with each trigger hair are large sensory cells, the sensory axons of which measure 15 to 20 micrometers in diameter. These are among the largest sensory neurons, and their size implies that these axons conduct information very rapidly.     

Transient pioneer neurons are essential for formation of an embryonic peripheral nerve

In developing nervous systems, many peripheral and central pathways are established by early arising populations of pioneer neurons. The growth cones of these pioneer neurons can migrate while embryonic distances are short and while intervening tissue is relatively uncomplicated. Are these pioneers necessary? In grasshopper embryos, a pair of pioneer neurons arise at the tips of limb buds and extend axons through the limb to the central nervous system. Growth cones of later arising sensory neurons migrate along the pioneer axons. After ingrowth of sensory axons, the pioneer neurons die. If the pioneer neurons are prevented from differentiating by heat shock, then the sensory growth cones that would have migrated along them are blocked and fail to reach the central nervous system. Thus, the pioneer axons are necessary for successful migration of these sensory growth cones. By crossing a segment boundary early in embryogenesis, the pioneers circumvent an incompatibility between differentiated segment boundary cells and growth cone migration. Pioneer neurons may resolve similar problems in many systems.     

Synaptic connections in vitro: modulation of number and efficacy by electrical activity

The functional architecture of synaptic circuits is determined to a crucial degree by the patterns of electrical activity that occur during development. Studies with an in vitro preparation of mammalian sensory neurons projecting to ventral spinal cord neurons slow that electrical activity induces competitive processes that regulate synaptic efficacy so as to favor activated pathways over inactive convergent pathways. At the same time, electrical activity initiates noncompetitive processes that increase the number of axonal connections between these sensory and spinal cord neurons.     

Identification of a peptide specific for Aplysia sensory neurons by PCR-based differential screening.

In order to identify genes specific for the sensory neurons of Aplysia, a miniaturized differential screening method based on the polymerase chain reaction and applicable to small amounts of tissue was used. One messenger RNA was isolated that is expressed in every mechanoreceptor sensory cluster of the Aplysia central nervous system. This messenger RNA encodes a peptide that seems to function as an inhibitory cotransmitter. The peptide selectively inhibits certain postsynaptic cells but not others and thereby allows the sensory neurons to achieve target-specific synaptic actions.     

Substance P: a putative sensory transmitter in mammalian autonomic ganglia

Repetitive presynaptic stimulation elicited slow membrane depolarization in neurons of inferior mesenteric ganglia from guinea pigs. This response was not blocked by cholinergic antagonists but was specifically and reversibly inhibited by a substance P analog, (D-Pro2, D-Phe7, D-Trp9)-substance P, which also depressed the depolarization induced by exogenously applied substance P. The atropine-sensitive slow excitatory and slow inhibitory postsynaptic potentials evoked in neurons of rabbit superior cervical ganglia were not affected by the substance P analog. These and previous results provide strong support for the hypothesis that substance P or a closely related peptide is the transmitter mediating the slow depolarization. The latter may represent a sensory input from the gastrointestinal tract to neurons of the prevertebral ganglia.     

Target-dependent structural changes accompanying long-term synaptic facilitation in Aplysia neurons

The mechanisms underlying structural changes that accompany learning and memory have been difficult to investigate in the intact nervous system. In order to make these changes more accessible for experimental analysis, dissociated cell culture and low-light-level video microscopy were used to examine Aplysia sensory neurons in the presence or absence of their target cells. Repeated applications of serotonin, a facilitating transmitter important in behavioral dishabituation and sensitization, produced growth of the sensory neurons that paralleled the long-term enhancement of synaptic strength. This growth required the presence of the postsynaptic motor neuron. Thus, both the structural changes and the synaptic facilitation of Aplysia sensorimotor synapses accompanying long-term behavioral sensitization can be produced in vitro by applying a single facilitating transmitter repeatedly. These structural changes depend on an interaction of the presynaptic neuron with an appropriate postsynaptic target.