Glutamate spillover mediates excitatory transmission in the rat olfactory bulb.

In the CNS, glutamate typically mediates excitatory transmission via local actions at synaptic contacts. In the olfactory bulb, mitral cell dendrites release glutamate at synapses formed only onto the dendrites of inhibitory granule cells. Here, I show excitatory transmission mediated solely by transmitter spillover between mitral cells in olfactory bulb slices. Dendritic glutamate release from individual mitral cells causes self-excitation via local activation of N-methyl-D-aspartate (NMDA) receptors. Paired recordings reveal that glutamate release from one cell generates NMDA receptor-mediated responses in neighboring mitral cells that are enhanced by blockade of glutamate uptake. Furthermore, spillover generates spontaneous NMDA receptor-mediated population responses. This simultaneous activation of neighboring mitral cells by a diffuse action of glutamate provides a mechanism for synchronizing olfactory principal cells.     

Pharmacological analysis of ionotropic glutamate receptor function in neuronal circuits of the zebrafish olfactory bulb

Although synaptic functions of ionotropic glutamate receptors in the olfactory bulb have been studied in vitro, their roles in pattern processing in the intact system remain controversial. We therefore examined the functions of ionotropic glutamate receptors during odor processing in the intact olfactory bulb of zebrafish using pharmacological manipulations. Odor responses of mitral cells and interneurons were recorded by electrophysiology and 2-photon Ca(2+) imaging. The combined blockade of AMPA/kainate and NMDA receptors abolished odor-evoked excitation of mitral cells. The blockade of AMPA/kainate receptors alone, in contrast, increased the mean response of mitral cells and decreased the mean response of interneurons. The blockade of NMDA receptors caused little or no change in the mean responses of mitral cells and interneurons. However, antagonists of both receptor types had diverse effects on the magnitude and time course of individual mitral cell and interneuron responses and, thus, changed spatio-temporal activity patterns across neuronal populations. Oscillatory synchronization was abolished or reduced by AMPA/kainate and NMDA receptor antagonists, respectively. These results indicate that (1) interneuron responses depend mainly on AMPA/kainate receptor input during an odor response, (2) interactions among mitral cells and interneurons regulate the total olfactory bulb output activity, (3) AMPA/kainate receptors participate in the synchronization of odor-dependent neuronal ensembles, and (4) ionotropic glutamate receptor-containing synaptic circuits shape odor-specific patterns of olfactory bulb output activity. These mechanisms are likely to be important for the processing of odor-encoding activity patterns in the olfactory bulb.     

Maternal behaviour and lamb survival: from neuroendocrinology to practical application

Parental care promotes offspring survival and, for livestock species, this care is provided solely by the mother. Maternal behaviour in the sheep has been exceptionally well-studied compared with other species and many of the underpinning biological processes leading to the expression of maternal care are known. In this review the current state of play with regard to the biology of maternal care will be reviewed, and its application to provide practical solutions to reduce lamb mortality considered. For maternal care to be elicited at birth the ewe requires elevated circulating oestradiol in late gestation, which stimulates the expression of oxytocin receptors in both peripheral and central areas (particularly the hypothalamic and limbic areas of the brain). At birth stretching of the vaginocervical canal elicits a spinal reflex which triggers the release of oxytocin primarily from neurones within the paraventricular nucleus of the hypothalamus. Oxytocin release causes an increase in the neurotransmitters noradrenaline, acetylcholine, glutamate and γ-aminobutyric acid (GABA) in the olfactory bulb, and other brain regions important for maternal behaviour. Finally, sensory cues provided by the lamb, in particular the amniotic fluids surrounding it, lead to the expression of maternal behaviours (licking, low-pitched bleats, acceptance of the lamb at the udder and suckling). This allows the expression of the two facets of maternal behaviour in the ewe: nurturance of the young and maternal selectivity, whereby a specific olfactory memory for the ewes own lamb is formed and the expression of maternal care is restricted to this lamb. Variation in the expression of maternal care has been demonstrated in primiparous ewes compared with multiparous, in different sheep genotypes, with undernutrition, stress in pregnancy, following a difficult delivery, and may occur with variation in ewe temperament. An understanding of the importance of the timing of various events in late pregnancy and during parturition, as well as the factors that can disrupt these events, can help to design management activities to minimise risks to the successful onset of maternal behaviour. Management practices that work with the biology of the ewe will be the most successful in ensuring that maternal care is expressed, so improving the welfare of the ewe and lamb, and the profitability of the farm.     

Glomerulus-specific synchronization of mitral cells in the olfactory bulb.

Odor elicits a well-organized pattern of glomerular activation in the olfactory bulb. However, the mechanisms by which this spatial map is transformed into an odor code remain unclear. We examined this question in rat olfactory bulb slices in recordings from output mitral cells. Electrical stimulation of incoming afferents elicited slow ( approximately 2 Hz) oscillations that originated in glomeruli and were highly synchronized for mitral cells projecting to the same glomerulus. Cyclical depolarizations were generated by glutamate activation of dendritic autoreceptors, while the slow frequency was determined primarily by the duration of regenerative glutamate release. Patterned stimuli elicited stimulus-entrained oscillations that amplified weak and variable inputs. We suggest that these oscillations maintain the fidelity of the spatial map by ensuring that all mitral cells within a glomerulus-specific network respond to odor as a functional unit.     

The nose knows who's who: chemosensory individuality and mate recognition in mice

Individual recognition is an important component of behaviors, such as mate choice and maternal bonding that are vital for reproductive success. This article highlights recent developments in our understanding of the chemosensory cues and the neural pathways involved in individuality discrimination in rodents. There appear to be several types of chemosensory signal of individuality that are influenced by the highly polymorphic families of major histocompatibility complex (MHC) proteins or major urinary proteins (MUPs). Both have the capability of binding small molecules and may influence the individual profile of these chemosignals in biological fluids such as urine, skin secretions, or saliva. Moreover, these proteins, or peptides associated with them, can be taken up into the vomeronasal organ (VNO) where they can potentially interact directly with the vomeronasal receptors. This is particularly interesting given the expression of major histocompatibility complex Ib proteins by the V2R class of vomeronasal receptor and the highly selective responses of accessory olfactory bulb (AOB) mitral cells to strain identity. These findings are consistent with the role of the vomeronasal system in mediating individual discrimination that allows mate recognition in the context of the pregnancy block effect. This is hypothesized to involve a selective increase in the inhibitory control of mitral cells in the accessory olfactory bulb at the first level of processing of the vomeronasal stimulus.     

P2Y1 receptor activation by photolysis of caged ATP enhances neuronal network activity in the developing olfactory bulb

It has recently been shown that adenosine-5'-triphosphate (ATP) is released together with glutamate from sensory axons in the olfactory bulb, where it stimulates calcium signaling in glial cells, while responses in identified neurons to ATP have not been recorded in the olfactory bulb yet. We used photolysis of caged ATP to elicit a rapid rise in ATP and measured whole-cell current responses in mitral cells, the output neurons of the olfactory bulb, in acute mouse brain slices. Wide-field photolysis of caged ATP evoked an increase in synaptic inputs in mitral cells, indicating an ATP-dependent increase in network activity. The increase in synaptic activity was accompanied by calcium transients in the dendritic tuft of the mitral cell, as measured by confocal calcium imaging. The stimulating effect of ATP on the network activity could be mimicked by photo release of caged adenosine 5'-diphosphate, and was inhibited by the P2Y(1) receptor antagonist MRS 2179. Local photolysis of caged ATP in the glomerulus innervated by the dendritic tuft of the recorded mitral cell elicited currents similar to those evoked by wide-field illumination. The results indicate that activation of P2Y(1) receptors in the glomerulus can stimulate network activity in the olfactory bulb.     

Connexin36 mediates spike synchrony in olfactory bulb glomeruli

Neuronal synchrony is important to network behavior in many brain regions. In the olfactory bulb, principal neurons (mitral cells) project apical dendrites to a common glomerulus where they receive a common input. Synchronized activity within a glomerulus depends on chemical transmission but mitral cells are also electrically coupled. We examined the role of connexin-mediated gap junctions in mitral cell coordinated activity. Electrical coupling as well as correlated spiking between mitral cells projecting to the same glomerulus was entirely absent in connexin36 (Cx36) knockout mice. Ultrastructural analysis of glomeruli confirmed that mitral-mitral cell gap junctions on distal apical dendrites contain Cx36. Coupled AMPA responses between mitral cell pairs were absent in the knockout, demonstrating that electrical coupling, not transmitter spillover, is responsible for synchronization. Our results indicate that Cx36-mediated gap junctions between mitral cells orchestrate rapid coordinated signaling via a novel form of electrochemical transmission.     

Presynaptic Glutamate Receptors Regulate Noradrenaline Release from Isolated Nerve Terminals

The wide-ranging neuronal actions of excitatory amino acids, such as glutamate, are thought to be mediated mainly by postsynaptic N-methyl-D-aspartate (NMDA) and non-NMDA receptors. We now report the existence of presynaptic glutamate receptors in isolated nerve terminals (synaptosomes) prepared from hippocampus, olfactory bulb, and cerebral cortex. Activation of these receptors by NMDA or non-NMDA agonists, in a concentration-dependent manner, resulted in Ca(2+)-dependent release of noradrenaline from vesicular transmitter stores. The NMDA-stimulated release was potentiated by glycine and was blocked by Mg2+ and selective NMDA antagonists. In contrast, release stimulated by selective non-NMDA agonists was blocked by 6-cyano-7-nitroquinoxaline-2,3- dione, but not by Mg2+ or NMDA antagonists. Our data suggest that the presynaptic glutamate receptors can be classified pharmacologically as both the NMDA and non-NMDA types. These receptors, localized on nerve terminals of the locus ceruleus noradrenergic neurons, may play an important role in interactions between noradrenaline and glutamate.     

Mother-lamb acoustic recognition in sheep: a frequency coding

Ewes of the domestic sheep ( Ovis aries ) display selective maternal investment by restricting care to their own offspring and rejecting alien young. This trait relies on individual recognition processes between ewes and lambs. Whereas identification at the udder is only olfactory, distance recognition is performed through visual and acoustic cues. We studied the effectiveness and modalities of mutual acoustic recognition between ewes and lambs by spectrographic analysis of their vocal signatures and by playbacks of modified calls in the field. Our results show that ewes and their lambs can recognize each other based solely on their calls. The coding of identity within the vocal signatures, previously unknown in sheep, is similar in lamb and ewe: it uses the mean frequency and the spectral energy distribution of the call, namely the timbre of the call. These results point out a simple signature system in sheep that uses only the frequency domain. This engenders a signal with low information content, as opposed to some highly social birds and mammal species that may integrate information both in the temporal and spectral domains. The simplicity of this system is linked to the roles played by vision and olfaction that corroborate the information brought by the vocal signature.     

Perinatal visceral events and brain mechanisms involved in the development of mother-young bonding in sheep

In sheep the onset of maternal responsiveness and the development of the mutual mother-young bond are under the combined influence of hormonal and visceral somatosensory stimulations. These stimuli are provided in the mother by parturition (via steroids and vaginocervical stimulation) and in the neonate by the first suckling episodes (via cholecystokinin and oro-gastro-intestinal stimulation). In addition, each partner relies on specific chemosensory stimulation for reciprocal attraction: amniotic fluids for the mother, colostrum for the young. In the ewe parturition activates several brain structures to respond specifically to sensory cues emanating from the young. The main olfactory bulbs undergo profound neurophysiological changes when exposed to offspring odors at parturition. Additional activations in the hypothalamus - preoptic area - and the amygdala - medial and cortical nuclei - also contribute to maternal responsiveness and memorization of lamb odors. In the neonate, post-ingestive stimulations activate the brain stem via vagal afferents. Like in the ewe, several regions of the hypothalamus and the amygdala respond to colostrum ingestion suggesting common ground for the integrative neural processes involved in early learning and bonding. This leads to rapid visual and auditory recognition in both partners although olfaction remains important in the ewe to display selective nursing. It is concluded that the biological basis for the development of maternal and filial bonding in sheep presents striking similarities.     

Dendritic action potentials connect distributed dendrodendritic microcircuits

Lateral inhibition of cells surrounding an excited area is a key property of sensory systems, sharpening the preferential tuning of individual cells in the presence of closely related input signals. In the olfactory pathway, a dendrodendritic synaptic microcircuit between mitral and granule cells in the olfactory bulb has been proposed to mediate this type of interaction through granule cell inhibition of surrounding mitral cells. However, it is becoming evident that odor inputs result in broad activation of the olfactory bulb with interactions that go beyond neighboring cells. Using a realistic modeling approach we show how backpropagating action potentials in the long lateral dendrites of mitral cells, together with granule cell actions on mitral cells within narrow columns forming glomerular units, can provide a mechanism to activate strong local inhibition between arbitrarily distant mitral cells. The simulations predict a new role for the dendrodendritic synapses in the multicolumnar organization of the granule cells. This new paradigm gives insight into the functional significance of the patterns of connectivity revealed by recent viral tracing studies. Together they suggest a functional wiring of the olfactory bulb that could greatly expand the computational roles of the mitral-granule cell network.     

Influence of Olfactory Epithelium on Mitral/Tufted Cell Dendritic Outgrowth

Stereotypical connections between olfactory sensory neuron axons and mitral cell dendrites in the olfactory bulb establish the first synaptic relay for olfactory perception. While mechanisms of olfactory sensory axon targeting are reported, molecular regulation of mitral cell dendritic growth and refinement are unclear. During embryonic development, mitral cell dendritic distribution overlaps with olfactory sensory axon terminals in the olfactory bulb. In this study, we investigate whether olfactory sensory neurons in the olfactory epithelium influence mitral cell dendritic outgrowth in vitro. We report a soluble trophic activity in the olfactory epithelium conditioned medium which promotes mitral/tufted cell neurite outgrowth. While the trophic activity is present in both embryonic and postnatal olfactory epithelia, only embryonic but not postnatal mitral/tufted cells respond to this activity. We show that BMP2, 5 and 7 promote mitral/tufted cells neurite outgrowth. However, the BMP antagonist, Noggin, fails to neutralize the olfactory epithelium derived neurite growth promoting activity. We provide evidence that olfactory epithelium derived activity is a protein factor with molecular weight between 50–100 kD. We also observed that Follistatin can effectively neutralize the olfactory epithelium derived activity, suggesting that TGF-beta family proteins are involved to promote mitral/tufted dendritic elaboration.     

Patterns of heterogeneous expression of pannexin 1 and pannexin 2 transcripts in the olfactory epithelium and olfactory bulb

Pannexins form membrane channels that release biological signals to communicate with neighboring cells. Here, we report expression patterns of pannexin 1 (Panx1) and pannexin 2 (Panx2) in the olfactory epithelium and olfactory bulb of adult mice. In situ hybridization revealed that mRNAs for Panx1 and Panx2 were both expressed in the olfactory epithelium and olfactory bulb. Expression of Panx1 and Panx2 was mainly found in cell bodies below the sustentacular cell layer in the olfactory epithelium, indicating that Panx1 and Panx2 are expressed in mature and immature olfactory neurons, and basal cells. Expression of Panx2 was observed in sustentacular cells in a few locations of the olfactory epithelium. In the olfactory bulb, Panx1 and Panx2 were expressed in spatial patterns. Many mitral cells, tufted cells, periglomerular cells and granule cells were Panx1 and Panx2 positive. Mitral cells located at the dorsal and lateral portions of the olfactory bulb showed weak Panx1 expression compared with those in the medial side. However, the opposite was true for the distribution of Panx2 positive mitral cells. There were more Panx2 mRNA positive mitral cells and granule cells compared to those expressing Panx1. Our findings on pannexin expression in the olfactory system of adult mice raise the novel possibility that pannexins play a role in information processing in the olfactory system. Demonstration of expression patterns of pannexins in the olfactory system provides an anatomical basis for future functional studies.     

Sparse Distributed Representation of Odors in a Large-scale Olfactory Bulb Circuit

In the olfactory bulb, lateral inhibition mediated by granule cells has been suggested to modulate the timing of mitral cell firing, thereby shaping the representation of input odorants. Current experimental techniques, however, do not enable a clear study of how the mitral-granule cell network sculpts odor inputs to represent odor information spatially and temporally. To address this critical step in the neural basis of odor recognition, we built a biophysical network model of mitral and granule cells, corresponding to 1/100th of the real system in the rat, and used direct experimental imaging data of glomeruli activated by various odors. The model allows the systematic investigation and generation of testable hypotheses of the functional mechanisms underlying odor representation in the olfactory bulb circuit. Specifically, we demonstrate that lateral inhibition emerges within the olfactory bulb network through recurrent dendrodendritic synapses when constrained by a range of balanced excitatory and inhibitory conductances. We find that the spatio-temporal dynamics of lateral inhibition plays a critical role in building the glomerular-related cell clusters observed in experiments, through the modulation of synaptic weights during odor training. Lateral inhibition also mediates the development of sparse and synchronized spiking patterns of mitral cells related to odor inputs within the network, with the frequency of these synchronized spiking patterns also modulated by the sniff cycle.     

Homeostatic regulation of glutamate release in response to depolarization

Proper nervous system function requires a balance between excitation and inhibition. Systems of homeostasis may have evolved in neurons to help maintain or restore balance between excitation and inhibition, presumably because excessive excitation can cause dysfunction and cell death. This article reviews evidence for homeostatic mechanisms within the hippocampus that lead to differential regulation of glutamate and gamma-aminobutyric acid release in response to conditions of excess depolarization. We recently found differential effects on glutamate release at the level of action potential coupling to transmitter release, vesicular release probability, and vesicle availability. Such differential regulation may help to prevent excitotoxicity and runaway excitation.     

Olfactory regulation of maternal behavior in mammals

In mammals, olfactory cues are extensively used in many aspects of maternal care to ensure the coordination of mother-infant interactions and consequently the normal development of the offspring. Outside the period of parturition and lactation, when the young are not a behavioral priority, olfactory cues play an inhibitory role on maternal responsiveness since in most mammalian species studied so far, nonpregnant females find the odor of young aversive. On the contrary at the time of parturition, a shift in the hedonic value of infantile odors occurs so that the young now become a very potent stimulus and this sensorial processing constitutes an important part of the maternal motivational system. Moreover, infants' odors provide a basis for individual recognition by their mothers and some species (ungulates) have developed highly specialized mechanisms for processing of the infant signals. Perception of the smell of the young also regulates various aspects of maternal behavior. Dodecyl propionate, a compound released by of pup's preputial glands, has been shown to influence anogenital licking behavior, a fundamental pattern of maternal behavior in rodents. While there is no functional specificity of either the main or the accessory olfactory systems in the development of maternal behavior amongst species, it appears that only the main olfactory system is implicated when individual odor discrimination of the young is required. Neural structures, such as the main olfactory bulb, undergo profound changes when exposed to offspring odors at parturition. These changes in synaptic circuitry contribute both to maternal responsiveness to these odors, to their memorization, and to effects of long-term maternal experience.     

Olfactory recognition memory

Olfactory recognition which occurs in the context pregnancy block by male pheromones is acquired with one-trial learning contingent on mating. A memory trace is established in the accessory bulb (AOB) and is represented by a gain in Gaba-ergic feedback inhibition of granule cells on excitatory glutaminergic mitral cells. This occurs in the sub-population of mitral cells that specifically respond to an individual male's pheromones, and is dependent on noradrenaline release at mating. Although relatively simple, the AOB has both structural and functional similarities with other trilaminar neural structures involved in learning, which suggests some evolutionary conservation of mechanisms subserving memory.     

Transregulation of erbB expression in the mouse olfactory bulb.

Previously, we have shown that erbB-3 expression is restricted to the ensheathing cells of the olfactory nerve layer, while erbB-4 is found in the periglomerular and mitral/tufted cells of the olfactory bulb and in cells coming out from the rostral migratory stream of the subependymal layer. In the present work, we have treated adult mice with zinc sulfate intranasal irrigation and analyzed erbB-3 and erbB-4 expression in the deafferented olfactory bulb. Following treatment, olfactory axons undergo degeneration, as indicated by the loss of OMP expression in the deafferented olfactory bulb. The thickness of the olfactory nerve layer is reduced, but the specific intensity of erbB-3 labeling in the remaining olfactory nerve layer is increased with respect to control. Interestingly, following deafferentation, erbB-4 immunoreactivity decreases specifically in cell types that normally make synaptic contacts with primary olfactory neurons in the glomeruli, i.e. periglomerular and mitral/tufted cells. Partial lesion of the olfactory epithelium allows regenerative axon growth of olfactory neurons to the olfactory bulb. Following olfactory axon regeneration, erbB-3 and erbB-4 immunoreactivity in the olfactory bulb is similar to control. Thus, like tyrosine hydroxylase, the down regulation of erbB-4 expression in the periglomerular cells is reversible.     

Dynamic connectivity in the mitral cell-granule cell microcircuit

The interactions between excitatory mitral cells and inhibitory granule cells are critical for the regulation of olfactory bulb activity. Here we review anatomical and physiological data on the mitral cell-granule cell circuit and provide a quantitative estimate of how this connectivity varies as a function of distance between mitral cells. We also discuss the ways in which the functional connectivity can be altered rapidly during olfactory bulb activity.     

哺乳动物嗅觉与母性识别

嗅觉通讯在陆生哺乳动物母性识别中具有重要作用。通过嗅觉信息,早熟性动物(有蹄类)产后早期能够迅速建立专一性的母性识别和母子联系,并具有母性识别的敏感期。在敏感期内,分娩经验、催产素及一氧化氮等神经递质的释放有助于这种识别和联系的形成。多项研究表明,晚熟性动物(如啮齿类)母性识别的形成主要基于断乳前母兽与幼仔共处获得的熟悉性,产后早期不能迅速形成专一性的母性识别和母子联系,母兽对亲生幼仔和非亲生幼仔的选择性哺育不完全取决于识别。实验方法及识别的判定标准对研究啮齿类的母性识别尤其重要。包括人类在内的灵长类母亲产后只通过嗅觉信息即可以对婴儿进行识别。在哺乳动物的母性识别中,妊娠和分娩过程会诱导嗅觉系统的高度可塑性,有利于促进母亲对幼体气味的学习,但硬连接(hard-wired)路径也可能参与母性识别。