Olfactory Bulb Network Research Articles

Stability of fast oscillations in the mammalian olfactory bulb: Experiments and modeling

In the rat olfactory bulb (OB), fast oscillations of the local field potential (LFP) are observed during the respiratory cycle. Gamma-range oscillations (40–90 Hz) occur at the end of inspiration, followed by beta-range oscillations (15–30 Hz) during exhalation. These oscillations are highly stereotypical, and their frequencies are stable under various conditions. In this study, we investigate the effect of stimulus intensity on activity in the OB. Using a double-cannulation protocol, we showed that although the frequency of the LFP oscillation does depend on the respiratory cycle phase, it is relatively independent of the intensity of odorant stimulation. In contrast, we found that the individual firing rate of mitral OB cells dramatically changed with the intensity of the stimulation. This suggests that OB fast oscillation parameters, particularly frequency, are fully determined by intrinsic OB network parameters. To test this hypothesis, we explored a model of the OB where fast oscillations are generated by the interplay between excitatory mitral/tufted cells and inhibitory granule cells with graded inhibition. We found that our model has two distinct activity regimes depending on the amount of noise. In a low-noise regime, the model displays oscillation in the beta range with a stable frequency across a wide range of excitatory inputs. In a high-noise regime, the model displays oscillatory dynamics with irregular cell discharges and fast oscillations, similar to what is observed during gamma oscillations but without stability of the oscillation frequency with respect to the network external input. Simulations of the full model and theoretical studies of the network’s linear response show that the characteristics of the low-noise regime are induced by non-linearities in the model, notably, the saturation of graded inhibition. Finally, we discuss how this model can account for the experimentally observed stability of the oscillatory regimes.

Stabilisation of beta and gamma oscillation frequency in the mammalian olfactory bulb

The dynamics of the mammalian olfactory bulb (OB) is characterized by local field potential (LFP) oscillations either slow, in the theta range (2-10Hz, tightly linked to the respiratory rhythm), or fast, in the beta (15-30Hz) or gamma (40-90Hz) range. These fast oscillations are known to be modulated by odorant features [1] and animal experience or state [2][3], but both their mechanisms and implication in coding are still not well understood. In this study, we used a double canulation protocol to impose artificial breathing rhythms to anesthetized rats while recording the LFP in the OB. We observed that despite the changes in the input air flow parameters (frequency or flow rate), the main characteristics of fast oscillations (duration, frequency or amplitude) were merely constant. We thus made the hypothesis that fast beta and gamma oscillations dynamics are entirely determined by the OB network properties and that external stimulation was only able put the network in a state which permits the generation of one or the other oscillations (they are never present simultaneously). To test this hypothesis, we studied a simplified OB model based on previous modeling studies. In particular it includes resonant mitral cells [4] and graded synaptic inhibition [5]. Detailed analysis and numerical simulations of the model showed that two oscillatory dynamical regime can be sustained. First, a low noise regime where at each cycle, a subset of mitral cells are tightly synchronized and yield a saturation of the graded inhibition, during which mitral cell discharge is prevented. Because of this saturation, the network frequency is governed by the dynamics of the graded inhibition decay. Interestingly, this dynamics is not very sensitive to the number of mitral cells that lead to the saturation. Consequently, there is a wide range of mitral cell firing rate during which the network frequency is stable. Using standard parameters in our model, we found an oscillation frequency stable between 25 and 30Hz while the average mitral cell firing rate increased from 5Hz to 25Hz. Second, a high noise regime can be observed where the mitral cell discharge is much less regular. In this case, the network oscillations are of lower amplitude compared to the low noise regime and thus the graded inhibition is never saturated by fluctuations around its mean. The network can then be well described by a mean field approach (as described in [ 6]) and is close to a previous model of in vitro gamma oscillations [4]. With our model parameters, oscillations in this regime have higher frequency, typically in the gamma range (50Hz-90Hz) but their frequency is highly sensitive to the level of input excitation to the mitral cells. This discrepancy with our experimental result could be relieved by the in vitro experimental observation that mitral cell stimulus excitatory input is all or none [7]. Indeed this could provide a stable external input to the network and thus also stabilize the gamma frequency. Finally, we have shown that our model can account for the two stable oscillatory regimes observed in the OB in vivo. However our model does not take into account the spatial activation of the OB and the study of how spatially segregated oscillatory generators interact and potentially synchronize is an ongoing work.

Loss of olfactory cell adhesion molecule reduces the synchrony of mitral cell activity in olfactory glomeruli

Odours generate activity in olfactory receptor neurons, whose axons contact the dendritic tufts of mitral cells within olfactory bulb glomeruli. These axodendritic synapses are anatomically separated from dendrodendritic synapses within each glomerulus. Mitral cells within a glomerulus show highly synchronized activity as assessed with whole-cell recording from pairs of mitral cells. We examined glomerular activity in mice lacking the olfactory cell adhesion molecule (OCAM). Glomeruli in mice lacking OCAM show a redistribution of synaptic subcompartments, but the total area occupied by axonal inputs was similar to wild-type mice. Stimulation of olfactory nerve bundles showed that excitatory synaptic input to mitral cells as well as dendrodendritic inhibition was unaffected in the knockout. However, correlated spiking in mitral cells was significantly reduced, as was electrical coupling between apical dendrites. To analyse slow network dynamics we induced slow oscillations with a glutamate uptake blocker. Evoked and spontaneous slow oscillations in mitral cells and external tufted cells were broader and had multiple peaks in OCAM knockout mice, indicating that synchrony of slow glomerular activity was also reduced. To assess the degree of shared activity between mitral cells under physiological conditions, we analysed spontaneous sub-threshold voltage oscillations using coherence analysis. Coherent activity was markedly reduced in cells from OCAM knockout mice across a broad range of frequencies consistent with a decrease in tightly time-locked activity. We suggest that synchronous activity within each glomerulus is dependent on segregation of synaptic subcompartments.

Integration and maturation of newborn neurons in the adult olfactory bulb – from synapses to function

In adult mammals, thousands of new neurons integrate in the olfactory bulb (OB) each day. This process of adult neurogenesis has received a great deal of scientific attention aimed at understanding how mature neural networks withstand neuronal replacement, and medical interest to explore the promise that these cells may be manipulated for brain repair therapies. In the present review, we focus on the mechanisms and consequences of the functional integration of newborn interneurons in the OB network. We first describe the steps of synaptic integration and functional maturation of adult-born interneurons in the OB. We then examine the physiological control of cell maturation and survival. Finally, we explore the potential impact of adult neurogenesis on the function of the OB.

Fragile X Mental Retardation Protein Regulates New Neuron Differentiation in the Adult Olfactory Bulb

The fragile X mental retardation protein (FMRP) is an RNA-binding protein essential for multiple aspects of neuronal mRNA metabolism. Its absence leads to the fragile X syndrome, the most prevalent genetic form of mental retardation. The anatomical landmark of the disease, also present in the Fmr1 knock-out (KO) mice, is the hyperabundance of immature-looking lengthened dendritic spines. We used the well known continuous production of adult-born granule cells (GCs) in the mouse olfactory bulb (OB) to analyze the consequences of Fmrp loss on the differentiation of GCs. Morphological analysis of GCs in the Fmr1 KO mice showed an increase in spine density without a change in spine length. We developed an RNA interference strategy to cell-autonomously mutate Fmr1 in a wild-type OB network. Mutated GCs displayed an increase in spine density and spine length. Detailed analysis of the spines through immunohistochemistry, electron microscopy, and electrophysiology surprisingly showed that, despite these abnormalities, spines receive normal glutamatergic synapses, and thus that mutated adult-born neurons are synaptically integrated into the OB circuitry. Time-course analysis of the spine defects showed that Fmrp cell-autonomously downregulates the level and rate of spine production and limits their overgrowth. Finally, we report that Fmrp does not regulate dendritogenesis in standard conditions but is necessary for activity-dependent dendritic remodeling. Overall, our study of Fmrp in the context of adult neurogenesis has enabled us to carry out a precise dissection of the role of Fmrp in neuronal differentiation and underscores its pleiotropic involvement in both spinogenesis and dendritogenesis.

NKCC1 controls GABAergic signaling and neuroblast migration in the postnatal forebrain.

From an early postnatal period and throughout life there is a continuous production of olfactory bulb (OB) interneurons originating from neuronal precursors in the subventricular zone. To reach the OB circuits, immature neuroblasts migrate along the rostral migratory stream (RMS). In the present study, we employed cultured postnatal mouse forebrain slices and used lentiviral vectors to label neuronal precursors with GFP and to manipulate the expression levels of the Na-K-2Cl cotransporter NKCC1. We investigated the role of this Cl- transporter in different stages of postnatal neurogenesis, including neuroblast migration and integration in the OB networks once they have reached the granule cell layer (GCL). We report that NKCC1 activity is necessary for maintaining normal migratory speed. Both pharmacological and genetic manipulations revealed that NKCC1 maintains high [Cl-]i and regulates the resting membrane potential of migratory neuroblasts whilst its functional expression is strongly reduced at the time cells reach the GCL. As in other developing systems, NKCC1 shapes GABAA-dependent signaling in the RMS neuroblasts. Also, we show that NKCC1 controls the migration of neuroblasts in the RMS. The present study indeed indicates that the latter effect results from a novel action of NKCC1 on the resting membrane potential, which is independent of GABAA-dependent signaling. All in all, our findings show that early stages of the postnatal recruitment of OB interneurons rely on precise, orchestrated mechanisms that depend on multiple actions of NKCC1.

CREB signalling regulates early survival, neuronal gene expression and morphological development in adult subventricular zone neurogenesis

Neural stem cells in the subventricular zone (SVZ) of the lateral ventricles give rise to new interneurons of the olfactory bulb (OB) throughout life. SVZ/OB neurogenesis is influenced by olfactory network activity, which modulates the survival of new neurons during their integration into the OB network. Previous work suggested that such activity-dependent survival is regulated via the CREB signalling pathway. Curiously, CREB signalling is already active during the early developmental stages of adult SVZ/OB neurogenesis. To investigate the role of cell autonomous CREB signalling during early stages of adult SVZ/OB neurogenesis, we ablated CREB-pathway activity in the SVZ/OB neurogenic lineage using a retroviral strategy. Surprisingly, loss of CREB signalling resulted in increased cell death and loss of expression of the neurogenic transcription factor Pax 6, and of a subset of neuronal proteins in migrating neurons of the RMS. Moreover, post-migratory neurons in the OB displayed impaired dendritic development. These results demonstrate an essential role for CREB signalling in maturation of newborn neurons in the OB and uncover a novel role for CREB signalling in the survival and maintenance of neuronal gene expression during the early stages of SVZ/OB neurogenesis.

GABA signals modulate neuronal production

Event Abstract Back to Event GABA signals modulate neuronal production Angelique Bordey1* 1 Yale School of Medicine, Department of Signal Processing, United States The neurotransmitter gamma-aminobutyric acid (GABA) acting at GABAA receptors is critical for multiple developmental processes such as cell proliferation, migration, neurite extension, and network integration. Recent work has emphasized the importance of GABA on postnatal neurogenesis including the hippocampal subgranular zone and the subventricular zone (SVZ). The SVZ is the largest neurogenic zone where 10,000-30,000 neurons are produced per day and integrate in the olfactory bulb network. In this region, GABA exerts a negative feedback on neural progenitor cell proliferation and regulates neuroblast migration and differentiation. However, the ultimate in vivo function of GABA on SVZ neurogenesis remains unknown. To address this issue, we took advantage of and manipulated the depolarizing action of GABA. GABA effect is thought to result from its depolarization-induced calcium increases in both SVZ astrocytes and neuroblasts. We used a RNA interference approach against the Na-K-2Cl co-transporter 1 (NKCC1), which allows Cl- influx in immature cells, to reduce or eliminate GABA depolarization. Short hairpin RNA (shRNA) and a fluorescent reporter (GFP or RFP) were introduced into neural progenitor cells using in vivo electroporation in neonates. Using electrophysiology and calcium imaging, we found that shRNA expression to knock down (KD) NKCC1 (noted NKCC1KD) led to a premature hyperpolarization in neuroblasts integrating into the olfactory bulb network. We also found that 40% fewer NKCC1KD neuroblasts reached the olfactory bulb. This effect was not due to cell apoptosis measured with activated caspase-3 staining or a defect in cell migration. Indeed, NKCC1KD neuroblasts migrated at the same speed as neuroblasts containing a control shRNA. Finally, newly integrated NKCC1KD neurons displayed morphological defects compared to control. In conclusion, modulating NKCC1 expression in vivo significantly decreases the numbers of newly born neurons in the olfactory bulb and alters their morphology. Since there is a lack of either apoptotic or migratory defects, there is likely a proliferation defect in the astrocyte-like stem cells, neuroblasts, or potentially both. Conference: EMBO workshop: Gaba Signalling and Brain Networks , Amsterdam, Netherlands, 30 Jun - 2 Jul, 2010. Presentation Type: Oral Presentation Topic: Talks Citation: Bordey A (2010). GABA signals modulate neuronal production. Conference Abstract: EMBO workshop: Gaba Signalling and Brain Networks . doi: 10.3389/conf.fnins.2010.15.00028 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 22 Jun 2010; Published Online: 22 Jun 2010. * Correspondence: Angelique Bordey, Yale School of Medicine, Department of Signal Processing, New Haven, United States, angelique.bordey@yale.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Angelique Bordey Google Angelique Bordey Google Scholar Angelique Bordey PubMed Angelique Bordey Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Interneurons Produced in Adulthood Are Required for the Normal Functioning of the Olfactory Bulb Network and for the Execution of Selected Olfactory Behaviors

Olfactory bulb (OB) interneurons are continuously renewed throughout an animal's lifespan. Despite extensive investigation of this phenomenon, little is known about bulbar circuitry functioning and olfactory performances under conditions of ablated arrival of new neurons into the adult OB. To address this issue we performed morphological, electrophysiological, and behavioral analysis in mice with suppressed bulbar neurogenesis. Infusion of the antimitotic drug AraC to the lateral ventricle via 28 d osmotic minipumps abolished the arrival of newly born neurons into the adult OB without affecting the total number of granule cells. The number, dendritic arborization, and spine density of interneurons generated in adulthood, before pump installation, were also not affected by AraC treatment. As a result of ablated neurogenesis, mitral cells--the principal output neurons in the OB--receive fewer inhibitory synapses, display reduced frequency of spontaneous IPSCs, experience smaller dendrodendritic inhibition, and exhibit decreased synchronized activity. Consequently, short-term olfactory memory was drastically reduced in AraC-treated mice. In contrast, olfactory performances of AraC-treated animals were undistinguishable from those of control mice in other odor-associated tests, such as spontaneous odor discrimination and long-term odor-associative memory tasks. Altogether, our data highlight the importance of adult neurogenesis for the proper functioning of the OB network and imply that new bulbar interneurons are involved in some, but not all, odor-associated tasks.

GABAa Receptor Heterogeneity Modulates Dendrodendritic Inhibition

In the olfactory bulb, mitral and tufted cells receive GABAergic inhibition at dendrodendritic synapses with granule cells. Recent studies have revealed a remarkable variability in the subunit composition of GABA(a) receptors in dendrodendritic microcircuits, with differential expression patterns of the alpha1 and alpha3 subunits in different subtypes of mitral and tufted cells. In particular, all mitral cells express the alpha1 subunit, whereas GABA(a)alpha3 is restricted to a subgroup of mitral cells, as well as to several subtypes of tufted cells. To assess the functional relevance of this heterogeneity, we investigated a mouse strain carrying a genetic deletion of the alpha1 subunit. Elimination of GABA(a)alpha1 was partially compensated for in mitral cells by receptors containing the alpha3 subunit, substantially decreasing the frequency of spontaneous inhibitory postsynaptic currents, as well as prolonging their decay time. Evoked inhibition between granule and mitral cells was slower to rise and decay and had smaller amplitude in alpha1 mutants. Remarkably, these changes in synaptic inhibition were accompanied by a significant reduction in the frequency of field oscillations. Therefore, the subunit composition of GABA(a) receptors strongly influences rhythmic activities in the olfactory bulb network. Together, these data indicate that dendrodendritic circuits in the external plexiform layer segregate into parallel pathways involving distinct GABA(a) receptors that are expressed by different subtypes of mitral and tufted cells.

Low‐level Mechanisms for Processing Odor Information in the Behaving Animal

Sensory processing is typically thought to act on representations of sensory stimuli that are relatively fixed at low levels in the nervous system and become increasingly complex and subject to modulation at higher levels. Here we present recent findings from our laboratory demonstrating that, in the olfactory system, odor representations in the behaving animal can be transformed at low levels--as early as the primary sensory neurons themselves--via a variety of mechanisms. First, changes in odor sampling behavior, such as sniffing, can dramatically and rapidly alter primary odor representations by changing the strength and temporal structure of sensory input to the olfactory bulb, effectively shaping which features of the olfactory landscape are emphasized and likely altering how information is processed by the olfactory bulb network. Second, neural substrates exist for presynaptically modulating the strength of sensory input to the bulb as a function of behavioral state. The systems most likely to be involved in this modulation--cholinergic and serotonergic centrifugal inputs to the bulb--are linked to attention and arousal effects in other brain areas. Together, sniffing behavior and presynaptic inhibition have the potential to mediate, or at least contribute to, sensory processing phenomena, such as figure-ground separation, intensity invariance, and context-dependent and attentional modulation of response properties. Thus, "high order" processing can occur even before sensory neurons transmit information to the brain.

Bulbar Acetylcholine Enhances Neural and Perceptual Odor Discrimination

Experimental and modeling data suggest that the circuitry of the main olfactory bulb (OB) plays a critical role in olfactory discrimination. Processing of such information arises from the interaction between OB output neurons local interneurons, as well as interactions between the OB network and centrifugal inputs. Cholinergic input to the OB in particular has been hypothesized to regulate mitral cell odorants receptive fields (ORFs) and behavioral discrimination of similar odorants. We recorded from individual mitral cells in the OB in anesthetized rats to determine the degree of overlap in ORFs of individual mitral cells after exposure to odorant stimuli. Increasing the efficacy of the cholinergic neurotransmission in the OB by addition of the anticholinesterase drug neostigmine (20 mM) sharpened the ORF responses of mitral cells. Furthermore, coaddition of either the nicotinic antagonist methyllycaconitine citrate hydrate (MLA) (20 mM) or muscarinic antagonist scopolamine (40 mM) together with neostigmine (20 mM) attenuated the neostigmine-dependent sharpening of ORFs. These electrophysiological findings are predictive of accompanying behavioral experiments in which cholinergic modulation was manipulated by direct infusion of neostigmine, MLA, and scopolamine into the OB during olfactory behavioral tasks. Increasing the efficacy of cholinergic action in the OB increased perceptual discrimination of odorants in these experiments, whereas blockade of nicotinic or muscarinic receptors decreased perceptual discrimination. These experiments show that behavioral discrimination is modulated in a manner predicted by the changes in mitral cell ORFs by cholinergic drugs. These results together present a first direct comparison between neural and perceptual effects of a bulbar neuromodulator.

Local translation of mRNAs and its role in the development and plasticity of the mouse olfactory network

Event Abstract Back to Event Local translation of mRNAs and its role in the development and plasticity of the mouse olfactory network Alain Trembleau1* 1 Université Pierre et Marie Curie Paris 6, 9 quai Saint Bernard, Equipe Avenir/INSERM Développement et Plasticité des Réseaux Neuronaux, CNRS UMR 7102 - Neurobiologie des Processus Adaptatifs, France During the last decade, a growing body of evidence demonstrated that the regulated local translation of mRNAs in developing axons and mature dendrites could play critical roles in axon guidance and synaptic plasticity, respectively. However, little is known about molecular mechanisms at work in these regulations. Furthermore, several other possible functions of local translation have not been addressed yet. The project of my team is to investigate new functions of local translation in the development and plasticity of neurogenesis, making it amendable to in vivo manipulations. In the first part of my talk, I will present the approaches we develop in order to investigate the role of dendritic local translation in the processes of dendritogenesis, spinogenesis and synaptogenesis as new interneurons are functionally inserted into the adult olfactory bulb network. In the second part of my talk, I will present our recent data ocumenting a developmentally regulated local translation of Odorant Receptor-encoding mRNAs in olfactory sensory neuron axons, and I will discuss its possible role in the development and plasticity of the mouse olfactory map. Overall, our project addresses fundamental issues and molecular mechanisms involved not only in the normal development and plasticity of neural networks, but also in neurodevelopmental the mouse olfactory system, a model characterized by continuous pathologies like Fragile X mental retardation. Conference: 3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009. Presentation Type: Oral Presentation Topic: Plenary lectures Citation: Trembleau A (2009). Local translation of mRNAs and its role in the development and plasticity of the mouse olfactory network. Front. Neurosci. Conference Abstract: 3rd Mediterranean Conference of Neuroscience . doi: 10.3389/conf.neuro.01.2009.16.065 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 19 Nov 2009; Published Online: 19 Nov 2009. * Correspondence: Alain Trembleau, Université Pierre et Marie Curie Paris 6, 9 quai Saint Bernard, Equipe Avenir/INSERM Développement et Plasticité des Réseaux Neuronaux, CNRS UMR 7102 - Neurobiologie des Processus Adaptatifs, 75005 Paris, France, alain.trembleau@snv.jussieu.fr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Alain Trembleau Google Alain Trembleau Google Scholar Alain Trembleau PubMed Alain Trembleau Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

GABAergic inhibition at dendrodendritic synapses tunes γ oscillations in the olfactory bulb

In the olfactory bulb (OB), odorants induce oscillations in the gamma range (20-80 Hz) that play an important role in the processing of sensory information. Synaptic transmission between dendrites is a major contributor to this processing. Glutamate released from mitral cell dendrites excites the dendrites of granule cells, which in turn mediate GABAergic inhibition back onto mitral cells. Although this reciprocal synapse is thought to be a key element supporting oscillatory activity, the mechanisms by which dendrodendritic inhibition induces and maintains gamma oscillations remain unknown. Here, we assessed the role of the dendrodendritic inhibition, using mice lacking the GABA(A) receptor alpha1-subunit, which is specifically expressed in mitral cells but not in granule cells. The spontaneous inhibitory postsynaptic current frequency in these mutants was low and was consistent with the reduction of GABA(A) receptor clusters detected by immunohistochemistry. The remaining GABA(A) receptors in mitral cells contained the alpha3-subunit and supported slower decaying currents of unchanged amplitude. Overall, inhibitory-mediated interactions between mitral cells were smaller and slower in mutant than in WT mice, although the strength of sensory afferent inputs remained unchanged. Consequently, both experimental and theoretical approaches revealed slower gamma oscillations in the OB network of mutant mice. We conclude, therefore, that fast oscillations in the OB circuit are strongly constrained by the precise location, subunit composition and kinetics of GABA(A) receptors expressed in mitral cells.

Early olfactory computations and perception

In this talk I will present an overview of the olfactory bulb network from a computational point of view. I will discuss the functionality of the different types of neurons, the networks they form with respect to computing stable, context independent representations of olfactory stimuli. The shaping of these computations by olfactory context, neuromodulation and experience will be discussed in detail.

Olfactory bulb networks revealed by lateral olfactory tract stimulation in the in vitro isolated guinea-pig brain

Olfactory information processing is mediated by synaptic connections between the olfactory bulbs (OBs) and piriform–limbic cortices. Limited accessibility using common in vivo and in vitro preparations has hindered previous attempts to define these synaptic interactions. We utilized the isolated guinea-pig brain preparation to overcome these experimental limitations. Previous studies demonstrated extensive functional preservation in this preparation maintained in vitro by arterial perfusion. Field potential laminar profiles were performed with multi-channel probes in the OB following stimulation of both the lateral olfactory tract (LOT) and the anterior piriform cortex (APC). Current-source density analysis was carried out on laminar profiles to reconstruct current sinks/sources associated with intrinsic synaptic activities. LOT stimulation induced sequentially i) an antidromic population spike (at 2.66±0.39 ms) located in the mitral cell layer that was resistant to 100 Hz high-frequency stimulation (HFS) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10 μM), ii) a component located in the external plexiform layer at 3.85±0.63 ms that was unaffected by HFS, iii) a large amplitude potential (peak amplitude at 5.84±0.58 ms) generated in the external plexiform layer, abolished by HFS and CNQX, but not by bicuculline (50 μM), iv) a late response (onset at 20.00±2.94 ms) abolished by CNQX and enhanced by bicuculline. Stimulation of the APC also induced a late potential abolished by HFS and CNQX. Both APC-evoked and late LOT-evoked responses were abolished by a transverse cut to separate OB from APC. These results demonstrate in an isolated mammalian brain preparation the presence of reciprocal synaptic interactions between the OB and piriform cortical structures.

Dynamical Mechanisms of Odor Processing in Olfactory Bulb Mitral Cells

In the olfactory system, the contribution of dynamical properties such as neuronal oscillations and spike synchronization to the representation of odor stimuli is a matter of substantial debate. While relatively simple computational models have sufficed to guide current research in large-scale network dynamics, less attention has been paid to modeling the membrane dynamics in bulbar neurons that may be equally essential to sensory processing. We here present a reduced, conductance-based compartmental model of olfactory bulb mitral cells that exhibits the complex dynamical properties observed in these neurons. Specifically, model neurons exhibit intrinsic subthreshold oscillations with voltage-dependent frequencies that shape the timing of stimulus-evoked action potentials. These oscillations rely on a persistent sodium conductance, an inactivating potassium conductance, and a calcium-dependent potassium conductance and are reset via inhibitory input such as that delivered by periglomerular cell shunt inhibition. Mitral cells fire bursts, or clusters, of spikes when continuously stimulated. Burst properties depend critically on multiple currents, but a progressive deinactivation of I(A) over the course of a burst is an important regulator of burst termination. Each of these complex properties exhibits appropriate dynamics and pharmacology as determined by electrophysiological studies. Additionally, we propose that a second, inconsistently observed form of infrathreshold bistability in mitral cells may derive from the activation of ATP-activated potassium currents responding to hypoxic conditions. We discuss the integration of these cellular properties in the larger context of olfactory bulb network operations.

5-hydroxytryptamine action in the rat olfactory bulb: In vitro electrophysiological patch-clamp recordings of juxtaglomerular and mitral cells

The olfactory bulb, first relay of olfactory pathways, is densely innervated by serotoninergic centrifugal fibers originating from the raphe nuclei. Although serotonin innervation was reported to be involved in olfactory learning in mammals, the action of this neurotransmitter on its putative cellular targets has been never described through unitary recordings. This lack of data initiated the present study where the effects of 5HT on juxtaglomerular and mitral cells are analyzed using whole-cell recordings on olfactory bulb slices. Serotonin depolarizes 34% of 525 JG cells. A multivariate statistical analysis of juxtaglomerular cells characteristics shows that the serotonin responsive cell group can be individualized regarding their tonic discharge-mode in response to a direct current injection, their lower expression of hyperpolarization-activated cation current and their low membrane capacities. The use of ion channel blockers and ramp voltage protocol indicate that serotoninergic depolarization of juxtaglomerular cells may be due to a nonselective cation current with a reversal potential of −44 mV. Pharmacological tests with serotonin receptor antagonists and agonists reveal that 5HT action on juxtaglomerular cells would be mainly mediated by 5HT 2C receptors. In mitral cells, serotonin acts on 49.1% of the 242 tested cells, inducing two types of responses. A first subset of mitral cells (26.8%, n=65) were hyperpolarized by serotonin. This response would be indirect and mediated by action of GABA on GABA A receptors since it was antagonized by bicuculline. The involved GABAergic neurons are hypothesized to be juxtaglomerular and granular cells, on which serotonin would act mainly via 5HT 2C and via 5HT 2A receptors respectively. The second subset of mitral cells (22.3%, n=54) were directly depolarized by serotonin acting through 5HT 2A receptors. Our data on serotonin action on juxtaglomerular cells and mitral cells reveal a part of functional mechanisms whereby serotonin can act on olfactory bulb network. This is expected to enrich the understanding of its determining role in olfactory learning.

Simultaneous Single Unit Recording in the Mitral Cell Layer of the Rat Olfactory Bulb under Nasal and Tracheal Breathing

Odor perception depends on the odorant-evoked changes on Mitral/Tufted cell firing pattern within the olfactory bulb (OB). The OB exhibits a significant "ongoing" or spontaneous activity in the absence of sensory stimulation. We characterized this ongoing activity by simultaneously recording several single neurons in the mitral cell layer (MCL) of anesthetized rats and determined the extent of synchrony and oscillations under nasal and tracheal breathing. We recorded 115 neurons and found no significant differences in the mean firing rates between both breathing conditions. Surprisingly, nearly all single units exhibited a long refractory period averaging 14.4 ms during nasal respiration that was not different under tracheal breathing. We found a small incidence (2% of neurons) of gamma band oscillations and a low incidence (8.1%) of correlated firing between adjacent MCL cells. During nasal respiration, a significant oscillation at the respiratory rate was observed in 12% of cells that disappeared during tracheal breathing. Thus, in the absence of odorants, MCL cells exhibit a long refractory period, probably reflecting the intrinsic OB network properties. Furthermore, in the absence of sensory stimulation, MCL cell discharge does not oscillate in the gamma band and the respiratory cycle can modulate the firing of these cells.

Dendrodendritic inhibition and simulated odor responses in a detailed olfactory bulb network model.

In the olfactory bulb, both the spatial distribution and the temporal structure of neuronal activity appear to be important for processing odor information, but it is currently impossible to measure both of these simultaneously with high resolution and in all layers of the bulb. We have developed a biologically realistic model of the mammalian olfactory bulb, incorporating the mitral and granule cells and the dendrodendritic synapses between them, which allows us to observe the network behavior in detail. The cell models were based on previously published work. The attributes of the synapses were obtained from the literature. The pattern of synaptic connections was based on the limited experimental data in the literature on the statistics of connections between neurons in the bulb. The results of simulation experiments with electrical stimulation agree closely in most details with published experimental data. This gives confidence that the model is capturing features of network interactions in the real olfactory bulb. The model predicts that the time course of dendrodendritic inhibition is dependent on the network connectivity as well as on the intrinsic parameters of the synapses. In response to simulated odor stimulation, strongly activated mitral cells tend to suppress neighboring cells, the mitral cells readily synchronize their firing, and increasing the stimulus intensity increases the degree of synchronization. Preliminary experiments suggest that slow temporal changes in the degree of synchronization are more useful in distinguishing between very similar odorants than is the spatial distribution of mean firing rate.