Mitral cell spike synchrony modulated by dendrodendritic synapse location

On their long lateral dendrites, mitral cells of the olfactory bulb form dendrodendritic synapses with large populations of granule cell interneurons. The mitral-granule cell microcircuit operating through these reciprocal synapses has been implicated in inducing synchrony between mitral cells. However, the specific mechanisms of mitral cell synchrony operating through this microcircuit are largely unknown and are complicated by the finding that distal inhibition on the lateral dendrites does not modulate mitral cell spikes. In order to gain insight into how this circuit synchronizes mitral cells within its spatial constraints, we built on a reduced circuit model of biophysically realistic multi-compartment mitral and granule cells to explore systematically the roles of dendrodendritic synapse location and mitral cell separation on synchrony. The simulations showed that mitral cells can synchronize when separated at arbitrary distances through a shared set of granule cells, but synchrony is optimally attained when shared granule cells form two balanced subsets, each subset clustered near to a soma of the mitral cell pairs. Another constraint for synchrony is that the input magnitude must be balanced. When adjusting the input magnitude driving a particular mitral cell relative to another, the mitral-granule cell circuit served to normalize spike rates of the mitral cells while inducing a phase shift or delay in the more weakly driven cell. This shift in phase is absent when the granule cells are removed from the circuit. Our results indicate that the specific distribution of dendrodendritic synaptic clusters is critical for optimal synchronization of mitral cell spikes in response to their odor input

Dendrodendritic synapses in the mouse olfactory bulb external plexiform layer

Odor information relayed by olfactory bulb projection neurons, mitral and tufted cells (M/T), is modulated by pairs of reciprocal dendrodendritic synaptic circuits in the external plexiform layer (EPL). Interneurons, which are accounted for largely by granule cells, receive depolarizing input from M/T dendrites and in turn inhibit current spread in M/T dendrites via hyperpolarizing reciprocal dendrodendritic synapses. Because the location of dendrodendritic synapses may significantly affect the cascade of odor information, we assessed synaptic properties and density within sublaminae of the EPL and along the length of M/T secondary dendrites. In electron micrographs the M/T to granule cell synapse appeared to predominate and was equivalent in both the outer and inner EPL. However, the dendrodendritic synapses from granule cell spines onto M/T dendrites were more prevalent in the outer EPL. In contrast, individual gephyrin-immunoreactive (IR) puncta, a postsynaptic scaffolding protein at inhibitory synapses used here as a proxy for the granule to M/T dendritic synapse was equally distributed throughout the EPL. Of significance to the organization of intrabulbar circuits, gephyrin-IR synapses are not uniformly distributed along M/T secondary dendrites. Synaptic density, expressed as a function of surface area, increases distal to the cell body. Furthermore, the distributions of gephyrin-IR puncta are heterogeneous and appear as clusters along the length of the M/T dendrites. Consistent with computational models, our data suggest that temporal coding in M/T cells is achieved by precisely located inhibitory input and that distance from the soma is compensated for by an increase in synaptic density.Fil: Bartel, Dianna L.. University Of Yale. School Of Medicine; Estados UnidosFil: Rela, Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Hsieh, Lawrence. University Of Yale. School Of Medicine; Estados UnidosFil: Greer, Charles A. . University Of Yale. School Of Medicine; Estados Unido

Presynaptic T-Type Ca²⁺ Channels Modulate Dendrodendritic Mitral–Mitral and Mitral–Periglomerular Connections in Mouse Olfactory Bulb

Mitral cells express low-voltage activated Cav3.3 channels on their distal apical tuft dendrites (McKay et al., 2006; Johnston and Delaney, 2010). They also discharge Na -dependent dendritic action potentials and release glutamate from these dendrites. Around resting membrane potentials, between 65 and 50 mV, Cav3.x channels are a primary determinant of cytoplasmic [Ca 2 ]. In this study using C57 mice, we present evidence that subthreshold Cav3.x-mediated Ca 2 influx modulates action potential evoked transmitter release and directly drives asynchronous release from distal tuft dendrites. Presynaptic hyperpolarization and selective block of Cav3.x channels with Z941 (Tringham et al., 2012) reduce mitral-to-mitral EPSP amplitude, increase the coefficient of variation of EPSPs, and increase paired-pulse ratios, consistent with a reduced probability of transmitter release. Both hyperpolarization and Cav3.x channel blockade reduce steady-state cytoplasmic [Ca 2 ] in the tuft dendrite without reducing action potential evoked Ca 2 influx, suggesting that background [Ca 2 ] modulates evoked release. We demonstrate that Cav3.x-mediated Ca 2 influx from even one mitral cell at membrane potentials between 65 and 50 mV is sufficient to produce feedback inhibition from periglomerular neurons. Deinactivation of Cav3.x channels by hyperpolarization increases T-type Ca 2 influx upon repolarization and increases feedback inhibition to produce subthreshold modulation of the mitral-periglomerular reciprocal circuit

Distributed organization of a brain microcircuit analyzed by three-dimensional modeling : the olfactory bulb

The functional consequences of the laminar organization observed in cortical systems cannot be easily studied using standard experimental techniques, abstract theoretical representations, or dimensionally reduced models built from scratch. To solve this problem we have developed a full implementation of an olfactory bulb microcircuit using realistic three-dimensional (3D) inputs, cell morphologies, and network connectivity. The results provide new insights into the relations between the functional properties of individual cells and the networks in which they are embedded. To our knowledge, this is the first model of the mitral-granule cell network to include a realistic representation of the experimentally-recorded complex spatial patterns elicited in the glomerular layer (GL) by natural odor stimulation. Although the olfactory bulb, due to its organization, has unique advantages with respect to other brain systems, the method is completely general, and can be integrated with more general approaches to other systems. The model makes experimentally testable predictions on distributed processing and on the differential backpropagation of somatic action potentials in each lateral dendrite following odor learning, providing a powerful 3D framework for investigating the functions of brain microcircuits

Glomerular and mitral-granule cell microcircuits coordinate temporal and spatial information processing in the olfactory bulb

The olfactory bulb processes inputs from olfactory receptor neurons (ORNs) through two levels: the glomerular layer at the site of input, and the granule cell level at the site of output to the olfactory cortex. The sequence of action of these two levels has not yet been examined. We analyze this issue using a novel computational framework that is scaled up, in three-dimensions (3D), with realistic representations of the interactions between layers, activated by simulated natural odors, and constrained by experimental and theoretical analyses. We suggest that the postulated functions of glomerular circuits have as their primary role transforming a complex and disorganized input into a contrast-enhanced and normalized representation, but cannot provide for synchronization of the distributed glomerular outputs. By contrast, at the granule cell layer, the dendrodendritic interactions mediate temporal decorrelation, which we show is dependent on the preceding contrast enhancement by the glomerular layer. The results provide the first insights into the successive operations in the olfactory bulb, and demonstrate the significance of the modular organization around glomeruli. This layered organization is especially important for natural odor inputs, because they activate many overlapping glomeruli

Towards Brains in the Cloud: A Biophysically Realistic Computational Model of Olfactory Bulb

abstract: The increasing availability of experimental data and computational power have resulted in increasingly detailed and sophisticated models of brain structures. Biophysically realistic models allow detailed investigations of the mechanisms that operate within those structures. In this work, published mouse experimental data were synthesized to develop an extensible, open-source platform for modeling the mouse main olfactory bulb and other brain regions. A “virtual slice” model of a main olfactory bulb glomerular column that includes detailed models of tufted, mitral, and granule cells was created to investigate the underlying mechanisms of a gamma frequency oscillation pattern (“gamma fingerprint”) often observed in rodent bulbar local field potential recordings. The gamma fingerprint was reproduced by the model and a mechanistic hypothesis to explain aspects of the fingerprint was developed. A series of computational experiments tested the hypothesis. The results demonstrate the importance of interactions between electrical synapses, principal cell synaptic input strength differences, and granule cell inhibition in the formation of the gamma fingerprint. The model, data, results, and reproduction materials are accessible at https://github.com/justasb/olfactorybulb. The discussion includes a detailed description of mechanisms underlying the gamma fingerprint and how the model predictions can be tested experimentally. In summary, the modeling platform can be extended to include other types of cells, mechanisms and brain regions and can be used to investigate a wide range of experimentally testable hypotheses.Dissertation/ThesisDoctoral Dissertation Neuroscience 201

Intratraglomerular communication in the mammalian olfactory bulb.

The olfactory bulb (OB) is the first processing structure in the olfactory system it receives direct sensory input from the olfactory sensory neurons and relays processed information to the olfactory cortex and other structures in the brain. The axons from sensory neurons expressing the same olfactory receptor molecule converge onto the same discrete structure on the surface of the OB, termed glomerulus. Each glomerulus forms a modular unit which confines the single apical tufts of about 25 mitral cells (MC). Understanding how intraglomerular cells communicate with one another will therefore improve our understanding of how the glomerular network processes the olfactory signal. Using whole cell recordings from mitral cells in acute mouse olfactory bulb slices I have examined various modes of MC-MC communication. MC dendrites are known to release glutamate from their apical and lateral dendrites which has been shown to depolarize their own presynaptic dendrites (self excitation SE). I first examined the anatomical locus of SE by investigating its properties in intact versus dendrotomized (those with amputated tufts) MCs. While dendrotomized cells lacked detectable self excitatory potentials I have found that all morphologically identified MCs with an intact apical tuft displayed robust SE. This form of SE was mediated by Ca2+ permeable AMPA receptors as it was completely blocked by their specific antagonist Naphthyl-acethyl-spermine (NAS). Electrical coupling between MCs was assessed by injecting large hyperpolarizing pulses. I have found that MCs that shared the same glomerulus were always bidirectionally coupled via gap junctions though the magnitude of coupling (CC) was variable across different pairs. Action potentials evoked in one MC also results in EPSP-like depolarizations in intraglomerular partners (lateral excitation LE). In contrast to the previously mentioned forms of communication LE was not reliably present in all intraglomerular pairs. I have found LE is mainly a unidirectional form of communication, although both bidirectional and complete lack of measurable LE can also occur. The magnitude of LE varied independently of that of other forms of communication (CC and SE amplitude) as well as with morphometric characteristics of the apical tufts (number of nodes, surface area). Despite being dependent on glutamate receptors LE contrasted with SE in that it was insensitive to NAS and therefore is a distinct form of chemical communication that relies on different AMPA receptor subtypes. I have also investigated whether in vivo-relevant patterns of theta-burst stimulation (TBS) could evoke significant long-term changes in LE efficacy similar to those observed at axo-dendritic connections. This form of communication showed a unique sensitivity to TBS in that the polarity and amplitude of change in efficacy was linearly and inversely correlated with the initial strength of LE. Small connections were enhanced while larger ones depressed, the change in efficacy was accompanied with a change in paired pulse ratio consistent with a presynaptic change in release probability after TBS. All together these data show that SE, electrical coupling and LE are independent forms of intraglomerular communication which might serve independent roles on glomerular processing. While SE and electrical coupling have been shown to facilitate spike synchrony across the network, LE provides the OB with a means of modulating intraglomerular excitation in response to in vivo -relevant patterns of activity

LOCAL AND TOP-DOWN REGULATION OF OLFACTORY BULB CIRCUITS

The olfactory bulb (OB) is the first place in the brain where chemosensory processing occurs. The neurophysiological mechanisms underlying these processes are mostly driven by inhibition, which is implemented by a large population of local inhibitory neurons, and among them, the granule cell (GCs) is the most prominent type. Local inhibitory interneurons sculpt the coding of output neurons, affecting odor detection, discrimination, and learning. Therefore, the regulation of inhibitory circuits is critical to OB function and fine-tuning OB output. Specifically, inhibitory tone in the OB can be regulated by the dynamic interactions between cell-intrinsic factors affecting neuronal excitability and extrinsic top-down modulation associated with an animal’s behavioral state. Here, I provide new evidence for intrinsic mechanisms governing inhibitory interneuron excitability in the OB and how modulation by noradrenaline works in concert with these intrinsic mechanisms to affect circuit function. This work highlights circuit- and cell-specific differences in noradrenergic modulation with regards to short- and long-term plasticity within OB circuits

Dendritic neurotransmitter release and its modulation in accessory olfactory bulb circuits

Dendrites are classically regarded as the brain's "listeners," while neuronal output is thought to be the exclusive privilege of the axon. Although we now appreciate the complexity of dendritic integration, the role of dendrites as output structures has received less attention. This is becoming an increasingly important topic, as the list of cell types with release competent dendrites continues to grow. One boon of coupling dendritic activity to dendritic release is that outputs from a single neuron - typically thought to occur from fixed sites with stereotyped dynamics - may occur for signals of varying spatial extent, timecourse, and release efficacy. In essence, dendritic output may "inherit" the same diversity characteristic of events in excitable dendrites. Here I studied dendritic transmitter output and its modulation in cells of the accessory olfactory bulb - a CNS structure critical for processing species-specific chemical signals called pheromones. Because of the stereotypy of its inputs, the prevalence of dendritic transmitter release from its cells, and its well-defined outputs, the AOB offers a superb model system for studying the integrative and output properties of dendrites. I first characterized basic excitable properties of the apical dendrites of mitral cells (the principal AOB neurons), and observed that they conduct non-decremental action potentials (APs). In addition to APs, these dendrites were also found to support compartmentalized, synaptically-evoked calcium spikes. Both APs and local spikes were triggers of dendritic glutamate release and feedback inhibition, suggesting that neuronal output can be flexibly routed to particular populations of postysynaptic cells. I next asked whether the relative efficacy of particular dendritic events as triggers of transmitter release can be altered, as this could provide an additional level of control over single neuron output. I found that metabotropic glutamate receptors (mGluRs) play a key role in controlling dendritic output from AOB mitral cells and an obligatory role in concomitant feedback inhibition. This work culminates with the demonstration of a new principle of neuronal signaling: the ability of mGluRs to gate a transition between phasic and tonic dendritic transmitter release. Taken in total, these results extend our understanding of how the outputs from single neurons are controlled