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Odorant-Evoked Responses of Juxtaglomerular Neurons in the Mammalian Olfactory Bulb

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Odorant-Evoked Responses of Juxtaglomerular Neurons in the Mammalian Olfactory Bulb * Manuscript Odorant-evoked responses of juxtaglomerular neurons in the mammalian olfactory bulb. RUNNING TITLE: Organization of juxtaglomer ular odorant responses. R. Homma2,3, L.B. Cohen2,3,#, A. Konnerth1, O. Garaschuk1,*,# 1Institute of Neuroscience, Technical University Munich, 80802 Munich, Germany, 2Dept. of Physiology, Yale University, New Haven, CT, 06510, USA, 3NeuroImaging Cluster, Marine Biological Laboratory, Woods Hole, MA, 02543, USA. * Present address: Institute of Physiology Department II, Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany. #Address for correspondence: Lawrence B. Cohen Dept. of Physiology, Yale University, New Haven, CT, 06510, USA E-mail: [email protected] #Olga Garaschuk Institute of Physiology Department II, Eberhard Karls Universität Tübingen, Wilhelmstr. 27 72076 Tübingen, Germany. E-mail: [email protected] SUMMARY Anatomical observations suggest that juxtaglomerular neurons play a key role in shaping the input from olfactory receptor neurons in the mammalian olfactory bulb. However, their responses to odorants and the spatial organization of responsive neurons remain unclear. In in vivo recordings we show that individual mouse juxtaglomerular neurons code for many perceptual characteristics of the olfactory stimulus including odor identity, odorant concentration, odorant onset and offset, and odorant accommodation. Three basic response types were recognized, ON, OFF and INHIBITED. Monitoring a population of neurons revealed additional aspects of coding, such as the recruitment of new responding neurons as odorant concentration increased and clustering of neurons with similar response properties. Neurons with an ON response were closely clustered around glomeruli that also had an ON signal. Whereas some juxtaglomeruluar response features are directly triggered by the activity of olfactory receptor neurons, others have to be created by processing within the glomerular neuronal network. 2 INTRODUCTION The mammalian olfactory epithelium consists of a single layer of non-interacting olfactory receptor neurons that send their axons to glomerular neuropil in the olfactory bulb. It is in the bulb that the first stage of olfactory processing occurs. Extensive information about the time course and amplitude of the odorant evoked input to the dorsal bulb is available from measurements of calcium or synaptopHluorin in the receptor neuron nerve terminals (Wachowiak and Cohen, 2001; Bozza et al, 2004; Wachowiak et al 2004). What is now needed is information about the post-synaptic response in the bulb both at the level of individual neurons and at a glomerular scale. In the glomerular layer there are three major morphologically distinct classes of local interneurons – periglomerular cells, short-axon cells, and external tufted cells – they are collectively referred to as juxtaglomerular neurons. The information about odorants is transmitted from olfactory receptor neurons either directly or indirectly to these juxtaglomerular interneurons and to the principal neurons (mitral/tufted cells). In the mouse each glomerulus is surrounded by several hundred juxtaglomerular neurons with rich synaptic connections with each other and with the mitral/tufted cells. Synaptic interactions occur both within a glomerulus and in surrounding glomeruli (Shepherd et al, 2004). These juxtaglomerular neurons are presumed to play a significant but as yet undefined role in shaping the neural representation of odors. Previous electrophysiological measurements using in vitro slice preparations have revealed basic physiological characteristics and synaptic connections of some of the juxtaglomerular neurons (e.g. McQuiston et al, 2001; Aungst et al, 2003; Hayer et al., 2004). However, very little is known how these juxtaglomerular neurons respond to odorants and where they are located relative to activated glomeruli. Because of their relatively small cell body size, microelectrode recordings of odor-evoked responses have been reported from only four juxtaglomerular neurons (Wellis and Scott, 1990; Scott, 1991). These four were thought to be periglomerular neurons. All four cells responded with bursts of action potentials to the onset of odorant presentation. Adaptation/desensitization of the response to a repeated odorant presentation was observed in three of the four recorded cells. Two of the cells were spontaneously active and one was silent. A recent in vivo study (Petzold et al, 2008) have reported robust increases in the intracellular calcium concentration in juxtaglomerular neurons in response to odorant stimulation emphasizing the important role of these neurons in the olfactory processing. Here we combined the multi-cell bolus-loading technique (MCBL, Stosiek et al, 2003; Garaschuk et al, 2006b) and in vivo two-photon imaging to measure simultaneously the odorant-evoked Ca2+ signals of hundreds of juxtaglomerular neurons in each preparation. 3 Previous in vivo studies have shown that such somatic Ca2+ signals are often directly proportional to the number of action potentials fired by a cell (Kerr et al., 2005; Yaksi et al., 2006; Garaschuk et al, 2006a, but see Lin et al, 2007). RESULTS In vivo identification of cells and glomeruli Using the multi-cell bolus-loading technique (Fig. 1A, green), we stained the cells and processes within a spherical volume with a diameter of approximately 300 µm. Stained tissue included the cell bodies of the juxtaglomerular neurons and glial cells and the processes of juxtaglomerular neurons, mitral/tufted cells, glial cells and the axons and nerve terminals of both the olfactory receptor neurons and neurons providing centrifugal input from higher olfactory centers (Shepherd et al., 2004). Fig. 1B shows examples of the images obtained in a preparation that was stained with two dyes, bolus loading with Oregon Green 488 BAPTA-1 AM (OGB-1) and nasal staining (Fig. 1A, red; Wachowiak and Cohen, 2001) with Alexa Fluor 594 dextran. OGB-1 staining showed regions with densely packed cell bodies and cell body free oval-shaped regions that correspond to glomeruli (Fig.1B, Oregon Green 488 BAPTA-1 AM). Alexa Fluor 594 dextran injected into the nose selectively stained the axons and terminals of olfactory receptor neurons. As expected, the terminals of Alexa Fluor 594-positive olfactory receptor neurons were found exclusively in the glomerular regions (Fig. 1B, merged image). In an effort to discriminate glial cells from neurons we attempted to label astrocytes with a cortical astrocyte marker, sulforhodamine 101 (Nimmerjahn et al., 2004). Surprisingly, using a protocol which reliably stains cortical astrocytes (Garaschuk et al, 2006b), we were unable to find any cells in the bulb labeled clearly with sulforhodamine 101. Even though sulforhodamine 101 failed to provide a label for the glial cells in the bulb, it seems most likely that the cellular calcium responses shown below originate from neurons because calcium signals generated in glial cells have longer latencies than the signals reported here (Ikegaya et al., 2005; Wang et al, 2006; Petzold et al, 2008; Schummers et al, 2008). Three basic types of odorant-evoked calcium signals in juxtaglomerular neurons Using frame rates of 5-10 Hz we measured odorant evoked calcium signals in 46 preparations. All of the results come from single trial recordings; signal averaging was not used. The traces are presented such that an increase in calcium concentration is shown as an upward deflection. Because the odorant was presented at random times relative to the respiratory cycle of the mouse, there is a variable latency between the onset of odorant presentation and the response. This occurs both from trial to trial and from presentation to presentation in trials with multiple odorant presentations. In some trials the modulation of odorant responses by individual breaths 4 can be seen. In the absence of odorant presentation the only calcium signals we observed were infrequent events, ~ 1/min; these were always associated with deep breaths and were not studied further. We were unable to detect signals that might have been associated with action potentials in spontaneously active cells. One limitation was the peak-to-peak noise of 5% to 20% in the ∆F/F measured from individual cells. Detection of spontaneous signals will also be compromised if the spontaneous spike rate is high compared to the time for the cell body calcium signal to return to the baseline (tau 300-800 ms; see Stosiek, et al 2003; Kerr, et al, 2005). Presentations of odorants elicited intracellular Ca2+ transients both in neuronal cell bodies (Figs. 2-5) and in glomeruli (Figs. 4, and 6). Fig. 2A and B illustrates recordings from five cells and from adjacent neuropil regions. Three of the five cells responded with an increase in calcium at the onset of each of the three presentations of the odorant (Fig. 2A). Cells with increases in calcium at odorant onset were termed ON cells. ON cells were the most common responding cells. The kinetics of the change in intracellular calcium in ON neurons varied substantially (e.g., cells 1 and 3 in Fig. 4C). Some ON cell responses were prolonged far beyond the odorant offset. The ON signals we measured (Figs. 2-5) were generally somewhat slower than the calcium signals measured with the same technique in principal neurons in the cortex (Stosiek, et al 2003; Kerr, et al, 2005). Increasing the time resolution of the recording to 200 Hz by using line scans (Figure 2D, right panel) did not result in faster signals (rise times
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