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Independent control of gamma and theta activity by distinct interneuron networks in the olfactory bulb

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Abstract

Circuits in the brain possess the ability to orchestrate activities on different timescales, but the manner in which distinct circuits interact to sculpt diverse rhythms remains unresolved. The olfactory bulb is a classic example of a place in which slow theta and fast gamma rhythms coexist. Furthermore, inhibitory interneurons that are generally implicated in rhythm generation are segregated into distinct layers, neatly separating local and global motifs. We combined intracellular recordings in vivo with circuit-specific optogenetic interference to examine the contribution of inhibition to rhythmic activity in the mouse olfactory bulb. We found that the two inhibitory circuits controlled rhythms on distinct timescales: local, glomerular networks coordinated theta activity, regulating baseline and odor-evoked inhibition, whereas granule cells orchestrated gamma synchrony and spike timing. Notably, granule cells did not contribute to baseline rhythms or sniff-coupled odor-evoked inhibition. Thus, activities on theta and gamma timescales are controlled by separate, dissociable inhibitory networks in the olfactory bulb.

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Figure 1: Efficiency and specificity of optogenetic silencing of granule cells in vitro and in vivo.
Figure 2: Glomerular layer inhibition structures the baseline theta rhythm.
Figure 3: Sniff coupling of distinct JGC populations.
Figure 4: GL inhibition, rather than GC lateral inhibition, underlies slow odor-evoked inhibition.
Figure 5: Feedforward circuit in the GL likely mediates the evoked inhibition.
Figure 6: Granule cells coordinate neuronal activities on a fast timescale.
Figure 7: GCs contribute to fast, but not slow, activities in awake animals.

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  • 22 July 2014

    In the version of this article initially published, the first construct under "Virus generation and stereotaxic injections" in the Online Methods was given as AAV-EF1A-DIO-Chr2-GFP. The correct construct is AAV-EF1A-DIO-Chr2-EYFP. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank M. Kaiser, E. Stier and G. Matthies for technical assistance, A. Balz and S. Martin for stereotactic injections, S. Belanca for morphological reconstructions, J. Reinert for virus characterization, A. Schmaltz and M. Abdelhamid for help with setting up the head-fixed awake preparation, G. Giese and A. Scherbarth for glass brain preparation and imaging, B. Lowell, L. Vong and V. Murthy (Harvard University) for providing Vgat-IRES-Cre knock-in mice, R. Sprengel (MPI for Medical Research) for the Cre antibody, T. Margrie, T. Cleland and W. Denk for discussion, and T. Margrie, D. Burdakov, H. Monyer, R. Jordan, A. Grabska-Barwiń´ska and M. Helmstaedter for comments on earlier versions of the manuscript. This work was supported by the Max Planck Society, the DFG-SPP1392, the Federal Ministry of Education and Research (US-German collaboration computational neuroscience), the Alexander von Humbold Foundation (AvH), the Medical Research Council (MC_UP_1202/5), the ExcellenzCluster CellNetworks, and the Gottschalk foundation.

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Authors and Affiliations

Authors

Contributions

I.F. and A.T.S. conceived and designed the experiments and wrote the paper with inputs from all authors. I.F. performed in vivo experiments in anesthetized and awake animals. J.H. performed in vitro physiology experiments and made and characterized AAV. M.K. contributed data from awake animals. E.S.B. provided ArchT viral constructs and assisted with the design of the optogenetic experiments.

Corresponding authors

Correspondence to Izumi Fukunaga or Andreas T Schaefer.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Schematic of how inhibition in the OB structures the timing of activities.

(a) Simplified OB circuitry: glutamatergic inputs from the olfactory nerve (ON) are transmitted to principal neurons within glomeruli in the glomerular layer (GL). In the GL, juxtaglomerular cells (JGC) mediate largely local inhibition. Granule cells (GC) in the granule cell layer (GCL) inhibit the lateral dendrites of principal neurons across larger distances. (b) Inhibition in the OB establishes a phase-shift in sniff-coupled activities between MCs (pink) and TCs (blue) at rest16. Gray trace (bottom) represents the nasal airflow, with lighter gray indicating inhalation. (c) Odor presentation frequently results in slow inhibition of M/TCs13,19,20,34, causing a pause in their action potential discharge. (d) Faster, gamma range activities in the OB or its insect analogue are evoked by odors and require inhibition4,10,11. (e) Schematic of the finding. Glomerular layer interneurons (orange) structure activities on the theta timescale, setting phase preferences and modulate amplitudes of sniff-coupled activities. Theta activities are regulated during baseline period, as well as during responses to odors. Activities on a faster timescale, here in the gamma frequency range, are observed often nested in theta rhythms, and are controlled by the circuits in the granule cell layer (blue). Thus the OB outputs are highly regulated in both theta and gamma range frequencies by actions of dissociable circuits in the glomerular layer and GC layer.

Supplementary Figure 2 GC silencing at different depths.

Optogenetic manipulations in vivo require light to penetrate thicker tissues to achieve sufficiently high light intensities at relevant light activatable receptors. Plots here show light evoked Vm deviation in GCs recorded at various depths (vertical distance from the OB surface) for Gad2-Cre animals (anaesthetized) and Vgat-Cre animals (awake, head-fixed) injected into the GCL with AAV-FLEX-ArchT. Each data point corresponds to one GC.

Supplementary Figure 3 Sniff-coupled inhibition is reduced with glomerular layer silencing in both Gad2-Cre and Vgat-Cre mice.

(a) Example of local infection with glomerular injection of AAV-FLEX-ArchT in a Gad2-Cre animal. Scale bars = 1 mm (left) and 0.1 mm (right). Less than <0.05% of GCL interneurons were infected with glomerular injection (n = 2 OB). (b) Example high-resolution image from another animal. (c) Odor-evoked hyperpolarization under control (odor only) conditions and with light application (+LED) in Gad2-Cre (blue; n = 3 cells) and Vgat-Cre (brown; n = 4 cells) animals with glomerular layer injection of AAV-FLEX-ArchT.

Supplementary Figure 4 Possible involvement of GL feedforward circuit in evoked inhibition.

(a) An example recording from an M/TC, where an odor evoked inhibition. Pink arrowhead indicates the preferred phase of hyperpolarization for this example cell. The dotted line indicates the onset of first inhalation after valve opening. Sniff cycle 1 is the first complete cycle after the opening of the odor valve. (b) An example of whole-cell recording from a PGo with an excitatory response to an odor. Pink arrowhead is the preferred phase of M/TC hyperpolarization as in (a). PGo was identified as described in Fig 3. (c) Summary PSTH from all action potential times recorded from all PGo cell – odor pairs where an excitatory response was observed (n= 3 PGo cells). Time = 0 is the inhalation onset. Pink arrowhead is the preferred phase of M/TC hyperpolarization as in (a). (d) Polar histogram of individual AP phase from the 3 PGo cells. The range shown in pink is the preferred phase of inhibition evoked in all M/TCs (n=31 cells) during sniff cycle 1 (a). Ticks indicate the 25, 50 & 75 percentiles. Scale bar = π/6 radians, corresponding to 33.7 ms when calibrated to the average sniff cycle length. (e) In some cells, as shown in this example, increasing the concentration of odor that at low concentrations evoked hyperpolarization resulted in emergence of excitatory responses. No drugs were applied for this experiment. Values on the left are the concentrations of isoamylacetate presented (% of saturated vapour). (f) Data from Fig 5b is replotted, also as histograms (blue = hyperpolarizing response during control; black = no detectable response during control). (g) Histogram of evoked Vm in M/TCs recorded only in the GABAA-clamp condition, without paired control showing similar distribution to (f). (h) Conversion to depolarization in GABAA-clamp was often strong enough to elicit action potentials. Cell-odor pairs here showed evoked inhibition during control. n = 11 cells (same cells and odor as in Fig 5b). Each data point is the average of 2-6 repeated trials. (i) Top: Two example cells with odor-evoked activity during control and GABAA-clamp. Below: Relationship of odor-evoked depolarization/hyperpolarization between control and GABAA-clamp. Note the inverse relationship between responses evoked during control and unmasked with GABAA-clamp. r = -0.56, p = 0.01, n = 20 cells.

Supplementary Figure 5 Fast inhibitory transients are reduced during GCL silencing.

(a) Experimental configuration: whole-cell recordings were made in vitro from MCs in OB slices cut from Gad2-Cre animals with GC layer injection of AAV- FLEX-ArchT. Depolarising current was injected to elicit bursts of APs in MCs, which evoke recurrent inhibition in the recorded cell. (b) In addition to slow recurrent hyperpolarization, individual, fast recurrent IPSPs can be resolved (detected events indicated by gray arrowheads). (c) Same cell and conditions as in (b) but with light-evoked silencing of GCs. (+LED, green). Scale bars = 1 mV, 10 ms. (d) Summary histograms of the change in IPSP count due to light-mediated GCL silencing. (n = 25 cells).

Supplementary Figure 6 GC silencing does not cause significant change in firing rates.

(a) Experimental configuration: odors were presented to anaesthetized Vgat-Cre mice injected with AAV-FLEX-ArchT into the GC layer while whole-cell recordings from TCs were made. GCs were silenced for intermittent trials. (b) Examples of evoked depolarizing response to odor during control condition (above, black trace) and during GC silencing (below, green). Scale bars = 5 mV, 50 ms, same example as in Fig. 6e,f on a magnified scale. (c) Scatter plot of instantaneous firing rates for control (black dots) and during GC silencing (green). Each dot is the reciprocal of the interval between an action potential that occurs at time indicated (x axis) and the next action potential, in Hz. (Same cell as in b, n = 6 trials each for control and +LED). (d) Histogram of instantaneous firing rates for all cells (n = 9 TCs; the same as shown in Fig. 6). (e) Summary data showing average instantaneous firing rate for individual cells.

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Supplementary Figures 1–6 (PDF 2342 kb)

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Extent of GCL infection imaged with light sheet.

Extent of GFP expression following GCL injection in the left olfactory bulb was imaged in a cleared tissue using a light sheet microscopy (courtesy of Guenter Giese and AnneMarie Scherbarth). Image was taken every 5 m to produce this z-stack. (MOV 5311 kb)

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Fukunaga, I., Herb, J., Kollo, M. et al. Independent control of gamma and theta activity by distinct interneuron networks in the olfactory bulb. Nat Neurosci 17, 1208–1216 (2014). https://doi.org/10.1038/nn.3760

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