Developmental broadening of inhibitory sensory maps

Abstract

Sensory maps are created by networks of neuronal responses that vary with their anatomical position, such that representations of the external world are systematically and topographically organized in the brain. Current understanding from studying excitatory maps is that maps are sculpted and refined throughout development and/or through sensory experience. Investigating the mouse olfactory bulb, where ongoing neurogenesis continually supplies new inhibitory granule cells into existing circuitry, we isolated the development of sensory maps formed by inhibitory networks. Using in vivo calcium imaging of odor responses, we compared functional responses of both maturing and established granule cells. We found that, in contrast to the refinement observed for excitatory maps, inhibitory sensory maps became broader with maturation. However, like excitatory maps, inhibitory sensory maps are sensitive to experience. These data describe the development of an inhibitory sensory map as a network, highlighting the differences from previously described excitatory maps.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Genetically targeting populations of granule cells in the adult olfactory bulb.
Figure 2: Comparison of membrane and firing properties of functionally immature Dlx5/6 versus functionally mature Crhr1 granule cells.
Figure 3: Olfactory sensory maps from different populations of olfactory bulb neurons visualized through calcium imaging.
Figure 4: Inhibitory sensory maps broaden with maturation.
Figure 5: Mature granule cells show recruitment over refinement of synaptic inputs.
Figure 6: Individual granule cells respond to more odors with maturation.
Figure 7: Decreased sensory experience prevents sensory map expansion.
Figure 8: Olfactory learning precociously expands inhibitory sensory maps.

References

  1. 1

    Markram, H. et al. Interneurons of the neocortical inhibitory system. Nat. Rev. Neurosci. 5, 793–807 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Cang, J. & Feldheim, D.A. Developmental mechanisms of topographic map formation and alignment. Annu. Rev. Neurosci. 36, 51–77 (2013).

    CAS  Article  Google Scholar 

  3. 3

    Iwasato, T. et al. NMDA receptor-dependent refinement of somatotopic maps. Neuron 19, 1201–1210 (1997).

    CAS  Article  Google Scholar 

  4. 4

    Gordon, J.A. & Stryker, M.P. Experience-dependent plasticity of binocular responses in the primary visual cortex of the mouse. J. Neurosci. 16, 3274–3286 (1996).

    CAS  Article  Google Scholar 

  5. 5

    Ackman, J.B., Burbridge, T.J. & Crair, M.C. Retinal waves coordinate patterned activity throughout the developing visual system. Nature 490, 219–225 (2012).

    CAS  Article  Google Scholar 

  6. 6

    Kakizawa, S., Yamasaki, M., Watanabe, M. & Kano, M. Critical period for activity-dependent synapse elimination in developing cerebellum. J. Neurosci. 20, 4954–4961 (2000).

    CAS  Article  Google Scholar 

  7. 7

    White, J.J. et al. Cerebellar zonal patterning relies on Purkinje cell neurotransmission. J. Neurosci. 34, 8231–8245 (2014).

    Article  Google Scholar 

  8. 8

    Thivierge, J.P. & Marcus, G.F. The topographic brain: from neural connectivity to cognition. Trends Neurosci. 30, 251–259 (2007).

    CAS  Article  Google Scholar 

  9. 9

    Taniguchi, H. et al. A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron 71, 995–1013 (2011).

    CAS  Article  Google Scholar 

  10. 10

    Murphey, D.K., Herman, A.M. & Arenkiel, B.R. Dissecting inhibitory brain circuits with genetically-targeted technologies. Front. Neural Circuits 8, 124 (2014).

    Article  Google Scholar 

  11. 11

    Sohya, K., Kameyama, K., Yanagawa, Y., Obata, K. & Tsumoto, T. GABAergic neurons are less selective to stimulus orientation than excitatory neurons in layer II/III of visual cortex, as revealed by in vivo functional Ca2+ imaging in transgenic mice. J. Neurosci. 27, 2145–2149 (2007).

    CAS  Article  Google Scholar 

  12. 12

    Kerlin, A.M., Andermann, M.L., Berezovskii, V.K. & Reid, R.C. Broadly tuned response properties of diverse inhibitory neuron subtypes in mouse visual cortex. Neuron 67, 858–871 (2010).

    CAS  Article  Google Scholar 

  13. 13

    Cazakoff, B.N., Lau, B.Y., Crump, K.L., Demmer, H.S. & Shea, S.D. Broadly tuned and respiration-independent inhibition in the olfactory bulb of awake mice. Nat. Neurosci. 17, 569–576 (2014).

    CAS  Article  Google Scholar 

  14. 14

    Fino, E. & Yuste, R. Dense inhibitory connectivity in neocortex. Neuron 69, 1188–1203 (2011).

    CAS  Article  Google Scholar 

  15. 15

    Nusser, Z., Kay, L.M., Laurent, G., Homanics, G.E. & Mody, I. Disruption of GABAA receptors on GABAergic interneurons leads to increased oscillatory power in the olfactory bulb network. J. Neurophysiol. 86, 2823–2833 (2001).

    CAS  Article  Google Scholar 

  16. 16

    Lagier, S., Carleton, A. & Lledo, P.M. Interplay between local GABAergic interneurons and relay neurons generates gamma oscillations in the rat olfactory bulb. J. Neurosci. 24, 4382–4392 (2004).

    CAS  Article  Google Scholar 

  17. 17

    Sohal, V.S., Zhang, F., Yizhar, O. & Deisseroth, K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459, 698–702 (2009).

    CAS  Article  Google Scholar 

  18. 18

    Kuhlman, S.J., Tring, E. & Trachtenberg, J.T. Fast-spiking interneurons have an initial orientation bias that is lost with vision. Nat. Neurosci. 14, 1121–1123 (2011).

    CAS  Article  Google Scholar 

  19. 19

    Ohki, K., Chung, S., Ch'ng, Y.H., Kara, P. & Reid, R.C. Functional imaging with cellular resolution reveals precise micro-architecture in visual cortex. Nature 433, 597–603 (2005).

    CAS  Article  Google Scholar 

  20. 20

    Shepherd, G.M. The Synaptic Organization of the Brain 5th edn. (Oxford Univ. Press, 2004).

  21. 21

    Carleton, A., Petreanu, L.T., Lansford, R., Alvarez-Buylla, A. & Lledo, P.M. Becoming a new neuron in the adult olfactory bulb. Nat. Neurosci. 6, 507–518 (2003).

    CAS  Article  Google Scholar 

  22. 22

    Vassar, R. et al. Topographic organization of sensory projections to the olfactory bulb. Cell 79, 981–991 (1994).

    CAS  Article  Google Scholar 

  23. 23

    Mombaerts, P. et al. Visualizing an olfactory sensory map. Cell 87, 675–686 (1996).

    CAS  Article  Google Scholar 

  24. 24

    Belluscio, L. & Katz, L.C. Symmetry, stereotypy, and topography of odorant representations in mouse olfactory bulbs. J. Neurosci. 21, 2113–2122 (2001).

    CAS  Article  Google Scholar 

  25. 25

    Isaacson, J.S. & Strowbridge, B.W. Olfactory reciprocal synapses: dendritic signaling in the CNS. Neuron 20, 749–761 (1998).

    CAS  Article  Google Scholar 

  26. 26

    Margrie, T.W., Sakmann, B. & Urban, N.N. Action potential propagation in mitral cell lateral dendrites is decremental and controls recurrent and lateral inhibition in the mammalian olfactory bulb. Proc. Natl. Acad. Sci. USA 98, 319–324 (2001).

    CAS  Article  Google Scholar 

  27. 27

    Bozza, T., McGann, J.P., Mombaerts, P. & Wachowiak, M. In vivo imaging of neuronal activity by targeted expression of a genetically encoded probe in the mouse. Neuron 42, 9–21 (2004).

    CAS  Article  Google Scholar 

  28. 28

    Soucy, E.R., Albeanu, D.F., Fantana, A.L., Murthy, V.N. & Meister, M. Precision and diversity in an odor map on the olfactory bulb. Nat. Neurosci. 12, 210–220 (2009).

    CAS  Article  Google Scholar 

  29. 29

    Rubin, B.D. & Katz, L.C. Optical imaging of odorant representations in the mammalian olfactory bulb. Neuron 23, 499–511 (1999).

    CAS  Article  Google Scholar 

  30. 30

    Spors, H. & Grinvald, A. Spatio-temporal dynamics of odor representations in the mammalian olfactory bulb. Neuron 34, 301–315 (2002).

    CAS  Article  Google Scholar 

  31. 31

    Wachowiak, M. et al. Optical dissection of odor information processing in vivo using GCaMPs expressed in specified cell types of the olfactory bulb. J. Neurosci. 33, 5285–5300 (2013).

    CAS  Article  Google Scholar 

  32. 32

    Kohwi, M. et al. A subpopulation of olfactory bulb GABAergic interneurons is derived from Emx1- and Dlx5/6-expressing progenitors. J. Neurosci. 27, 6878–6891 (2007).

    CAS  Article  Google Scholar 

  33. 33

    Garcia, I. et al. Local CRH signaling promotes synaptogenesis and circuit integration of adult-born neurons. Dev. Cell 30, 645–659 (2014).

    CAS  Article  Google Scholar 

  34. 34

    Garcia, I. et al. Local corticotropin releasing hormone (CRH) signals to its receptor CRHR during postnatal development of the mouse olfactory bulb. Brain Struct. Funct. 221, 1–20 (2016).

    CAS  Article  Google Scholar 

  35. 35

    Chen, Q. et al. Imaging neural activity using Thy1-GCaMP transgenic mice. Neuron 76, 297–308 (2012).

    CAS  Article  Google Scholar 

  36. 36

    Chen, T.W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295–300 (2013).

    CAS  Article  Google Scholar 

  37. 37

    Shipley, M.T. & Adamek, G.D. The connections of the mouse olfactory bulb: a study using orthograde and retrograde transport of wheat germ agglutinin conjugated to horseradish peroxidase. Brain Res. Bull. 12, 669–688 (1984).

    CAS  Article  Google Scholar 

  38. 38

    Laaris, N., Puche, A. & Ennis, M. Complementary postsynaptic activity patterns elicited in olfactory bulb by stimulation of mitral/tufted and centrifugal fiber inputs to granule cells. J. Neurophysiol. 97, 296–306 (2007).

    CAS  Article  Google Scholar 

  39. 39

    Balu, R., Pressler, R.T. & Strowbridge, B.W. Multiple modes of synaptic excitation of olfactory bulb granule cells. J. Neurosci. 27, 5621–5632 (2007).

    CAS  Article  Google Scholar 

  40. 40

    Huang, L. et al. Task learning promotes plasticity of interneuron connectivity maps in the olfactory bulb. J. Neurosci. 36, 8856–8871 (2016).

    CAS  Article  Google Scholar 

  41. 41

    Cummings, D.M., Henning, H.E. & Brunjes, P.C. Olfactory bulb recovery after early sensory deprivation. J. Neurosci. 17, 7433–7440 (1997).

    CAS  Article  Google Scholar 

  42. 42

    Shepherd, G.M., Chen, W.R., Willhite, D., Migliore, M. & Greer, C.A. The olfactory granule cell: from classical enigma to central role in olfactory processing. Brain Res. Rev. 55, 373–382 (2007).

    Article  Google Scholar 

  43. 43

    Hensch, T.K. Critical period plasticity in local cortical circuits. Nat. Rev. Neurosci. 6, 877–888 (2005).

    CAS  Article  Google Scholar 

  44. 44

    Ehrlich, I. et al. Amygdala inhibitory circuits and the control of fear memory. Neuron 62, 757–771 (2009).

    CAS  Article  Google Scholar 

  45. 45

    Breton-Provencher, V., Lemasson, M., Peralta, M.R. III & Saghatelyan, A. Interneurons produced in adulthood are required for the normal functioning of the olfactory bulb network and for the execution of selected olfactory behaviors. J. Neurosci. 29, 15245–15257 (2009).

    CAS  Article  Google Scholar 

  46. 46

    Moreno, M.M. et al. Olfactory perceptual learning requires adult neurogenesis. Proc. Natl. Acad. Sci. USA 106, 17980–17985 (2009).

    CAS  Article  Google Scholar 

  47. 47

    Sakamoto, M. et al. Continuous postnatal neurogenesis contributes to formation of the olfactory bulb neural circuits and flexible olfactory associative learning. J. Neurosci. 34, 5788–5799 (2014).

    Article  Google Scholar 

  48. 48

    Alonso, M. et al. Olfactory discrimination learning increases the survival of adult-born neurons in the olfactory bulb. J. Neurosci. 26, 10508–10513 (2006).

    CAS  Article  Google Scholar 

  49. 49

    Mandairon, N. et al. Neurogenic correlates of an olfactory discrimination task in the adult olfactory bulb. Eur. J. Neurosci. 24, 3578–3588 (2006).

    Article  Google Scholar 

  50. 50

    Monory, K. et al. The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51, 455–466 (2006).

    CAS  Article  Google Scholar 

  51. 51

    Justice, N.J., Yuan, Z.F., Sawchenko, P.E. & Vale, W. Type 1 corticotropin-releasing factor receptor expression reported in BAC transgenic mice: implications for reconciling ligand-receptor mismatch in the central corticotropin-releasing factor system. J. Comp. Neurol. 511, 479–496 (2008).

    CAS  Article  Google Scholar 

  52. 52

    Arenkiel, B.R. et al. In vivo light-induced activation of neural circuitry in transgenic mice expressing channelrhodopsin-2. Neuron 54, 205–218 (2007).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We would like to thank A. Herman, C. Kim, H. Lu, D. Murphey, K. Schulze and R. Sillitoe for discussion and critical input on this manuscript. This work was supported by the McNair Medical Institute, the Charif Souki Fund, IRACDA Fellowship K12 GM084897 to K.Q., NRSA F31NS089178 to K.U., NINDS grant F31NS081805 to I.G., NINDS R01NS078294 to B.R.A., U54HD083092 to the BCM IDDRC, and the Intelligence Advanced Research Projects Activity (IARPA) via Department of Interior/Interior Business Center (DoI/IBC) contract number D16PC00003 to A.S.T. The US Government is authorized to reproduce and distribute reprints for Governmental purposes notwithstanding any copyright annotation thereon. Disclaimer: The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of IARPA, DoI/IBC or the US Government.

Author information

Affiliations

Authors

Contributions

K.B.Q. and B.R.A. designed the study, performed the analysis and wrote the manuscript. K.B.Q. performed most of the experiments. K.U. contributed to the behavior and wide-field imaging. E.F. and A.S.T. performed the two-photon experiments. L.H. performed the optogenetic mapping experiments on the AOD set up designed by L.H., K.C., P.S. and B.R.A. A.P.A., J.O.-G. and I.H. assisted with behavior, histology and surgeries.

Corresponding author

Correspondence to Benjamin R Arenkiel.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Stable cell morphology.

(a) Overview of olfactory bulb slices from Dlx5/6-Cre and Crhr1-Cre animals injected with high titer AAV-flex-GFP (Scale bar 500 μm). (b) Example GFP neuron outlines as traced in Neurolucida from immature Dlx5/6-Cre + AAV-flex-GFP (left) and mature Crhr1-Cre + AAV-flex-GFP (right) animals (Scale bar 50 μm). No significant changes in the size of the cell body (c), total apical dendrite length (d), number of basal dendrites (e) or the distance from the mitral cell layer (f). (data point represent individual cells, red line at the mean ±SEM).

Supplementary Figure 2 Viral GCaMP expression does not change the membrane properties of granule cells.

No significant changes between Dlx5/6 expressing neurons labeled with viral GFP or GCaMP6 measured by (a) membrane capacitance p = 0.1315, (b) membrane resistance p = 0.1626, (c) action potential half-width p = 0.9024, (d) frequency-current curves, (e) resting potential p = 0.4202, (f) current required for action potential (resting potential between -60 and -65 mV)p = 0.0720, or (g) time to action potential peak in response to 30 pA current injection p = 0.5480. (data points represent individual cells, bars at averages ± SEM, n = 26 for GFP, n = 11 for GCaMP6).

Supplementary Figure 3 Analyzing ΔF/F of pentanol activation.

(a and b) Example sensory map for pentanol (top), and the area activated at 50% or more of the maximal change in fluorescence (50% max ΔF/F) (bottom) (Scale bar 1 mm). (c) No change in maximal ΔF/F value across animals. (d) Significant increase in the 50% max ΔF/F area of the mature granule cells. (data points represent individual animals, bar at mean ± SEM, n = 7 animals per genotype, minimum of 3 trials per odorant, * p = 0.0491 Students t-test)

Supplementary Figure 4 Broader sensory maps of mature inhibitory neurons for multiple stimuli.

Example ΔF sensory map for anisole (a and b), and isoamyl acetate (e and f) (Scale bar 1 mm). (c and g) No change in maximal ΔF value across animals. Significant increase in the 50% max ΔF area of the mature granule cells for both (d) p=0.0187 and (h) p=0.0345. (data points represent individual animals, bars at mean ± SEM, n = 7 animals per genotype, minimum of 3 trials per odorant, * p<0.05 Students t-test)

Supplementary Figure 5 Inhibitory sensory maps broaden with maturation regardless of genetic marker.

a) Example ΔF sensory maps for pentanol for a Dlx5/6-Cre animal 2-3 weeks after viral injection (top), a Crhr1-Cre animal 2-3 weeks after viral injection (middle) and a Dlx5/6-Cre animal 6-8 weeks after viral injection (bottom) (Scale bar 1 mm). (b) Significant increase in the 50% max ΔF area of the mature granule cells across stimuli regardless of genetic marker (data points represent averages ± SEM, n = 7 Dlx5/6, n = 7 Crhr1, n = 3 Dlx5/6 6-8 weeks, minimum of 3 trials per odorant, * p<0.05, ** p<0.01 One-way ANOVA, Sidak’s multiple comparison).

Supplementary Figure 6 AOD-assisted optogenetic targeting of mitral cells.

(a) Diagram of AOD microscope and patched cells, (yellow = mitral cells as in Supplemental Fig. 6, red = granule cell as in Fig. 5). (b) Example patched mitral cell and location of light stimulation grid to ensure excitation of mitral cells was limited to stimulation over cell body as quantified in (c) which shows the probability of eliciting and action potential from AOD stimulation over a 30 μm2 grid around a patched mitral cell (asterisk) (n = 6 mitral cells). (d) Representative action potentials elicited from light stimulation over the soma of an example mitral cell. (Scale bar: 10 mV, 5 ms).

Supplementary Figure 7 Olfactory learning and immature granule cell synaptic changes.

(a) Performance of mice across many trials (about 200 trials/day) increases through training. (data points represent averages ± SEM, n = 10 animals for Dlx5/6-Cre and n=12 for Crhr1-Cre). (b) Example ΔF sensory maps for control and trained Dlx5/6-Cre mice in response to the S- odor (carvone(+)) and a novel odor (anisole) (e and f) and quantification in (c) showing map expansion is generalizable to other trained odors. (data points represent individual animals, bar at mean values ± SEM, n = 5 animals trained, 6 animals control, * p = 0.0123, One-way ANOVA, Sidak’s correction). (d) Representative mEPSC traces from Dlx5/6 expressing neurons from either control (top) or trained animals (bottom) with example averaged event on right (Scale bars full trace: 20 pA, 1 s; average: 8 pA, 10 ms). (e) Cumulative interval and (f) cumulative amplitude are significantly different in control versus trained mice (p < 0.0001 KS test), however the mean frequency (e, inset) shows increased variance (F test p < 0.0001) and trend toward increased frequency and no change in mean amplitude (f, inset) (data points represent individual cells, bars at mean values ± SEM, for mini data: n = 13 control granule cells and 12 trained cells from 4 animals each control and trained, injected with AAV-flex-GFP or AAV-flex-tdTomato).

Supplementary Figure 8 Passive odor exposure does not expand inhibitory sensory maps.

(a) Diagram of experimental setup showing 2 tea-strainer balls containing different odors that were hung in the animal’s home cage for an hour per day. (b) Timeline of experiment. (c) Example ΔF sensory maps for control and exposed mice in response to one exposed odor (anisole) and a novel odor (acetephenone) and quantification in (d) showing map no expansion. (data points represent individual animals, bars at mean values ± SEM, n = 4 Dlx5/6-Cre animals control, 4 Dlx5/6-Cre animals exposed, all injected with AAV-flex-GCaMP6m).

Supplementary Figure 9 Olfactory learning does not expand sensory maps for mature granule cells.

(a) Representative ΔF sensory map for control and trained mice in response to the unrewarded trained odor (carvone (+) and a novel odor (anisole) (scale bar 1 mm). (b) Mean activated area (± SEM, n = 4 animals control, 4 animals exposed all Crhr1-Cre injected with AAV-flex-GCaMP6). (c) Representative mEPSC traces from Crhr1 expressing neurons from either control (left) or trained animals (right) with example averaged event below (Scale bars full trace: 20 pA, 1 s; average: 8 pA, 10 ms). Cumulative interval distribution (d) and amplitude distribution (e) with cell means inset. (bar graphs represent mean values ± SEM, for mini data: n = 13 control granule cells and 8 occluded cells from 4 Crhr1-Cre animals + AAV-flex-GFP, each control and trained).

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Quast, K., Ung, K., Froudarakis, E. et al. Developmental broadening of inhibitory sensory maps. Nat Neurosci 20, 189–199 (2017). https://doi.org/10.1038/nn.4467

Download citation

Further reading

Search

Quick links

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing