Fast and slow feedforward inhibitory circuits for cortical odor processing

  1. Norimitsu Suzuki
  2. Malinda LS Tantirigama
  3. K Phyu Aung
  4. Helena HY Huang
  5. John M Bekkers

  • Curated by eLife

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    Evaluation Summary:

    Feedforward inhibition (FFI) typically exerts a powerful effect shaping neural activity. In this paper, Suzuki et al use a combination of in vivo and in vitro experiments to characterize, for the first time, responses in the two main classes of FFIs in the mouse olfactory cortex, neurogliaform cells (NG) and horizontal cells (HZ). They find that these two cell types have different responses and different connectivity, which partially explains their different responses. This paper also helps resolve a previously perplexing result from a recent high-profile publication that claimed that FFI in the mouse olfactory cortex appears to play a negligible role in shaping cortical odor responses, presumably because those authors were only recording from HZ cells.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

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Abstract

Feedforward inhibitory circuits are key contributors to the complex interplay between excitation and inhibition in the brain. Little is known about the function of feedforward inhibition in the primary olfactory (piriform) cortex. Using in vivo two-photon-targeted patch clamping and calcium imaging in mice, we find that odors evoke strong excitation in two classes of interneurons – neurogliaform (NG) cells and horizontal (HZ) cells – that provide feedforward inhibition in layer 1 of the piriform cortex. NG cells fire much earlier than HZ cells following odor onset, a difference that can be attributed to the faster odor-driven excitatory synaptic drive that NG cells receive from the olfactory bulb. As a result, NG cells strongly but transiently inhibit odor-evoked excitation in layer 2 principal cells, whereas HZ cells provide more diffuse and prolonged feedforward inhibition. Our findings reveal unexpected complexity in the operation of inhibition in the piriform cortex.

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  1. Version published to 10.7554/elife.73406 on eLife
  2. eLife

    Evaluation Summary:

    Feedforward inhibition (FFI) typically exerts a powerful effect shaping neural activity. In this paper, Suzuki et al use a combination of in vivo and in vitro experiments to characterize, for the first time, responses in the two main classes of FFIs in the mouse olfactory cortex, neurogliaform cells (NG) and horizontal cells (HZ). They find that these two cell types have different responses and different connectivity, which partially explains their different responses. This paper also helps resolve a previously perplexing result from a recent high-profile publication that claimed that FFI in the mouse olfactory cortex appears to play a negligible role in shaping cortical odor responses, presumably because those authors were only recording from HZ cells.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

  3. eLife

    Reviewer #1 (Public Review):

    In this paper, Suzuki et al use a combination of in vivo and in vitro experiments to characterize, for the first time, responses in the two main classes of FFIs in the mouse olfactory cortex, neurogliaform cells (NG) and horizontal cells (HZ). They find that these two cell types have different responses and different connectivity, which partially explains their different responses. This paper also helps resolve a previously perplexing result from a recent high-profile publication that claimed that FFI in the mouse olfactory cortex appears to play a negligible role in shaping cortical odor responses, presumably because those authors were only recording from HZ cells.

    Feedforward inhibition (FFI) typically exerts a powerful effect shaping neural activity. This paper characterizes the odor-evoked activity and connectivity of two classes of feedforward interneurons (FFIs) in the mouse piriform cortex, horizontal cells (HZs) and Neurogliaform cells (NGs). They do this first by 2-P targeted recordings in anesthetized mice and brain slices. They find that both NGs and HZs are broadly tuned (consistent with Poo & Isaacson, 2009), but they have very different response types. NGs exhibit strong, fast, and phasic odor responses, while HZs exhibit much weaker, delayed, and prolonged responses. In slice recordings, they show that NGs inhibit HZs but that HZs do not inhibit NGs, which presumably explains, fully or in large part, their differential odor responses.

    This is a timely and important piece of work. It also helps explain a puzzling result from a recent high-profile study (Bolding & Franks, 2018), and a modeling study from the same group (Stern et al, 2018), which showed negligible odor responses in FFIs, which seems odd and incongruent with previous slice experiments from multiple other labs (Bekkers, Isaacson, Schoppa, etc). Here, Suzuki et al suggest, very reasonably, that the Bolding paper probably recorded primarily from HZ cells and therefore missed the phasic odor responses in NGs. Moreover, they delicately suggest why Bolding & Franks got it wrong (L. 466: "...placement of the electrodes (close to or far from the LOT)"). Indeed, Bolding & Franks' recordings are almost certainly biased for HZ cells Furthermore, in their modeling study, Stern et al had all-to-all connectivity amongst a homogenous population of FFIs, which would yield slow, weak, and HZ-like responses.

    Therefore, not only does this paper provide the first cell-type-specific characterization of FFIs in piriform cortex in vivo, it helps clarify, and possibly fully resolves, a previously confusing result.

  4. eLife

    Reviewer #2 (Public Review):

    The study is good starting point for understanding how specific inhibitory circuitry shapes cortical responses in olfaction. In these experiments, whole-cell recordings were made in vivo from identified L1 inhibitory interneurons- neurogliaform (NG) and horizontal (HZ), in anterior piriform cortex. Given the ventral location of the piriform cortex, recordings such as these are difficult and rarely performed. The main finding is that odors evoke strong, transient and short latency responses in NG neurons while HZ neurons are activated later and have prolonged and lower firing rates. Both classes are broadly tuned consistent with previous reports of broadly tuned feedforward inhibition in piriform cortex. Analysis of subthreshold currents revealed enhanced respiration phase locking during odors in NG but not HZ interneurons. Further analysis revealed that underlying synaptic inputs were consistent with spike responses, EPSPs peaked sooner and decayed more quickly in NG than HZ neurons. Interestingly, these findings seem to contradict previous in vitro work from the same group. In vitro analysis of short-term plasticity in the afferent pathway has shown that afferent EPSPs onto NGs facilitate while EPSPs onto HZs depress. This would result in opposite temporal responses to those seen in vivo. The authors directly address this and partially resolve the discrepancy for NG neurons. Additional investigation of inhibitory inputs onto NG and HZ neurons revealed that NG inhibit HZ neurons but not the reverse. This could contribute to the delayed response properties of HZ neurons. Finally, the influence of feedforward inhibition onto pyramidal neurons was investigated. Unfortunately, there is currently no means of selectively inhibiting NG versus HZ neurons in vivo. Therefore in vitro experiments were conducted to build a model of how these two classes affect feedforward inhibition. The results of these final experiments though plausible, were somewhat underwhelming. Overall, this study performs an important characterization of two understudied classes of inhibitory interneuron and provides some limited mechanistic insight into their function in the cortical circuit.

  5. eLife

    Reviewer #3 (Public Review):

    In this manuscript, Suzuki and colleagues report a careful analysis of L1 interneuron-mediated feedforward inhibitions in the piriform cortex. Using in vivo two-photon targeted patch clamping recordings, in vivo functional calcium imaging, and in vitro multiple simultaneous patch clamping recordings, the authors found that L1 neurogliaform cells mediate a strong but transient feedforward inhibition, whereas HZ cells supply a more diffuse and prolonged feedforward inhibition during odor sensation. The findings are fascinating, and experimental data are of high quality. The study represents a significant advance of our understanding of L1 neuron-mediated inhibitions in information processing, which should appeal the general readers of eLife.

    Strengths:

    1. The study is very topical.
    2. The study employs a combination of cutting-edge technologies that reveals unexpected differences and potential functions of the two odor-evoked feedforward inhibitions, which would not be possible for unit recordings, for example.
    3. The experiments employed are in general rigorously designed and executed.

    Weaknesses:

    1. The mechanisms underlying the functional differences of feedforward inhibitions is not fully illustrated. The authors did propose a few possible mechanisms based on their preliminary investigation. This is a minor weakness given the significant finding about distinct forms of feedforward inhibitions.
  6. Version published to 10.1101/2021.09.19.460974v1 on bioRxiv