Synaptic mechanisms of top-down control in the non-lemniscal inferior colliculus

  1. Hannah M Oberle
  2. Alexander N Ford
  3. Deepak Dileepkumar
  4. Jordyn Czarny
  5. Pierre F Apostolides

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    Evaluation Summary:

    This paper will be of interest to neuroscientists who wish to understand how descending cortical projections interact in auditory midbrain neurons with their ascending inputs. The results have implications for other sensory systems and potentially other subcortical structures too. The data support the main conclusions of the manuscript, but additional control experiments and clarification of some parts are needed to strengthen the conclusions drawn and ensure that the findings of this interesting study can provide the basis for future modelling work.

    (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. All reviewers agreed to share their names with the authors.)

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Abstract

Corticofugal projections to evolutionarily ancient, subcortical structures are ubiquitous across mammalian sensory systems. These ‘descending’ pathways enable the neocortex to control ascending sensory representations in a predictive or feedback manner, but the underlying cellular mechanisms are poorly understood. Here, we combine optogenetic approaches with in vivo and in vitro patch-clamp electrophysiology to study the projection from mouse auditory cortex to the inferior colliculus (IC), a major descending auditory pathway that controls IC neuron feature selectivity, plasticity, and auditory perceptual learning. Although individual auditory cortico-collicular synapses were generally weak, IC neurons often integrated inputs from multiple corticofugal axons that generated reliable, tonic depolarizations even during prolonged presynaptic activity. Latency measurements in vivo showed that descending signals reach the IC within 30 ms of sound onset, which in IC neurons corresponded to the peak of synaptic depolarizations evoked by short sounds. Activating ascending and descending pathways at latencies expected in vivo caused a NMDA receptor-dependent, supralinear excitatory postsynaptic potential summation, indicating that descending signals can nonlinearly amplify IC neurons’ moment-to-moment acoustic responses. Our results shed light upon the synaptic bases of descending sensory control and imply that heterosynaptic cooperativity contributes to the auditory cortico-collicular pathway’s role in plasticity and perceptual learning.

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  1. Version published to 10.7554/elife.72730 on eLife
  2. eLife

    Author Response:

    Reviewer #2 (Public Review):

    Oberle et al. provide a detailed analysis of how descending projections from the auditory cortex interact with ascending auditory projections on neurons in the shell region of the inferior colliculus on a cellular basis. Using optogenetic activation of auditory cortical neurons or projections and electrical stimulation of fibres in combination with whole-cell patch clamp recordings in vivo and in vitro, they show that most neurons in the shell region of the inferior colliculus receive several monosynaptic cortical inputs. In vitro, these descending synapses show sublinear summation with a major tonic component for prolonged stimuli. Both in vivo and in vivo experiments support the idea that descending cortical inputs and ascending inputs from the central inferior colliculus temporally overlap and both activate NMDA and non-NMDA receptors. This cooperativity of inputs leads to supra-linear summation and boosting of the response.

    Strengths:

    • The manuscript provides a first detailed analysis of a loop between the cortex and midbrain. It elegantly combines in vivo and in vitro electrophysiological techniques to study this network on a cellular/synaptic level.

    • These experiments thoroughly characterize the nature of cortical and midbrain excitatory inputs onto shell IC neurons and elucidate how they integrate the ascending and descending inputs on a cellular level.

    Weaknesses:

    • A major weakness of this study is that they do not directly show that ascending and descending inputs to the IC shell neurons actually coincide, but only imply that this should be the case, considering different latency measurements. Latencies that are measured in the anesthetized preparation may change in the awake behaving animals which may change the timing of the respective inputs.

    We rectify this issue in our revision with new data showing that the latency of sound-evoked activity in the superficial IC is similar in anesthetized and awake mice. We acknowledge that the conduction velocity of descending axons may differ between anesthetized and awake state. However, existing data show that conduction velocities of cortical axons increase in the alert brain compared to non-alert conditions (Stoelzel et al., 2017). Taken together, we would expect an increased temporal coincidence of ascending and descending signals in awake compared to anesthetized animals, which all available evidence suggests would enhance NMDAR-dependent non-linearities such as those we described (Gasparini et al., 2004; Gasparini and Magee, 2006; Losonczy and Magee, 2006; Takahashi and Magee, 2009; Branco et al., 2010; Branco and Häusser, 2011). We now revise our Results to highlight that our latency measurements in anesthetized mice represent the upper bound for the arrival of auditory cortical EPSPs.

    In addition, the authors do not show to what extent coincidence of ascending and descending inputs to shell IC neurons is maintained for longer and more complex sounds as compared to click stimuli.

    Previous work shows that auditory cortico-collicular neurons sustain firing during long, complex sounds (Williamson and Polley, 2019), and our data show that descending transmission is maintained for extended periods of corticofugal activity both in vitro and in vivo (Figure 4E-H). Thus, we would expect temporal overlap of ascending and descending inputs to occur under these conditions as well. We agree that Reviewer #2 touches upon an important knowledge gap. However, we believe that a full investigation of which sounds do and do not engage descending modulation merits a separate, in-depth study.

    • The manuscript does not address the question of whether the different neuron types that they encounter in the shell region based on the firing pattern to current injections, vary in their input latencies, their number and distribution of NMDA receptors or their integrative properties. This may have some additional effect on how these neurons process ascending and descending information.

    We agree that correlating intrinsic and synaptic properties could reveal something interesting. However, our initial analyses (Figure 3) did not show any striking correlation between membrane biophysics and the half-width or amplitude of descending EPSPs. As such, we had no a priori basis to hypothesize that synaptic integration differs systematically with measurable membrane properties, and the low-throughput of dual pathway stimulation experiments (Figures 6 and 8) precluded collecting a large dataset needed to convincingly determine if any synaptic non-linearity does or does not meaningfully correlate with the cellular biophysics.

    We acknowledge this limitation of our study in our revised Discussion. Future studies, perhaps leveraging cell-type specific markers for different IC neurons (Goyer et al., 2019; Naumov et al., 2019; Silveira et al., 2020; Kreeger et al., 2021) will be required to clarify this issue.

    • The authors have not demonstrated that silencing of descending inputs from the AC affects IC shell activity.

    We did not initially perform this experiment given the extensive literature establishing that silencing auditory cortex modifies the magnitude, timing, and/or selectivity of IC neuron sound responses (Yan and Suga, 1999; Nwabueze-Ogbo et al., 2002; Popelár et al., 2003; Nakamoto et al., 2008, 2010; Anderson and Malmierca, 2013; Popelář et al., 2016; Weible et al., 2020). Indeed, these classic results were a major motivation for us to focus on the cellular mechanisms that support corticofugal transmission. We thus reasoned that a cortical inactivation experiment would be largely confirmatory of prior knowledge, and limited in its potential for mechanistic interpretation given the known caveats of cortical loss-of-function manipulations (Li et al., 2019; Andrei et al., 2021; Slonina et al., 2021). However, we acknowledge that such an experiment is useful to frame our cellular-level findings in a broader, systems-level context. As such, we address Reviewer #2’s concern in our revision with a new experiment demonstrating that auditory cortical silencing indeed affects sound-evoked activity in the IC of awake mice.

    Reviewer #3 (Public Review):

    Overall, this manuscript is generally nicely written and well-illustrated. I don´t really have any major issues. I like the manuscript but I have a few comments and some issues that need to be addressed.

    My main concern is that the authors claim several times that the projections to the central nucleus of IC are weak and they neglect their potential functional role. I think this is a little bit unfortunate. It is true that the large AC projection primarily targets the cortical regions or shell of IC, but it is beyond doubt that it also targets the central nucleus (e.g. Saldaña's studies) . We cannot know whether it is a weak projection or not without central nucleus recordings. Admittedly, these experiments would be challenging, so I would ask the authors to tone down a bit these comments throughout the ms. Also, the reason for the 'weak' projection to the central nucleus may be due to the size and location of the injections made in the auditory cortex. Thus, I would like to see the injections site of Chronos if possible. Likewise, fig 1B is too small and of low quality (at least in my pdf file for review) to appreciate details of labeling. I would suggest that the authors make a separate figure showing the injection site in the AC and larger and clearer labeling in the IC.

    We agree that in vitro recordings from the central IC in adult mice are quite challenging. As suggested we have toned down claims of the “weak” projection to central IC and provide micrographs of Chronos injection sites. However, we concur that this is an important point. Thus, we include a new transsynaptic tracing experiment showing the somata of presumptive postsynaptic targets of auditory cortex neurons in the IC. Although the data show that the majority of cortico-recipient IC neurons are located in the shell regions, a few central IC neurons are indeed clearly labeled. Future studies will be required to test the extent and potency of this direct auditory cortex->central IC projection, and to compare the synaptic properties with our results in the shell IC.

    Also I wonder if the title of the manuscript should refer to the non-lemniscal IC as most of the data is related to this area.

    We have changed the title of the paper to Synaptic Mechanisms of Top-Down Control in the Non-Lemniscal Inferior Colliculus.

    While the dogma is that the descending projections are glutamatergic, the authors may care to consider a recently published paper https://www.frontiersin.org/articles/10.3389/fncir.2021.714780/full, which challenges this view by showing that inhibitory long-range VIP-GABAergic neurons target the IC. It would be interesting if the authors could comment on how this projection may have influenced the results of the present study.

    We thank Reviewer #3 for pointing out this new study which does indeed relate to our work. However, we don’t think direct GABAergic projections contributed much, if at all to our results. Indeed, the experiments of Figure 5A did not reveal any inhibitory postsynaptic potentials following bath application of NBQX as one might expect from direct stimulation of VIP-GABA axons (these experiments were performed without SR95531 in the bath). Rather, it may be that the VIP-GABA synapses have low release probability, transmit mainly via non-synaptic diffusion (e.g., spillover), or may primarily release the neuropeptide VIP which would be difficult to detect via whole-cell patch-clamp electrophysiology. We now address the work of Bertero et al. in the Discussion section.

    References

    Anderson LA, Malmierca MS (2013) The effect of auditory cortex deactivation on stimulus-specific adaptation in the inferior colliculus of the rat. Eur J Neurosci 37:52–62.

    Andrei AR, Debes S, Chelaru M, Liu X, Rodarte E, Spudich JL, Janz R, Dragoi V (2021) Heterogeneous side effects of cortical inactivation in behaving animals. eLife 10:e66400.

    Branco T, Clark BA, Häusser M (2010) Dendritic discrimination of temporal input sequences in cortical neurons. Science 329:1671–1675.

    Branco T, Häusser M (2011) Synaptic integration gradients in single cortical pyramidal cell dendrites. Neuron 69:885–892.

    Gasparini S, Magee JC (2006) State-dependent dendritic computation in hippocampal CA1 pyramidal neurons. J Neurosci Off J Soc Neurosci 26:2088–2100.

    Gasparini S, Migliore M, Magee JC (2004) On the initiation and propagation of dendritic spikes in CA1 pyramidal neurons. J Neurosci Off J Soc Neurosci 24:11046–11056.

    Goyer D, Silveira MA, George AP, Beebe NL, Edelbrock RM, Malinski PT, Schofield BR, Roberts MT (2019) A novel class of inferior colliculus principal neurons labeled in vasoactive intestinal peptide-Cre mice. eLife 8:e43770.

    Kreeger LJ, Connelly CJ, Mehta P, Zemelman BV, Golding NL (2021) Excitatory cholecystokinin neurons of the midbrain integrate diverse temporal responses and drive auditory thalamic subdomains. Proc Natl Acad Sci U S A 118:e2007724118.

    Li N, Chen S, Guo ZV, Chen H, Huo Y, Inagaki HK, Chen G, Davis C, Hansel D, Guo C, Svoboda K (2019) Spatiotemporal constraints on optogenetic inactivation in cortical circuits. eLife 8:e48622.

    Losonczy A, Magee JC (2006) Integrative properties of radial oblique dendrites in hippocampal CA1 pyramidal neurons. Neuron 50:291–307.

    Nakamoto KT, Jones SJ, Palmer AR (2008) Descending projections from auditory cortex modulate sensitivity in the midbrain to cues for spatial position. J Neurophysiol 99:2347–2356.

    Nakamoto KT, Shackleton TM, Palmer AR (2010) Responses in the inferior colliculus of the guinea pig to concurrent harmonic series and the effect of inactivation of descending controls. J Neurophysiol 103:2050–2061.

    Naumov V, Heyd J, de Arnal F, Koch U (2019) Analysis of excitatory and inhibitory neuron types in the inferior colliculus based on Ih properties. J Neurophysiol 121:2126–2139.

    Nwabueze-Ogbo FC, Popelár J, Syka J (2002) Changes in the acoustically evoked activity in the inferior colliculus of the rat after functional ablation of the auditory cortex. Physiol Res 51 Suppl 1:S95–S104.

    Popelár J, Nwabueze-Ogbo FC, Syka J (2003) Changes in neuronal activity of the inferior colliculus in rat after temporal inactivation of the auditory cortex. Physiol Res 52:615–628.

    Popelář J, Šuta D, Lindovský J, Bureš Z, Pysanenko K, Chumak T, Syka J (2016) Cooling of the auditory cortex modifies neuronal activity in the inferior colliculus in rats. Hear Res 332:7–16.

    Silveira MA, Anair JD, Beebe NL, Mirjalili P, Schofield BR, Roberts MT (2020) Neuropeptide Y Expression Defines a Novel Class of GABAergic Projection Neuron in the Inferior Colliculus. J Neurosci 40:4685–4699.

    Slonina ZA, Poole KC, Bizley JK (2021) What can we learn from inactivation studies? Lessons from auditory cortex. Trends Neurosci:S0166-2236(21)00203-4.

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  3. eLife

    Evaluation Summary:

    This paper will be of interest to neuroscientists who wish to understand how descending cortical projections interact in auditory midbrain neurons with their ascending inputs. The results have implications for other sensory systems and potentially other subcortical structures too. The data support the main conclusions of the manuscript, but additional control experiments and clarification of some parts are needed to strengthen the conclusions drawn and ensure that the findings of this interesting study can provide the basis for future modelling work.

    (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. All reviewers agreed to share their names with the authors.)

  4. eLife

    Reviewer #1 (Public Review):

    This study aims at better characterizing the synaptic and cellular integration mechanisms orchestrating the interplay between the cortical feedback arriving in the shell of inferior colliculus (IC) and the feedforward input. Combining optogenetic tools with in vivo and in vitro patch clamp the authors describe the strength and kinetics at different time scales of corticofugal inputs, and theoretically deduce based on this that the top-down and bottom-up inputs are ideally timed to collide in the shell of the IC. They then show that coincidence of top-down and bottom-up inputs leads to supra-linear summation in an NMDA-dependent manner. The data provided in the first descriptive part of the paper is sound and useful for the community to better model corticofugal projections. The finding that coincident arrival of corticofugal and bottom-up inputs leads to non-linear boosting of IC neurons is sound and represents a very important result for further understanding and modeling of corticofugal inputs to IC, even if the authors did not illustrate it with a concrete example during realistic auditory processing where this phenomenon would be at play (some hypotheses are given). The NMDA dependence is even more striking in that it depends on receptors located on bottom-up synapses, a surprising and mind-blowing result.

  5. eLife

    Reviewer #2 (Public Review):

    Oberle et al. provide a detailed analysis of how descending projections from the auditory cortex interact with ascending auditory projections on neurons in the shell region of the inferior colliculus on a cellular basis. Using optogenetic activation of auditory cortical neurons or projections and electrical stimulation of fibres in combination with whole-cell patch clamp recordings in vivo and in vitro, they show that most neurons in the shell region of the inferior colliculus receive several monosynaptic cortical inputs. In vitro, these descending synapses show sublinear summation with a major tonic component for prolonged stimuli. Both in vivo and in vivo experiments support the idea that descending cortical inputs and ascending inputs from the central inferior colliculus temporally overlap and both activate NMDA and non-NMDA receptors. This cooperativity of inputs leads to supra-linear summation and boosting of the response.

    Strengths:
    • The manuscript provides a first detailed analysis of a loop between the cortex and midbrain. It elegantly combines in vivo and in vitro electrophysiological techniques to study this network on a cellular/synaptic level.
    • These experiments thoroughly characterize the nature of cortical and midbrain excitatory inputs onto shell IC neurons and elucidate how they integrate the ascending and descending inputs on a cellular level.

    Weaknesses:
    • A major weakness of this study is that they do not directly show that ascending and descending inputs to the IC shell neurons actually coincide, but only imply that this should be the case, considering different latency measurements. Latencies that are measured in the anesthetized preparation may change in the awake behaving animals which may change the timing of the respective inputs. In addition, the authors do not show to what extent coincidence of ascending and descending inputs to shell IC neurons is maintained for longer and more complex sounds as compared to click stimuli.
    • The manuscript does not address the question of whether the different neuron types that they encounter in the shell region based on the firing pattern to current injections, vary in their input latencies, their number and distribution of NMDA receptors or their integrative properties. This may have some additional effect on how these neurons process ascending and descending information.
    • The authors have not demonstrated that silencing of descending inputs from the AC affects IC shell activity.

  6. eLife

    Reviewer #3 (Public Review):

    Overall, this manuscript is generally nicely written and well-illustrated. I don´t really have any major issues. I like the manuscript but I have a few comments and some issues that need to be addressed.

    My main concern is that the authors claim several times that the projections to the central nucleus of IC are weak and they neglect their potential functional role. I think this is a little bit unfortunate. It is true that the large AC projection primarily targets the cortical regions or shell of IC, but it is beyond doubt that it also targets the central nucleus (e.g. Saldaña's studies) . We cannot know whether it is a weak projection or not without central nucleus recordings. Admittedly, these experiments would be challenging, so I would ask the authors to tone down a bit these comments throughout the ms. Also, the reason for the 'weak' projection to the central nucleus may be due to the size and location of the injections made in the auditory cortex. Thus, I would like to see the injections site of Chronos if possible. Likewise, fig 1B is too small and of low quality (at least in my pdf file for review) to appreciate details of labeling. I would suggest that the authors make a separate figure showing the injection site in the AC and larger and clearer labeling in the IC.
    Also I wonder if the title of the manuscript should refer to the non-lemniscal IC as most of the data is related to this area.
    While the dogma is that the descending projections are glutamatergic, the authors may care to consider a recently published paper
    https://www.frontiersin.org/articles/10.3389/fncir.2021.714780/full, which challenges this view by showing that inhibitory long-range VIP-GABAergic neurons target the IC. It would be interesting if the authors could comment on how this projection may have influenced the results of the present study.

  7. Version published to 10.1101/2021.07.26.453816v2 on bioRxiv
  8. Version published to 10.1101/2021.07.26.453816v1 on bioRxiv