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Phasic, Suprathreshold Excitation and Sustained Inhibition Underlie Neuronal Selectivity for Short-Duration Sounds

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Phasic, Suprathreshold Excitation and Sustained Inhibition Underlie Neuronal Selectivity for Short-Duration Sounds Phasic, suprathreshold excitation and sustained PNAS PLUS inhibition underlie neuronal selectivity for short-duration sounds Rishi K. Alluria, Gary J. Rosea,1, Jessica L. Hansona, Christopher J. Learyb, Gustavo A. Vasquez-Opazoa, Jalina A. Grahamc, and Jeremy Wilkersond aDepartment of Biology, University of Utah, Salt Lake City, UT 84112; bDepartment of Biology, University of Mississippi, Oxford, MS 38677; cNeuroscience Program, University of California, Davis, CA 95616; and dTalkingApe.org, Redwood City, CA 94063 Edited by Eric I. Knudsen, Stanford University School of Medicine, Stanford, CA, and approved January 29, 2016 (received for review October 23, 2015) Sound duration is important in acoustic communication, including experiments (18), suggested that sustained inhibition might be speech recognition in humans. Although duration-selective auditory critical for generating duration tuning. Whole-cell patch record- neurons have been found, the underlying mechanisms are unclear. ings in bats (19, 20) provided direct evidence that interplay be- To investigate these mechanisms we combined in vivo whole-cell tween excitation and inhibition contributed to duration selectivity. patch recordings from midbrain neurons, extraction of excitatory This work inspired a second type of coincidence model of duration and inhibitory conductances, and focal pharmacological manipula- selectivity (Fig. 1B) in which delayed, subthreshold excitation tions. We show that selectivity for short-duration stimuli results maximally summates with rebound from short-latency inhibition from integration of short-latency, sustained inhibition with delayed, (and/or offset excitation) over a narrow range of durations. Al- phasic excitation; active membrane properties appeared to amplify ternatively, Fuzessery and Hall (21) proposed an anticoincidence responses to effective stimuli. Blocking GABA receptors attenuated A model (Fig. 1C) in which inhibition tracks stimulus duration and stimulus-related inhibition, revealed suprathreshold excitation at overlaps temporally with delayed excitation only when tone burst all stimulus durations, and decreased short-pass selectivity without changing resting potentials. Blocking AMPA and NMDA receptors to duration exceeds a particular value; the phasic, delayed excitation NEUROSCIENCE attenuate excitation confirmed that inhibition tracks stimulus dura- is suprathreshold, and therefore, rebound from inhibition is not tion and revealed no evidence of postinhibitory rebound depolar- required. Subsequent whole-cell patch recordings from duration- ization inherent to coincidence models of duration selectivity. These selective neurons in the anuran IC provided some limited support results strongly support an anticoincidence mechanism of short-pass for this latter model, at least for short-pass selectivity; short- selectivity, wherein inhibition and suprathreshold excitation show latency inhibition appeared to track stimulus duration with little or greatest temporal overlap for long duration stimuli. no rebound depolarization at the offset of long-duration tone bursts (3, 22). The results of this earlier work, however, did not whole-cell | GABA | synaptic conductance | gabazine | inferior colliculus reveal critical properties of the excitatory input to short-pass neurons. First, the study did not address whether the amplitude of principal goal in neuroscience is to understand the compu- excitation changed with tone burst duration; if excitatory post- Atational mechanisms that underlie selectivity for particular synaptic potential (EPSP) amplitude decreases with stimulus dura- types of information. Sensory neurons have been identified that tion, short-pass selectivity could be a property of the inputs to IC show selectivity for biologically relevant stimulus features; how- neurons. Second, the former investigation did not determine ever, the underlying mechanisms are, in most cases, poorly un- whether the excitation was suprathreshold and phasic; both types derstood. A notable exception involves mechanisms of selectivity of models require phasic excitation, which should be subthreshold for sound duration, particularly in bat and anuran auditory sys- in the case of the coincidence hypothesis. Further, this study did tems (1–3). Duration-selective neurons were first found in the midbrain torus semicircularis of anurans (4, 5), homolog of the Significance mammalian inferior colliculus (IC) and referred to here as the IC . In anurans and many mammalian species, midbrain an Understanding how excitatory and inhibitory inputs are inte- neurons have been identified that show short-pass, band-pass, or grated to achieve sensory selectivity is an important, but elusive, long-pass duration selectivity (3, 6–11). These neurons code for goal in neuroscience. Whole-cell recordings in vivo have revealed temporal properties of acoustic signals that are important in excitation and inhibition, but the computational mechanisms are communication and echolocation. Processing sound duration is generally unclear. In the inferior colliculus, neurons exist that re- also critical for human speech communication, and deficiencies spond selectively to short-duration sounds; the mechanistic basis in the neural processing of this and other temporal information of this selectivity has long been debated. We combined whole-cell feature prominently in disorders of speech recognition (12, 13). recordings, in vivo, with conductance extraction algorithms and Hence, understanding the mechanisms of duration selectivity is focal pharmacological manipulations to show that duration se- of considerable importance. lectivity results from an anticoincidence of suprathreshold exci- Several models of duration selectivity have been proposed. tation and inhibition. These results challenge the widely held The first model, derived from extracellular recordings in the view that postinhibitory rebound depolarization must coincide anuran IC (4), incorporates delayed, onset excitation and short- with subthreshold excitation to generate duration selectivity. latency offset excitation that coincide for the optimal stimulus duration (Fig. 1A). Subsequent extracellular recordings from IC Author contributions: R.K.A., G.J.R., and C.J.L. designed research; R.K.A., G.J.R., J.L.H., C.J.L., neurons in bats showed that blocking receptors of inhibitory neu- G.A.V.-O., J.A.G., and J.W. performed research; R.K.A., G.J.R., C.J.L., and J.W. contributed rotransmitters eliminated, or greatly attenuated, duration selectiv- new reagents/analytic tools; R.K.A., G.J.R., J.L.H., C.J.L., G.A.V.-O., and J.W. analyzed data; ity (14–16). Further, the temporal pattern of discharges shifted and R.K.A., G.J.R., J.L.H., C.J.L., and G.A.V.-O. wrote the paper. from offset to onset type following attenuation of inhibition. These The authors declare no conflict of interest. results, along with the findings that first-spike latency did not in- This article is a PNAS Direct Submission. crease directly with tone burst duration (17) and temporal masking 1To whom correspondence should be addressed. Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1520971113 PNAS Early Edition | 1of9 Downloaded by guest on September 30, 2021 the relatively small stimulus-elicited depolarizations and spike re- sponse of this cell. The duration of Δgi increased approximately linearly with that of the stimulus, whereas Δge duration was rela- tively independent of tone burst duration. Across all cells (Fig. 3B), the Δgi profiles in response to 40-, 80-, and 160-ms duration tone bursts were significantly longer than those for 20-ms tone bursts [Wilcoxonsignedranktests,z = −2.36, P = 0.018, n = 7 (20 vs. 40 ms); z = −2.8, P = 0.005, n = 10 (20 vs. 80 ms); z = −2.98, P = 0.003, n = 12 (20 vs. 160 ms)], whereas durations of Δge did not differ across these comparisons [Wilcoxon signed rank tests, z = −1.86, P = 0.06, n = 7 (20 vs. 40 ms); z = −0.15, P = 0.88, n = 10 (20 vs. 80 ms); z = −0.53, P = 0.59, n = 12 (20 vs. 160 ms)]. Results of conductance analyses across cells also indicated that excitatory inputs to these ICan neurons did not already show short- Fig. 1. Coincidence (A and B) and anticoincidence (C) models for duration pass duration selectivity; peak amplitudes of excitatory conduc- selectivity (short-pass instantiation). (B) Adapted with permission from The tances were highly similar for short and long tone burst durations American Physiological Society (refs. 14, 17); data from refs. 19, 20; and (C)data [medians = 0.74 nS (20 ms) and 0.69 nS (160 ms); Wilcoxon signed from ref. 21. Excitation (orange) is triggered by either stimulus onset (ONE)or rank test, z = 1.26, P = 0.21, n = 12]. Across short-pass cells, Δge stimulus offset (OFFE). Inhibition (blue) is triggered by stimulus onset (ONI), peaks for responses to 20-ms tone bursts were ∼29.9 ms delayed with a shorter latency than that of ONE.InB, the blue trace represents onset (median value, range = 2.2–56.7 ms) relative to those for Δgi. inhibition (ONI) followed by postinhibitory rebound depolarization (OFFE). Further, offsets of tone bursts did not trigger secondary peaks of excitation, as predicted from the coincidence model of Fig. 1A. not test whether short-duration tone bursts elicit postinhibitory These findings are consistent, therefore, with models of duration rebound depolarization. selectivity that incorporate short-latency, sustained inhibition and To determine the mechanisms that underlie duration selec- delayed, relatively phasic excitation (Fig.
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