Stange-Marten et al. Input Timing for Spatial Processing.….

Input timing for spatial processing is precisely tuned via constant synaptic delays and myelination patterns in the auditory brainstem

Annette Stange-Marten Alisha L. Nabel, James L. Sinclair, Matthew Fischl, Olga Alexandrova, Hilde Wohlfrom, Conny Kopp-Scheinpflug, Michael Pecka, Benedikt Grothe

  1. Edited by Eric I. Knudsen, Stanford University School of Medicine, Stanford, CA, and approved May 8, 2017 (received for review February 10, 2017)

PNAS Proceedings of the National Academy of Sciences of the United States of America

Significance

Neural computation depends on precisely timed synaptic inputs, but the way that the timing of inputs is tuned to match postsynaptic processing requirements is not well understood. Here, we studied the same brainstem sound localization pathway in two species with dissimilar temporal processing requirements. Two factors that limit precise timing are synaptic delay and axonal conduction time. In gerbils, which depend on precise timing for sound localization, synaptic delays in fast conducting axons are stable across activity level, and axon myelination is adapted to minimize conduction delays. In mice, which do not depend on precise timing, these specializations are absent. Our results suggest that both axonal and synaptic properties are optimized to the specific functional requirements of neural computation, advancing our understanding of the mechanisms that optimize neural circuits.

Abstract

Precise timing of synaptic inputs is a fundamental principle of neural circuit processing. The temporal precision of postsynaptic input integration is known to vary with the computational requirements of a circuit, yet how the timing of action potentials is tuned presynaptically to match these processing demands is not well understood. In particular, action potential timing is shaped by the axonal conduction velocity and the duration of synaptic transmission delays within a pathway. However, it is not known to what extent these factors are adapted to the functional constraints of the respective circuit. Here, we report the finding of activity-invariant synaptic transmission delays as a functional adaptation for input timing adjustment in a brainstem sound localization circuit. We compared axonal and synaptic properties of the same pathway between two species with dissimilar timing requirements (gerbil and mouse): In gerbils (like humans), neuronal processing of sound source location requires exceptionally high input precision in the range of microseconds, but not in mice. Activity-invariant synaptic transmission and conduction delays were present exclusively in fast conducting axons of gerbils that also exhibited unusual structural adaptations in axon myelination for increased conduction velocity. In contrast, synaptic transmission delays in mice varied depending on activity levels, and axonal myelination and conduction velocity exhibited no adaptations. Thus, the specializations in gerbils and their absence in mice suggest an optimization of axonal and synaptic properties to the specific demands of sound localization. These findings significantly advance our understanding of structural and functional adaptations for circuit processing.

Temporal integration of bioelectrical signals via chemical synapses is fundamental to neuronal computations. During circuit processing, neuronal information transfer via action potentials is controlled by exact differences in the occurrence between excitatory and inhibitory inputs (15). The arrival time of inputs within circuits in turn is largely shaped by the conduction delay of action potentials along the axons and during synaptic transmission. During ongoing activity, the transmission delays of chemical synapses generally increase in the range of hundreds of microseconds due to short-term adaptations (69). However, because temporal integration on postsynaptic neurons usually operates on time scales in the range of milliseconds or even longer (10, 11), sluggishness arising from synaptic mechanisms and axonal conductance is negligible for most of these computations. There are, however, some essential neuronal processing tasks that challenge the temporal precision of our nervous system. For instance, weakly electric fish detect miniature changes in the frequency of a constant electrical field. The neuronal circuits in these animals use electrical instead of chemical synapses in the periphery as a rather unique solution to speed up signal propagation along the first synaptic stages and to allow for stable (i.e., activity invariant) synaptic delays (SDs) (12).

The temporally most precise neuronal computations known in mammals (including humans) occur in the auditory system in circuits processing sound location information (13, 14). Here, individual neurons in the lateral and the medial superior olive (LSO and MSO, respectively) detect coincidences between inputs from the two ears. In both nuclei, this computation is based on precise interactions of glutamatergic excitation and glycinergic inhibition (15, 16), and indeed a subset of the respective inputs is shared between the two circuits (17). One striking shared structural feature is the contralateral inhibitory pathway that is specialized for speed and reliability (Fig. 1A). Globular bushy cells (GBCs) in the cochlear nucleus excite glycinergic cells of the medial nucleus of the trapezoid body (MNTB) via highly myelinated and rapidly conducting axons and the giant calyx of Held synapse (18, 19). However, the functional requirements for precise timing of this inhibitory pathway are different for the LSO and MSO circuit: the LSO predominantly computes differences in the relative level of high-frequency sounds between the ears [interaural level difference (ILD)] and shows temporal input precision in the millisecond range for faithful level measurement (13, 20) (see also Discussion). In the MSO, on the other hand, microsecond differences in the time of arrival of low-frequency sounds at the two ears [interaural time difference (ITD)] are processed and consequently the requirements for input timing are exceptionally higher (5, 21). Importantly, because the inhibitory pathways involve an additional synaptic stage compared with the excitatory inputs to the MSO, both absolute and constant relative timing represents a key challenge for this circuit (5, 15, 2224): Compared with onset information (i.e., action potential firing after longer periods of inactivity) passing through rested and thus less adapted calyx of Held synapses, inhibition would be progressively delayed relative to the excitation during ongoing activity by dozens to hundreds of microseconds due to the increase in synaptic delay (25). This activity-dependent increase in the overall delay of inhibition relative to excitation would corrupt the microsecond precision of inputs required for ITD processing. However, both at the level of single MSO neurons (26) as well as in human psychoacoustics (27), ITD detection does not differ between onset and ongoing sound components.

In addition to this problem of activity-dependent relative timing, ITD processing in MSO neurons is confronted by adapting the absolute timing of the individual inputs originating from the distinct pathways of different axonal lengths (ipsilateral vs. contralateral) and number of synapses. For example, contralateral inhibition via the GBCs and MNTB has been found to reliably precede the contralateral excitation by a few hundred microseconds despite its additional synapse (5, 22). We recently revealed structural adaptations in axonal caliber and the myelination pattern of GBC axons of Mongolian gerbils, providing an anatomical substrate for the observed temporal precedence of the inhibitory pathway (28). Intriguingly, we also discovered pronounced differences in axonal and myelin morphology within subpopulations of GBC axons tuned to low frequencies: although thicker in axon caliber, these GBC neurons exhibit shorter internode length, resulting in significantly faster conductance velocity and enhanced action potential precision (28). However, the MNTB targets not only MSO but many different auditory nuclei (29), including the LSO. It is therefore unclear whether differential myelination patterning and conduction velocity are specific adaptations for ITD processing or simply represent a general variation related to tonotopic organization per se.

Here, we observed activity-invariant relative input timing and examined whether the unusual myelination pattern observed in GBC fibers tuned to low frequencies is specifically related to ITD processing. To this end, we compared GBC axon morphology and synaptic transmission delays at the calyx of Held both in the Mongolian gerbil (an ITD user) and in the mouse (a non-ITD user). We found that the specializations in myelination and conduction velocity are highly specific to the functional requirements of ITD processing. We further revealed that explicitly in low-frequency tuned, fast conducting axons, the calyx of Held to MNTB synapse exhibited activity-invariant and thus stable delays.

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