Robustness of neuronal tuning to binaural sound localization cues against age-related loss of inhibitory synaptic inputs.
Robustness of neuronal tuning to binaural sound localization cues against age-related loss of inhibitory synaptic inputs.
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DOI：
10.1371/journal.pcbi.1009130
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发表时间：
2021-07
影响因子：
4.3
通讯作者：
Kretzberg J
中科院分区：
文献类型：
--
作者：
Ashida G;Tollin DJ;Kretzberg J
声音定位依赖于声音到达两只耳朵的时间和强度的微小差异。脑干侧上橄榄（LSO）神经元通过精确检测兴奋性和抑制性突触输入来处理这些耳间差异。衰老通常会导致沿整个听觉通路的抑制性突触传递选择性丧失，包括对LSO的抑制性传入的减少。然而，在动物的电生理记录中，仅报道了老年LSO的轻微功能变化。解剖和生理观察之间令人困惑的差异表明，活动依赖的可塑性可以帮助神经元在失去抑制输入的情况下保持双耳调节功能。为了探索这一假设，我们使用LSO的计算模型来研究观察到的抗年龄相关的抑制性输入丧失的功能稳健性的机制。LSO模型是一种由少量低压激活钾电导增强并由（非）均匀泊松输入驱动的集火型模型。在没有突触输入损失的情况下，模型尖峰率随声间时间和电平差异平滑变化，复制了LSO的经验调谐特性。通过减少抑制传入事件的数量来模拟与年龄相关的抑制丧失，总体峰值率增加，这对双耳调谐性能产生了负面影响，通过调节深度和神经元的可辨别性来衡量。为了模拟补偿抑制纤维损失的恢复过程，增加了剩余抑制输入的强度。通过这种修饰，抑制丧失对双耳调谐的影响大大减弱，导致功能性能的改善。这些神经元水平的观察结果通过群体模型进一步证实，其中多个LSO神经元的双耳调谐特性根据经验测量而变化。这些结果表明，体内平衡可塑性可以有效地抵消已知的LSO中抑制纤维的年龄依赖性损失，并表明声音定位的行为退化可能源于更集中发生的变化。准确定位声源是听觉系统最基本的功能之一。行为学研究表明，无论是实验动物还是人类，声音定位能力都会随着年龄的增长而退化。对老年动物的解剖研究发现，负责声音定位的神经元回路的抑制性输入显著减少。矛盾的是，脑干水平的生理学研究发现，声音定位回路的功能只有轻微的年龄相关变化。为了弥合这些观察结果之间令人困惑的差异，我们开发了相应的神经元回路模型，并通过改变抑制性传入事件的数量来模拟其功能。为了简单地模拟突触输入的活动依赖调节，我们还改变了剩余抑制的强度。与实证研究结果一致，我们的模拟表明，与抑制输入数量减少相比，声音定位回路的功能变化仍然相对较小。这种功能的稳健性通过调节突触强度进一步增强。这些结果表明，与年龄相关的声音定位行为的退化可能是由脑干水平以上听觉通路高级阶段的功能改变引起的。
Sound localization relies on minute differences in the timing and intensity of sound arriving at both ears. Neurons of the lateral superior olive (LSO) in the brainstem process these interaural disparities by precisely detecting excitatory and inhibitory synaptic inputs. Aging generally induces selective loss of inhibitory synaptic transmission along the entire auditory pathways, including the reduction of inhibitory afferents to LSO. Electrophysiological recordings in animals, however, reported only minor functional changes in aged LSO. The perplexing discrepancy between anatomical and physiological observations suggests a role for activity-dependent plasticity that would help neurons retain their binaural tuning function despite loss of inhibitory inputs. To explore this hypothesis, we use a computational model of LSO to investigate mechanisms underlying the observed functional robustness against age-related loss of inhibitory inputs. The LSO model is an integrate-and-fire type enhanced with a small amount of low-voltage activated potassium conductance and driven with (in)homogeneous Poissonian inputs. Without synaptic input loss, model spike rates varied smoothly with interaural time and level differences, replicating empirical tuning properties of LSO. By reducing the number of inhibitory afferents to mimic age-related loss of inhibition, overall spike rates increased, which negatively impacted binaural tuning performance, measured as modulation depth and neuronal discriminability. To simulate a recovery process compensating for the loss of inhibitory fibers, the strength of remaining inhibitory inputs was increased. By this modification, effects of inhibition loss on binaural tuning were considerably weakened, leading to an improvement of functional performance. These neuron-level observations were further confirmed by population modeling, in which binaural tuning properties of multiple LSO neurons were varied according to empirical measurements. These results demonstrate the plausibility that homeostatic plasticity could effectively counteract known age-dependent loss of inhibitory fibers in LSO and suggest that behavioral degradation of sound localization might originate from changes occurring more centrally. Accurately locating a sound source is one of the most fundamental functions of the auditory system. Behavioral studies report that sound localization ability generally degrades with aging in both laboratory animals and humans. Anatomical studies in aged animals have observed considerable reductions of inhibitory inputs into the neuronal circuit responsible for sound localization. Paradoxically, physiological studies at the brainstem level, however, find only minor age-related changes in the function of the sound localization circuit. In order to bridge the puzzling discrepancy between these observations, we developed a model of the corresponding neuronal circuit and simulate its function by varying the number of inhibitory afferents. To simply mimic the activity-dependent adjustment of synaptic inputs, we also varied the strength of remaining inhibition. Consistent with the empirical findings, our simulations demonstrate that functional changes of the sound localization circuit remain relatively small, compared to the reduced number of inhibitory inputs. This functional robustness is further enhanced by adjusting the synaptic strength. These results suggest that the age-related degradation of sound localization behavior might be caused by altered functions of higher stages in the auditory pathways above the level of the brainstem.
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影响因子：
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