The dependence of the synaptic responses on the history of activation and their large variability are both distinctive features of repetitive transmission at chemical synapses. Quantitative investigations have mostly focused on trial-averaged responses to characterize dynamic aspects of the transmission—thus disregarding variability—or on the fluctuations of the responses in steady conditions to characterize variability—thus disregarding dynamics. We present a statistically principled framework to quantify the dynamics of the probability distribution of synaptic responses under arbitrary patterns of activation. This is achieved by constructing a generative model of repetitive transmission, which includes an explicit description of the sources of stochasticity present in the process. The underlying parameters are then selected via an expectation-maximization algorithm that is exact for a large class of models of synaptic transmission, so as to maximize the likelihood of the observed responses. The method exploits the information contained in the correlation between responses to produce highly accurate estimates of both quantal and dynamic parameters from the same recordings. The method also provides important conceptual and technical advances over existing state-of-the-art techniques. In particular, the repetition of the same stimulation in identical conditions becomes unnecessary. This paves the way to the design of optimal protocols to estimate synaptic parameters, to the quantitative comparison of synaptic models over benchmark datasets, and, most importantly, to the study of repetitive transmission under physiologically relevant patterns of synaptic activation.
Temporal sequences of neural activity are essential for driving well-timed behaviors, but the underlying cellular and circuit mechanisms remain elusive. We leveraged the well-defined architecture of the cerebellum, a brain region known to support temporally precise actions, to explore theoretically whether the experimentally observed diversity of short-term synaptic plasticity (STP) at the input layer could generate neural dynamics sufficient for sub-second temporal learning. A cerebellar circuit model equipped with dynamic synapses produced a diverse set of transient granule cell firing patterns that provided a temporal basis set for learning precisely timed pauses in Purkinje cell activity during simulated delay eyelid conditioning and Bayesian interval estimation. The learning performance across time intervals was influenced by the temporal bandwidth of the temporal basis, which was determined by the input layer synaptic properties. The ubiquity of STP throughout the brain positions it as a general, tunable cellular mechanism for sculpting neural dynamics and fine-tuning behavior.
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