Quantitative properties of the creation and activation of a cell-intrinsic duration-encoding engram

Abstract

The engram encoding the interval between the conditional stimulus (CS) and the unconditional stimulus (US) in eyeblink conditioning resides within a small population of cerebellar Purkinje cells. CSs activate this engram to produce a pause in the spontaneous firing rate of the cell, which times the CS-conditional blink. We developed a Bayesian algorithm that finds pause onsets and offsets in the records from individual CS-alone trials. We find that the pause consists of a single unusually long interspike interval. Its onset and offset latencies and their trial-to-trial variability are proportional to the CS-US interval. The coefficient of variation (CoV = σ/μ) are comparable to the CoVs for the conditional eye blink. The average trial-to-trial correlation between the onset latencies and the offset latencies is close to 0, implying that the onsets and offsets are mediated by two stochastically independent readings of the engram. The onset of the pause is step-like; there is no decline in firing rate between the onset of the CS and the onset of the pause. A single presynaptic spike volley suffices to trigger the reading of the engram; and the pause parameters are unaffected by subsequent volleys. The Fano factors for trial-to-trial variations in the distribution of interspike intervals within the intertrial intervals indicate pronounced non-stationarity in the endogenous spontaneous spiking rate, on which the CS-triggered firing pause supervenes. These properties of the spontaneous firing and of the engram read out may prove useful in finding the cell-intrinsic, molecular-level structure that encodes the CS-US interval.

Mesoscale simulations predict the role of synergistic cerebellar plasticity during classical eyeblink conditioning

“…Preliminary simulations with altered intrinsic excitability show decreased or slowed-down CEBC (S8 Fig), due to an unbalance of facilitation and suppression mainly in downbound PCs: when PC baseline activity is lower, they are more sensitive to synaptic potentiation, resulting in facilitation of their activity at the end of learning [26], which prevents proper CEBC; when baseline activity is higher, depression still occurs but it takes longer to release the DCN, leading to slowed-down CEBC. Despite these promising preliminary results, the role of intrinsic plasticity mechanisms contributing to conditioned response timing remains to be evaluated [94][95][96] and should be considered in future implementations of the model. Experimental evidence supports a role for plasticity and recurrent connection loops also in the cerebellar nuclei.…”

Mesoscale simulations predict the role of synergistic cerebellar plasticity during classical eyeblink conditioning

“…Other mechanisms, like granular layer plasticity [76,77], may intervene in more complex tasks, where multiple sensory signals with different time scales are combined [14,78]. The role of PC intrinsic mechanisms contributing in conditioned response timing remains to be evaluated [79][80][81].…”