Neuromodulator timing regulates adult cortical plasticity via the synaptic eligibility trace

Abstract

Introduction

Learning-induced cortical reorganization is facilitated by neuromodulator release. However, the precise temporal relationship between neuromodulator release and neural activity required to induce plasticity is not well understood. In single synapses, eligibility traces regulate plasticity such that neuromodulator arrival must occur within seconds of activity. Cortical plasticity can also be induced by pairing neuromodulator release with neural activity, but it is unknown whether plasticity in populations of neurons is regulated by the same temporal constraints.

Methods

To determine whether the synaptic eligibility trace regulates cortical plasticity, we used vagus nerve stimulation (VNS) to drive neuromodulator release 3 s before, 1 s before, concurrent with, or 3 s after tone-evoked activity in auditory cortex. After 20 days of pairing, we used in vivo electrophysiology to quantify the proportion of auditory cortex responding to the paired tone frequency.

Results

We found that VNS 1 s before or concurrent with tone onset significantly expanded the representation of the paired tone frequency (-1s, p = 0.04; 0s, p = 0.02), whereas 3 s before or after did not (-3s, p = 0.87; +3s, p = 0.53). Confirming the role of neuromodulators in this eligibility trace, we found that depletion of norepinephrine prevented VNS-tone pairing-induced plasticity (0s + DSP4, p = 0.23).

Discussion

Our study demonstrates that cortical plasticity is regulated by time constraints similar to the synaptic eligibility trace and highlights the importance of considering the timing of neuromodulator release when employing methods to enhance plasticity.