Cellular Substrate of Eligibility Traces

The ability of synapses to undergo associative, activity-dependent weight changes constitutes a linchpin of current cellular models of learning and memory. It is, however, unclear whether canonical forms of Hebbian plasticity, which inherently detect correlations of cellular events occurring over short time scales, can solve the temporal credit assignment problem proper to learning driven by delayed behavioral outcomes. Recent evidence supports the existence of synaptic eligibility traces, a time decaying process that renders synapses momentarily eligible for a weight update by a delayed instructive signal. While eligibility traces offer a means of retrospective credit assignment, their material nature is unknown. Here, we combined whole-cell recordings with two-photon uncaging, calcium imaging and biophysical modeling to address this question. We observed and parameterized a form of behavioral timescale synaptic plasticity (BTSP) in layer 5 pyramidal neurons of mice prefrontal areas wherein the pairing of temporally separated pre- and postsynaptic events (0.5 s – 1 s), irrespective of order, induced synaptic potentiation. By imaging calcium in apical oblique dendrites, we reveal a short-term and associative plasticity of calcium dynamics (STAPCD) whose time-dependence mirrored the induction rules of BTSP. We identified a core set of molecular players that were essential for both STAPCD and BTSP and that, together with computational simulations, support a model wherein the dynamics of intracellular handling of calcium by the endoplasmic reticulum (ER) provides a latent memory trace of neural activity that instantiates synaptic weight updates upon a delayed instructive signal. By satisfying the requirements expected of eligibility traces, this mechanism accounts for how individual neurons can conjunctively bind cellular events that are separated by behaviorally relevant temporal delays, and thus offers a cellular model of reinforced learning. ### Competing Interest Statement The authors have declared no competing interest.