Figure 1.

Main directions of investigation for uncovering naturalistic plasticity rules, their circuit functions and causal link to learned behavior. (A) Uncovering naturalistic synaptic plasticity rules needs to rely on in vivo activity patterns, by considering the rate and timing of naturally incoming inputs, which can then be replayed in vitro. Mimicry experiments aim to mimic naturalistic stimulation, compatible with synaptic plasticity expression. Next, understanding the function of synaptic plasticity expression in a given circuit remains a major challenge. Different forms of plasticity, occurring at different synapses, expressed at different timescales and relying on different molecular cascades (constituting the plasticitome) may be evoked within a single event and hence requires a circuit-level investigation, that further considers the presence of third factors (e.g., neuromodulators, neuropeptides or glial cells), and also of macroscale factors (such as body–brain internal states or neuroenergetic load). Finally, determining causal links between synaptic plasticity and learned behavior has remained limited to stereotypical behavior. (B) Example of naturalistic stimulation, based on singing-related activity, leading to opposing heterosynaptic plasticity in the songbird cortex (robust nucleus of the arcopallium, RA), in which two inputs critical for song learning converge: afferences from premotor HVC (dark) and one from LMANN (red): when one input is potentiated, the other is depressed, and direction of plasticity (y-axis) shows a strong dependence on the relative timing of stimulation (lag, x-axis). Example traces of excitatory post-synaptic potentials (EPSC) pre and post-stimulation are displayed for 0 ms time lag. Adapted from Mehaffey and Doupe (2015). (C) Example of an evoked-bidirectional plasticity and induced-behavioral changes. LTP or LTD were induced at cortico-striatal synapses in vivo, using optogenetic tools and virally-mediated expression of excitatory opsins in medial prefrontal cortex and dorsomedial striatum (top schemas). Induction of LTP and LTD led rats trained to self-administer ethanol to actively press more the lever over several days post-plasticity induction protocol, leading to increased ethanol intake (orange trace), or long-lasting reduction of their number of lever presses (blue trace) their number of lever presses (blue trace), respectively. Adapted from Ma et al. (2018).