Abstract
Songbirds learn precisely sequenced motor skills (songs) subserved by distinct brain areas, including the premotor cortical analog HVC, which is essential for producing learned song, and a 'cortical'–basal ganglia loop required for song plasticity. Inputs from these nuclei converge in RA (robust nucleus of the arcopallium), making it a likely locus for song learning. However, activity-dependent synaptic plasticity has never been described in either input. Using a slice preparation, we found that stimulation patterns based on singing-related activity were able to drive opposing changes in the strength of RA's inputs: when one input was potentiated, the other was depressed, with the direction and magnitude of changes depending on the relative timing of stimulation of the inputs. Moreover, pharmacological manipulations that blocked synaptic plasticity in vitro also prevented reinforcement-driven changes to song in vivo. Together, these findings highlight the importance of precise timing in the basal ganglia–motor cortical interactions subserving adaptive motor skills.
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Acknowledgements
The authors would like to thank M. Brainard, M. Stryker, K. Bender, F. Fernandez, R. Nicoll, and members of the Doupe, Brainard and Sabes laboratories for discussions and comments on the manuscript, particularly the exceptional patience of M. Kao. This work was supported by US National Institutes of Health grant MH55987 and a NARSAD Distinguished Investigator award (A.J.D.), and Canadian Institute of Health Research and Grass Foundation Fellowships (W.H.M.).
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A.J.D. and W.H.M. designed the experiments and wrote the manuscript. W.H.M. conducted the experiments and analyzed the data.
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Integrated supplementary information
Supplementary Figure 1 Synaptic currents observed after LMAN stimulation are incompletely blocked at hyperpolarized potentials.
a) Stimulation of LMAN currents isolated with DNQX, and intracellular QX-314, D-890 and K-Methylsulfonate to inhibit AMPA, Na+, Ca2+, and K+ currents. Even at hyperpolarized potentials stimulation of LMAN axons reveals a DNQX insensitive, rectifying current. This current reverses slightly above 0mV (b,c) and shows voltage dependence, but is incompletely blocked at hyperpolarized potentials.
Supplementary Figure 2 Time Course of Stable Changes to Synaptic Strength.
a,b) Paired stimulation of LMAN and HVC can lead to stable changes in synaptic strength which could be observed out to 50 minutes (0 ms delay) and 35 minutes (-100 ms delay).
Supplementary Figure 3 GABAA mediated inhibition does not alter synaptic amplitude, timing, or plasticity and has little influence near choride reversal.
a) Gabazine has little to no effect on membrane potentials at -80 mV (a), but influences the membrane potentials at depolarized voltages (a, 0mV). Further, Gabazine does not seem to alter the peak timing or current of EPSCs at -80 mV (b,c, p < 0.05), likely due to the IPSCs occurring well after the EPSC peak (c). Further, the presence of GABAA blockers fails to prevent lasting plasticity after paired simultaneous stimulation (d).
Supplementary Figure 4 Application of mGlur2/3 agonist LY35470 causes synaptic changes similar to those seen during paired simultaneous stimulation.
a) LY354740 causes increased paired pulse ratio and synaptic depression in HVC, while causing an increase in synaptic strength in LMAN without altering paired pulse ratio (a,b). Further, LY35470 causes no significant change in the amplitude of minuature EPSCs, but lowers their frequency (c,d).
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Mehaffey, W., Doupe, A. Naturalistic stimulation drives opposing heterosynaptic plasticity at two inputs to songbird cortex. Nat Neurosci 18, 1272–1280 (2015). https://doi.org/10.1038/nn.4078
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DOI: https://doi.org/10.1038/nn.4078
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