Interplay of multiple plasticities and activity dependent rules: data, models and possible impact on

Gaetan Vignoud, Alexandre Mendes, Sylvie Perez, Jonathan Touboul*, Laurent Venance* (* equal contributions, email: fi[email protected]) College` de France, Center for Interdisciplinary Research in Biology, 11 Place Marcelin Berthelot, 75005 Paris, France

Abstract the millisecond timing of the paired activities on either side of , the activity-dependent evolution neuronal the (Feldman, 2012). As such, plasticity in the stria- connectivity, is admitted to underpin learning and memory. A tum has been widely studied and a variety of spike-timing de- paradigmatic plasticity depending on the spike timings of cells pendent plasticity were observed in response to a large num- on both sides of the synapse (STDP), was experimentally ev- ber of presentations of a fixed pre- and post-synaptic stim- idenced through multiple repetitions of fixed pre- and post- ulation pattern. Those plasticities were attributed to a di- synaptic spike patterns. Theoretical and experimental com- verse neurotransmitters and pathways including for instance munities often implicitly admit that plasticity is gradually estab- endocannabinoids (eCB), NMDA receptors, AMPA receptors lished as stimulus patterns are presented. Here, we evaluate or voltage-sensitive calcium channels. Moreover, the vast ma- this hypothesis experimentally and theoretically in the stria- jority of the studies focused on cortical inputs, and much less tum, where (i) may involve multiple pathways, or is known about thalamo-striatal plasticity rules. (ii) synaptic connections with multiple area exist. We The present contribution investigates on the possible inter- will present models and experiments leading to reevaluate play between multiple plasticities in the striatum, and consid- this hypothesis, showing that (i) multiple pathways may lead ers both the interaction between multiple pathways with var- to non-monotonic establishments of plasticity where plasticity ious dynamics and timescales at a single synapse, as well can be inverted depending on the number of stimulus presen- as multiple plasticities combining inputs from different brain tations, and (ii) that multiple connections with in particular tha- areas, here the combination of thalamo- and cortico-striatal lamus and cortex contribute to shaping their plasticities. We plasticity. The observation of complex history-dependent rules will propose a mathematical model building upon calcium tran- we lead us to discuss whether these are a negative aspect sients to precisely dissect these complex interplays on result- due to the biological substrate of plasticity, of it can lead an ing plasticities and reveal unexpected dependences on vari- advantage for learning. ables side variables (e.g. repetitions, frequency, temporal win- dow). These results invite to reevaluate how plasticity is im- Interplay of different mechanisms at the plemented as a global process, and to explore consequences cortico-striatal synapses on data processing capability and inspire new artificial intelli- gence techniques. We will start by presenting recent experimental plasticity data Keywords: Spike-Timing Dependent Plasticity; multiple path- from the dorsal striatum where the number of presentations of ways; mathematical modeling; calcium transients; a fixed timing of pre- and post-synaptic spikes is varied (Cui et al., 2015, 2016), and show that low numbers of pairing Introduction ( 5-10) induce an endocannabinoid-mediated spike-timing- The basal ganglia is a group of subcortical nuclei are involved dependent potentiation whereas larger numbers of pairings in goal-directed behavior, procedural learning, routine behav- ( 100) yield to anti-hebbian STDP, where potentiation is me- iors and cognition. Among those nuclei, the striatum con- diated by NMDA and depression is now dependent on en- stitutes the primary input layer to the basal ganglia and col- docannabinoids (see Fig. 1). This observation of the depen- lects information from both the cerebral cortex and the tha- dence of STDP to the number of pairings stands in contradic- lamus. The striatum constitutes a major site of memory for- tion with the implicit hypothesis of a monotonic establishment mation as the acquisition or extinction in the behavioral reper- of plasticity and points towards possible complex interplays of toire has been associated with cortico-striatal synaptic plas- pathways dynamics and timescales. To explore this hypothe- ticity (Koralek, Jin, Long, Costa, & Carmena, 2012). The stria- sis, we present here a new model building upon the calcium tum thus constitutes a key brain region to investigate in order hypothesis (Graupner & Brunel, 2012), generalized to com- to explore learning and cognition in the brain. bine multiple pathways within the same synapse. We show According to , neural networks refine their that the model is able to reproduce accurately the data, and connectivity by patterned firing of action potentials in pre- predict a variety of response as a function of the number of and postsynaptic . Spike-timing-dependent plasticity presentations but also their frequency. We develop this model (STDP) is a synaptic Hebbian that has been the to predict possible outcomes of Hebbian learning rules when focus of considerable attention in experimental and computa- those rely on multiple pathways, and will show that diverse tional . STDP relies on the precise order and (but not any) type of plasticity profiles may emerge as a func- a b Cortex Synaptic strength Pre-synaptic element

CB1R Χ Thalamus Glu

3.0 eCB-LTD 3.0 2.5 eCB-LTP 2.5 2.0 AMPAR mGluR 2.0 1.5 1.5 1.0 1.0 NMDAR 0.5 0.5 0.0 −0.10 −0.05 0.00 0.05 0.10 0.0 Δt (s) −0.10 −0.05 0.00 0.05 0.10 eCB Δt (s) synthesis - - + LTD + + LTD + 2+ LTP > θ LTP LTP > θ LTP Ca eCB,LTD eCB,LTD Striatum NMDAR-LTP > θeCB,LTP > θeCB,LTP > θNMDAR,LTP > θNMDAR,LTP VSCC Ca CamKII Calcium Calcium Cortex - Striatum Thalamus - Striatum Synapse 1 Synapse N

Post-synaptic element Change in synaptic strength c 0.04 0.04 1.5 2.5 0.02 0.02 ) s Δt < 0 ( S T

t 0.00 0.00 1.0 Δt > 0 Δ

Model Mean of 2.0 experimental data −0.02 −0.02 0.5

−0.04 −0.04

1.5 −0.04 −0.02 0.00 0.02 0.04 −0.04 −0.02 0.00 0.02 0.04 Δt (s) ΔtCS (s) CS

1.0

Change in synaptic strength synaptic in Change 0.5 Figure 2: Model for the coupled cortico- and thalamo-striatal 0 20 40 60 80 100 Number of pairings STDP: top: schematic description of the cortical (green) and thalamic (purple) input to the a striatal cell (pink), with distinct types of plas- ticities (green +: experimental points, fitted with the calcium model - Figure 1: Model for the cortico-striatal STDP dark blue curve). Bottom: predictions of the interplay of Cortico and (a-b) Synapse with the three distinct plasticity pathways, (c) interplay thalamo-striatal synaptic efficacy together with experimental points of eCB and NMDA plasticity in the dorsal striatum as a function of (circles) for double stimulations. the number of pairings: model (curves) and experimental points from (Cui et al., 2015, 2016). Acknowledgments This project was funded in part by Inserm, FRM, Inria Paris- tion of the number of stimulus presentations, and propose a Rocquencourt, College` de France and CNRS Mission pour simple methodology to distinguish experimentally those sce- l’interdisciplinarite´ (project Big Data for the brain). narios. References Thalamic vs cortical inputs on striatum Cui, Y., Paille,´ V., Xu, H., Genet, S., Delord, B., Fino, E., . . . Venance, L. (2015). Endocannabinoids mediate bidirec- Using ex vivo electrophysiology (patch-clamp recordings in tional striatal spike-timing-dependent plasticity. J. Physiol. acute rodent brain slices), we show new experimental data Lond., 593(13), 2833–2849. revealing bidirectional STDP at both thalamic and cortical in- Cui, Y., Prokin, I., Xu, H., Delord, B., Genet, S., Venance, puts, driving opposing changes at striatal synapses, respec- L., & Berry, H. (2016). Endocannabinoid dynamics gate tively Hebbian and anti-Hebbian, see Fig. 2. Using a double- spike-timing dependent depression and potentiation. eLife, stimulation protocol, we also observed that thalamo-striatal 5, e13185. STDP produced a heterosynaptic plasticity at non-stimulated Feldman, D. E. (2012, August). The spike-timing de- cortico-striatal synapses, and conversely at thalamo-striatal pendence of plasticity. , 75(4), 556–571. doi: synapses. These findings highlight the major impact of pre- 10.1016/j.neuron.2012.08.001 cise timing in cortical and thalamic activity for the memory Graupner, M., & Brunel, N. (2012). Calcium-based plastic- engram at striatal synapses. Via this heterosynaptic plas- ity model explains sensitivity of synaptic changes to spike ticity, thalamus efficiently shapes the cortico-striatal efficacy pattern, rate, and dendritic location. PNAS, 109(10), 3991– changes. Thus, these findings highlight the major impact of 3996. precise timing in cortical and thalamic activity for the mem- Koralek, A. C., Jin, X., Long, J. D., Costa, R. M., & Car- ory engram at striatal synapses. We further investigate ex mena, J. M. (2012). Corticostriatal plasticity is necessary vivo and in vivo the functional consequences of such mir- for learning intentional neuroprosthetic skills. Nature, 483, rored plasticity. Moreover, we will further develop our calcium 331–335. based-model to explore the possible origins of these mirror plasticities, and particularly the possible role of calcium diffu- sion across distinct compartments within the cell. This model, fitted to the data, allows to predict a number of unexpected plasticities for specific combinations of timings of thalamic and cortical spikes relative to striatal spikes, both on the thalamo- striatal and cortico-striatal synapses, that we are currently val- idating experimentally.