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Dynamic Modulation of Activity in Cerebellar Nuclei Neurons During 1 Dynamic Modulation of Activity in Cerebellar Nuclei Neurons during 2 Pavlovian Eyeblink Conditioning in Mice 3 M.M. ten Brinke1,4, S.A. Heiney2,4, X. Wang1,4, M. Proietti-Onori1, H.J. Boele1, J. Bakermans1, 4 J.F. Medina2,*, Z. Gao1,* and C.I. De Zeeuw1,3, 5 1 Department of Neuroscience, Erasmus Medical Center, 3000 DR Rotterdam, The 6 Netherlands 7 2 Department of Neuroscience, Baylor College of Medicine, Houston, Texas, 77030, USA 8 3 Netherlands Institute for Neuroscience, Royal Academy of Arts and Sciences (KNAW), 1105 9 BA Amsterdam, The Netherlands 10 4 These authors contributed equally 11 *Correspondence: [email protected] and [email protected] 12 13 Abstract 14 While research on the cerebellar cortex is crystallizing our understanding of its function in 15 learning behavior, many questions surrounding its downstream targets remain. Here, we 16 evaluate the dynamics of cerebellar interpositus nucleus (IpN) neurons over the course of 17 Pavlovian eyeblink conditioning. A diverse range of learning-induced neuronal responses was 18 observed, including increases and decreases in activity during the generation of conditioned 19 blinks. Trial-by-trial correlational analysis and optogenetic manipulation demonstrate that 20 facilitation in the IpN drives the eyelid movements. Adaptive facilitatory responses are often 21 preceded by acquired transient inhibition of IpN activity that, based on latency and effect, 22 appear to be driven by complex spikes in cerebellar cortical Purkinje cells. Likewise, during 23 reflexive blinks to periocular stimulation, IpN cells show excitation-suppression patterns that 24 suggest a contribution of climbing fibers and their collaterals. These findings highlight the 25 integrative properties of subcortical neurons at the cerebellar output stage mediating 26 conditioned behavior. 27 2 28 Introduction 29 The cerebellar cortex, like the neocortex, is well suited for establishing new associations 30 required during memory formation. It is becoming increasingly clear that, like cortical and 31 subcortical structures (e.g. Constantinople and Bruno, 2013; Koralek et al., 2012; Igarashi et 32 al., 2014; Douglas et al., 1995; Sherman and Guillery, 2004), the cerebellar cortex and nuclei 33 exhibit complex interplay, for instance through reciprocal nucleo-cortical projections (Gao et 34 al., 2016). Classical Pavlovian eyeblink conditioning has proven an ideal model for studying 35 the neural mechanisms underlying associative learning, and offers a suitable paradigm to 36 address the question of how the cerebellar nuclei integrate their cerebellar cortical and extra- 37 cerebellar input. 38 As a simple and quintessential behavioral manifestation of learning and memory, 39 eyeblink conditioning depends on the cerebellar cortex and nuclei (McCormick et al., 1982; 40 McCormick & Thompson, 1984; Yeo, Hardiman & Glickstein, 1985a, b), which are known to 41 facilitate processes that require precise timing (Ivry & Keele, 1989; Breska & Ivry, 2016). In 42 short, animals learn to respond to a neutral conditional stimulus (CS), such as a light, with a 43 well-timed conditioned blink response (CR), when the CS is consistently paired at a fixed 44 temporal interval with an unconditional blink-eliciting stimulus (US), such as a corneal air puff. 45 Lobule HVI of the cerebellar cortex and its downstream target, the interposed nucleus (IpN), 46 are essential for the manifestation of this conditioned eyelid behavior (McCormick et al., 1982; 47 McCormick and Thompson, 1984; Yeo, Hardiman, and Glickstein, 1985a, b; Clark et al., 1992; 48 Krupa and Thompson, 1997; Ohyama et al., 2006; Mostofi et al., 2010; Heiney et al., 2014b). 49 Genetic and pharmaceutical manipulations of cerebellar cortical Purkinje cells indicate that the 50 expression of CRs may require various cell physiological processes, including plasticity at the 51 excitatory parallel fiber to Purkinje cell synapse (Ito & Kano, 1982; Koekkoek et al., 2003; 52 Schonewille et al., 2010), inhibition at the molecular layer interneuron to Purkinje cell synapse 53 (Ten Brinke et al., 2015), as well as intrinsic mGluR7-mediated processes in Purkinje cells 54 (Johansson et al., 2015). IpN neurons that can drive eyeblink behavior through the red 55 nucleus and facial nucleus provide a feedback to the cerebellar cortex that amplifies the CR 56 (Gao et al., 2016; Giovannucci et al., 2017). Moreover, IpN neurons receive excitatory inputs 57 from mossy fiber and climbing fiber collaterals, which need to be integrated with the inhibitory 3 58 inputs from the Purkinje cells and local interneurons and possibly even from recurrent 59 collaterals of the nucleo-olivary neurons (Chan-Palay, 1973, 1977; De Zeeuw et al., 1988, 60 1997; Van Der Want et al., 1989; Uusisaari, Obata, and Knöpfel, 2007; Uusisaari and Knöpfel, 61 2008, 2011, 2012; Bagnall et al., 2009; Kodama et al., 2012; Witter et al., 2013; Boele et al., 62 2013; Najac and Raman, 2015; Canto et al., 2016). 63 IpN neurons and their inputs are endowed with ample forms of plasticity, all of which 64 may in principle be implicated in eyeblink conditioning (Ohyama et al., 2006; Foscarin et al., 65 2011; Zheng and Raman, 2010). These include for example short-term and long-term 66 potentiation (LTP) at the mossy fiber to IpN neuron synapse (Person and Raman, 2010), both 67 of which may facilitate the induction of intrinsic plasticity (Aizenman and Linden, 1999 and 68 2000; Zheng and Raman, 2010), and learning-dependent structural outgrowth of mossy fiber 69 collaterals in the cerebellar nuclei, which may be directly correlated to the rate and amplitude 70 of CRs (Boele et al., 2013). So far, extracellular recordings of neurons in the cerebellar nuclei 71 have revealed CR-related increases in activity that lead the eyeblink movement (anterior IpN; 72 McCormick and Thompson, 1984; Berthier and Moore, 1990; Gould and Steinmetz, 1996; 73 Choi and Moore, 2003; Halverson et al., 2010; Heiney et al., 2014b), and CR-related 74 increases and decreases in activity that lag the eyeblink movement (posterior IpN; Gruart et 75 al., 2000; Delgado-Garcia & Gruart, 2005; Sanchez-Campusano et al., 2007). However, 76 comprehensive trial-by-trial analysis of different components of IpN modulation in relation to 77 conditioned behavior, as well as evaluation against conditioning-related modulation of activity 78 in the cerebellar cortex and other non-cortical inputs, is lacking. 79 Here, we recorded conditioning-related activity in an identified blink area of the 80 anterior interpositus nucleus of awake behaving mice, and used in-depth trial-by-trial 81 correlational analysis, optogenetic manipulation and computationally modeled IpN output 82 based on previously reported eyelid-related Purkinje cell modulation (Ten Brinke et al., 2015) 83 to detail and cement the causal role of IpN activity in conditioned behavior. Our results reveal 84 an intricate dynamic modulation of cerebellar nuclei activity during the generation of 85 conditioned movements. We discuss how these findings shed light on a number of 86 electrophysiological properties of the olivocerebellar network as integrated at the IpN in the 87 normal functional context of eyeblink conditioning in awake, behaving mice. Together, our 4 88 results highlight how neurons in the IpN integrate cortical and non-cortical input to establish a 89 circuitry optimally designed to generate well-timed conditioned motor responses. 90 5 91 Results 92 93 Characterization of cerebellar IpN neurons 94 95 To explore the characteristics of IpN spike modulation and its relation to conditioned eyelid 96 behavior, we made extracellular recordings across 19 mice that were trained or in training. 97 During recordings, the mice were head-fixed on top of a cylindrical treadmill, fully awake and 98 able to show normal eyelid behavior in response to the experimental stimuli, which included a 99 260 ms green LED light (CS) that co-terminated with a 10 ms corneal air puff (US), yielding a 100 250 ms CS-US interval (Fig. 1A). 101 Initially, we collected 270 recordings of IpN cells that were located below Purkinje cell 102 layers at depths between 1500-3000 μm (Fig. 1B), that were recorded during at least 10 valid 103 CS-US trials, ánd that showed modulation in their firing rate in response to the CS and/or US. 104 Firing frequency was similar along the depth of the IpN (r = 0.085, p = 0.16, n = 270, Pearson), 105 averaging 67 ± 27 Hz. Within the entire dataset, 60 cells showed at least 5 Hz facilitation in the 106 CS-US interval (22.2%, Fig. 1C, F, I), and 23 cells showed at least 5 Hz suppression (8.5%, 107 Fig. 1D, G, J), leaving 187 cells that did not show any clear spike rate modulation within the 108 CS-US interval (69.3%, Fig. 1E, H, K; see Materials and Methods). 109 In terms of eyelid behavior across the dataset (Fig. 1L), CRs were present in at least 110 20% of trials in 103 cells (38%); this is the criterion used throughout the paper when referring 111 to recordings with behavior. The magnitude of spike facilitation showed a steady significant 112 increase over the course of conditioning (r = 0.413, p = 0.001, n = 60; Spearman); spike 113 suppression was similarly inclined (r = 0.354, p = 0.0972, n = 23; Spearman; Fig. 1M). 114 Although both types of spike rate modulation manifested before conditioned behavior did (Fig. 115 1M), they were more prevalent in recordings with conditioned behavior (Fig. 1O) than in those 116 without (Fig. 1N; facilitation: 29.1% (30/103) vs. 18% (30/167), p = 0.0463; suppression:
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