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Catecholaminergic Innervation of the Lateral Nucleus of the Cerebellum Modulates Cognitive Behaviors

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Catecholaminergic Innervation of the Lateral Nucleus of the Cerebellum Modulates Cognitive Behaviors Research Articles: Behavioral/Cognitive Catecholaminergic Innervation of the Lateral Nucleus of the Cerebellum Modulates Cognitive Behaviors https://doi.org/10.1523/JNEUROSCI.2406-20.2021 Cite as: J. Neurosci 2021; 10.1523/JNEUROSCI.2406-20.2021 Received: 14 September 2020 Revised: 12 January 2021 Accepted: 16 January 2021 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2021 the authors 1 Title: Catecholaminergic Innervation of the Lateral Nucleus of the Cerebellum Modulates 2 Cognitive Behaviors 3 Abbreviated Title: Lateral Cerebellar Nuclear Catecholamines Modulate Cognition 4 Authors: Erik S. Carlson*1,2, Avery Hunker3, Stefan G. Sandberg1, Timothy M. Locke3, Julianne 5 Geller2, Abigail Schindler2, Steven Thomas5, Martin Darvas4, Paul E. M. Phillips1, and Larry S. 6 Zweifel1,3. 7 1Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, USA, 8 98195 9 2Geriatric Research, Education and Clinical Center, Veteran's Affairs Medical Center, Puget 10 Sound, Seattle, USA, 98108 11 3Department of Pharmacology, University of Washington, Seattle, WA, USA, 98195 12 4Department of Pathology, University of Washington, Seattle, WA, USA, 98195 13 5Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA, 19104 14 *Corresponding author: 15 Erik S. Carlson, M.D., Ph.D. 16 Assistant Professor 17 University of Washington, Seattle 18 Department of Psychiatry and Behavioral Sciences 19 Veteran's Affairs Medical Center, Puget Sound 20 Geriatric Research, Education and Clinical Center 21 Building 100, 705 22 1660 S. Columbian Way 23 Seattle, WA, 98108 24 [email protected] 25 Number of pages: 50 26 Number of figures/tables: 1 table, 12 figures 27 Number of words: Abstract: 250. Introduction: 650. Discussion: 1500. 28 Conflict of interest statement: The authors declare that the submitted work was carried out 29 without the presence of any personal, professional, or financial relationships that could 30 potentially be construed as a conflict of interest. 31 Acknowledgements: This work was supported by Department of Veteran’s Affairs (salary for 32 ESC) and the National Institutes of Health Grant No. K08-MH104281 and R01-MH116883 to 33 ESC, and Grant Nos. R01-MH0945, R21-MH098177 to LSZ. We thank Zweifel and Carlson Lab 34 members for careful review (especially Marta Soden), Hirofumi Fujita, and Richard Palmiter for 35 scientific discussion, and Scott Ng-Evans for help with programming operant chambers. 36 Author Contributions: EC and LZ designed all experiments. EC, MD, ST, SS, and LZ wrote the 37 manuscript. AS and JG performed TH expression analysis in serial cerebellar sections. SS and 38 PP performed and analyzed the voltammetry experiments. EC, AH, SJ and TL performed 39 behavioral experiments and analyses. EC performed immunohistochemical analyses on viral 40 injected animals. AH performed Western Blots. 41 42 43 44 45 46 47 48 49 50 51 52 ABSTRACT: 53 The cerebellum processes neural signals related to rewarding and aversive stimuli, 54 suggesting that the cerebellum supports non-motor functions in cognitive and emotional 55 domains. Catecholamines are a class of neuromodulatory neurotransmitters well known for 56 encoding such salient stimuli. Catecholaminergic modulation of classical cerebellar functions 57 have been demonstrated. However, a role for cerebellar catecholamines in modulating 58 cerebellar non-motor functions is unknown. 59 Using biochemical methods in male mice, we comprehensively mapped tyrosine 60 hydroxylase (TH)+ fibers throughout the entire cerebellum and known precerebellar nuclei. 61 Using electrochemical (fast scan cyclic voltammetry, FSCV), and viral/genetic methods to 62 selectively delete Th in fibers innervating the lateral cerebellar nucleus (LCN), we interrogated 63 sources and functional roles of catecholamines innervating the LCN, which is known for its role 64 in supporting cognition. 65 The LCN has the most TH+ fibers in cerebellum, as well as the most change in rostro- 66 caudal expression among the cerebellar nuclei (CN). Norepinephrine is the major 67 catecholamine measured in LCN. Distinct catecholaminergic projections to LCN arise only from 68 locus coeruleus (LC), and a subset of Purkinje cells (PCs) that are positive for staining of TH. 69 LC stimulation was sufficient to produce catecholamine release in LCN. Deletion of Th in fibers 70 innervating LCN (LCN-Th-cKO) resulted in impaired sensorimotor integration, associative fear 71 learning, response inhibition, and working memory in LCN-Th-cKO mice. Strikingly, selective 72 inhibition of excitatory LCN output neurons with inhibitory DREADDs led to facilitation of 73 learning on the same working memory task impaired in LCN-Th-cKO mice. Collectively, these 74 data demonstrate a role for LCN catecholamines in cognitive behaviors. 75 76 Significance Statement 77 Here, we report on interrogating sources and functional roles of catecholamines innervating the 78 lateral nucleus of the cerebellum (LCN). We map and quantify expression of tyrosine 79 hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis, in the entire cerebellar 80 system, including several precerebellar nuclei. We utilized cyclic voltammetry and 81 pharmacology to demonstrate sufficiency of LC stimulation to produce catecholamine release in 82 LCN. We used advanced viral techniques to map and selectively knockout catecholaminergic 83 neurotransmission to the LCN, and characterized significant cognitive deficits related to this 84 manipulation. Finally, we show that inhibition of excitatory LCN neurons with DREADDs, 85 designed to mimic Gi-coupled catecholamine GPCR signaling, results in facilitation of a working 86 memory task impaired in LCN-specific TH knockout mice. 87 Introduction 88 Several recent reports indicate that the cerebellum processes non-motor signals related 89 to fear (Sacchetti et al., 2002; Sacchetti et al., 2004; Sacchetti et al., 2007; Scelfo et al., 2008) 90 and reward (Mittleman et al., 2008; Thoma et al., 2008; Rogers et al., 2011; Wagner et al., 91 2017; Carta et al., 2019; Heffley and Hull, 2019; Kostadinov et al., 2019; Tsutsumi et al., 2019), 92 which supports the hypothesis that cerebellum participates in non-motor functions. The 93 catecholamines dopamine (DA) and norepinephrine (NE) are neuromodulatory 94 neurotransmitters well known for processing such salient stimuli and facilitating learning 95 mechanisms related to approach, avoidance, and cognitive behaviors (Schultz, 2013; Aston- 96 Jones and Waterhouse, 2016). Dopaminergic (Ikai et al., 1992; Melchitzky and Lewis, 2000) 97 and noradrenergic (Hokfelt and Fuxe, 1969; Olson and Fuxe, 1971; Landis and Bloom, 1975; 98 Landis et al., 1975; Loughlin et al., 1986a; Loughlin et al., 1986b; Nelson et al., 1997) 99 innervation of the cerebellum has been documented in several species, and NE modulates 100 classical cerebellar functions (Watson and McElligott, 1983, 1984; Paredes et al., 2009). 101 Notably, NE regulates associative synaptic plasticity between climbing fibers and Purkinje cells 102 (PCs) (Carey and Regehr, 2009), and PCs release DA in an autocrine manner from dendrites to 103 regulate PC excitability (Kim et al., 2009). 104 We previously found that Dopamine D1 Receptor positive (D1R+) neurons residing in a 105 specific subregion of the lateral cerebellar nucleus (LCN) in mice project to several brainstem, 106 midbrain, and thalamic nuclei associated with cognitive functions (Locke et al., 2018). D1R+ 107 LCN neurons are necessary for spatial navigation memory, social recognition memory, 108 temporally dependent response inhibition, and maintenance of working memory in mice (Locke 109 et al., 2018). Pharmacological blockade of LCN D1Rs results in attenuation of neuronal firing 110 patterns in prefrontal cortex, and impaired interval timing performance associated with these 111 patterns (Heskje et al., 2019). Tyrosine hydroxylase (TH) expression by PCs is required for 112 performance in many cognitive domains (Locke et al., 2020). However, very little is known about 113 whether the LCN receives catecholaminergic innervation, or what the role of catecholaminergic 114 innervation of the LCN is in facilitating learning or modulating these cognitive functions in the 115 context of cerebellar function. 116 We hypothesized that the LCN could be targeted to interrogate catecholamine- 117 dependent cognitive functions of the cerebellum. In the context of cerebellar catecholamines, 118 the LCN is of great interest. Catecholamines modulate classical cerebellar associative eyeblink 119 conditioning in the interposed cerebellar nucleus (Cartford et al., 2004). In humans, the dentate 120 nucleus of the cerebellum (analog of rodent LCN) shows activation during cognitive 121 performance, and has divisions with differential activations during cognitive and motor tasks 122 (Kim et al., 1994; Dum and Strick, 2003; Kuper et al., 2011; Tellmann et al., 2015). Furthermore, 123 cerebellar nuclei (CN) contain output neurons with axons that bifurcate with projections to both 124 thalamus and to cerebellar cortex (CCtx) (Houck and Person, 2015), process efference copy 125 signals from cerebral cortex (Houck and Person, 2015) and
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