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Transcriptomes of Electrophysiologically Recorded Dbx1-Derived Inspiratory Neurons of 2 the Prebötzinger Complex in Neonatal Mice 3 Authors: 4 Prajkta S

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Transcriptomes of Electrophysiologically Recorded Dbx1-Derived Inspiratory Neurons of 2 the Prebötzinger Complex in Neonatal Mice 3 Authors: 4 Prajkta S bioRxiv preprint doi: https://doi.org/10.1101/2021.08.01.454659; this version posted August 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Title: Transcriptomes of Electrophysiologically Recorded Dbx1-derived Inspiratory Neurons of 2 the preBötzinger Complex in Neonatal Mice 3 Authors: 4 Prajkta S. Kallurkar1, ORCID: 0000-0003-2911-6595 5 Maria Cristina D. Picardo1, ORCID: 0000-0001-8912-2175 6 Yae K. Sugimura2, ORCID: 0000-0001-8840-797X 7 Margaret S. Saha3, ORCID: 0000-0003-0096-2667 8 Gregory D. Conradi Smith1, ORCID: 0000-0002-1054-6790 9 Christopher A. Del Negro1, ORCID: 0000-0002-7848-8224 10 Author affiliations: 11 1 Department of Applied Science, William & Mary, Williamsburg, Virginia, USA 12 2 Department of Neuroscience, Jikei University School of Medicine, Tokyo, Japan 13 3 Department of Biology, William & Mary, Williamsburg, Virginia, USA 14 Corresponding author: Christopher A. Del Negro, Ph.D., [email protected], 757-221-7808 15 Disclaimers: The views expressed in the submitted article are those of the authors and not the 16 official position of William & Mary. 17 Author Contributions: PK, MCP, and YS contributed equally to the project. PK, MCP and YS 18 performed the experiments. PK, CDN, MCP, MSS, and GDS analyzed the data. PK and CDN wrote 19 the paper. All authors edited and approved the final version. 20 Acknowledgements: funded by NIH R01 NS107296 (PI: Del Negro), NIH R01 AT01816 (PI: 21 Conradi Smith and Del Negro, NSF DMS 1951646 (PI: Conradi Smith), NSF DEB 2031275 (PI: 22 Conradi Smith), NIH R15 HD096415 (PI: Saha) 23 Number of figures and tables: 5 figures with 4 figure supplements; 3 table supplements 24 Number of words in Abstract: 151 25 Number of words in Introduction: 472 26 Conflict of interest: The authors declare no conflicting financial interests. bioRxiv preprint doi: https://doi.org/10.1101/2021.08.01.454659; this version posted August 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 27 Abstract 28 Breathing depends on interneurons in the preBötzinger complex (preBötC) derived from Dbx1- 29 expressing precursors. Here we investigate whether rhythm- and pattern-generating functions 30 reside in discrete classes of Dbx1 preBötC neurons. In a slice model of breathing with ~5 s cycle 31 period, putatively rhythmogenic Type-1 Dbx1 preBötC neurons activate 100-300 ms prior to 32 Type-2 neurons, putatively specialized for output pattern, and 300-500 ms prior to the 33 inspiratory motor output. We sequenced Type-1 and Type-2 transcriptomes and identified 34 differential expression of 123 genes including ionotropic receptors (Gria3 and Gabra1) that may 35 explain their preinspiratory activation profiles and Ca2+ signaling (Cracr2a, Sgk1) involved in 36 inspiratory and sigh bursts. Surprisingly, neuropeptide receptors that influence breathing (e.g., 37 µ-opioid and bombesin-like peptide receptors) were only sparsely expressed, which suggests 38 that cognate peptides and opioid drugs exert their profound effects on a small fraction of the 39 preBötC core. These data in the public domain help explain breathing’s neural origins. 40 Introduction 41 Inspiration, the preeminent active phase of breathing, originates in the preBötzinger complex 42 (preBötC) of the lower brainstem1,2. Interneurons derived from Dbx1-expressing precursors 43 (hereafter, Dbx1 neurons)3,4 comprise the preBötC core; they are responsible for generating 44 inspiratory rhythm and transmitting it as a rudimentary output pattern to premotoneurons and 45 motoneurons for pump and airway muscles5–9. 46 Cellular-level studies of inspiratory rhythm and pattern take advantage of transverse slices that 47 retain the preBötC and remain spontaneously rhythmic in vitro. Constituent preBötC neurons 48 can be recorded at the rostral slice surface while monitoring the inspiratory motor rhythm (~5 s 49 cycle period) via the hypoglossal (XII) cranial nerve. Inspiration begins with a low amplitude 50 preinspiratory phase attributable solely to rhythmogenic neurons. As their activity crosses 51 threshold, preinspiration leads to an inexorable high amplitude inspiratory burst, which recruits 52 an additional class of pattern-related neurons that drive motor output2,10–12. There are two 53 theories that differentiate the rhythm and pattern subsets of the Dbx1 preBötC neuron 54 population. 55 The first theory posits that the neuropeptide somatostatin (SST) is a marker for output/pattern 56 neurons. SST-expressing (SST+) preBötC neurons discharge during inspiration and 57 postinspiration, i.e., the output phases of the inspiratory breathing cycle, rather than during the 58 rhythmogenic preinspiratory phase. Furthermore, photostimulation in the preBötC of adult 59 mice that express channelrhodopsin (ChR2) in SST+ neurons preferentially affects inspiratory 60 motor pattern6. These findings, in the context of what we already know about Dbx1 neurons, 61 suggest that the Dbx1 SST+ preBötC neurons play a dominant role in inspiratory pattern- 62 generation and, by exclusion, that Dbx1 preBötC neurons lacking SST expression (SST-) are 63 inspiratory rhythmogenic6. 64 The second theory subdivides Dbx1 preBötC neurons electrophysiologically. Neurons that 65 activate with a ramp-like summation of synaptic potentials 300-500 ms before the onset of a 66 large-magnitude inspiratory burst13,14 are considered “Type-1” and putatively rhythmogenic. + 67 Type-1 neurons also express A-type transient K current (IA) whose blockade perturbs 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.08.01.454659; this version posted August 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 68 preinspiratory activity and destabilizes the inspiratory rhythm in vitro15. Neurons that activate 69 ~300 ms later than Type-113,14 are considered “Type-2”, putatively downstream from Type-1 70 and tasked with generating preBötC output10,14. Type-2 neurons express hyperpolarization- 13 71 activated cationic current (Ih) whose blockade profoundly affects motor output with mild 72 effects on rhythm16. 73 We subdivided rhythm and pattern Dbx1 preBötC neurons based on the latter theory, which 74 provides multiple criteria that can be measured during whole-cell recordings. We retrieved 75 cytoplasmic contents and performed next-generation RNA sequencing on 17 samples: 7 Type-1, 76 9 Type-2, and 1 neuron, referred to here as Unknown, that did not precisely fit either category 77 but was Dbx1-derived and inspiratory. These data elucidate the transcriptional profile at the 78 cellular point of origin for breathing, a key physiological behavior for humans and all mammals. 79 The data are publicly available (National Center for Biotechnology Information [NCBI] Gene 80 Expression Omnibus [GEO] Accession code: GSE175642) to facilitate future studies of the Dbx1 81 preBötC core that interrogate the neural mechanisms of breathing. 82 Results and Discussion 83 We analyzed Dbx1 preBötC neurons using Patch-Seq17, which entails whole-cell patch-clamp 84 recording followed by next-generation sequencing (Supplementary Fig. 1A) and bioinformatics 85 (Supplementary Fig. 1B). 86 The maximum yield of high-quality RNA was inversely proportional to whole-cell recording 87 duration (5 min on average, 3-8 min in all experiments). Inspiratory burst characteristics and 88 intrinsic membrane properties for Type-1 and Type-2 neurons (Fig. 1A top and bottom, 89 respectively) are already well established13,14. Given the time constraints, we focused on 90 measuring the intrinsic membrane properties i.e., delayed excitation and sag potentials, at the 91 expense of recording fewer inspiratory burst cycles. 92 Our patch-clamp recordings confirmed the previously published disparities between Type-1 and 93 Type2 neurons. Type-1 neurons showed delayed excitation of 167 ± 40 ms (n = 7) when 94 subjected to suprathreshold current steps from a baseline membrane potential below -70 mV 95 (i.e., evidence of IA; Fig. 1B, top trace) but negligible sag potentials (2 ± 1 mV, n = 7) when 96 subjected to hyperpolarizing current steps from a baseline membrane potential of -50 mV (i.e., 97 no evidence of Ih; Fig. 1C, top trace). 98 Type-2 neurons exhibited minimal delays in excitation (76 ± 40 ms, n = 9) when subjected to 99 suprathreshold current steps from a baseline membrane potential below -70 mV (i.e., no 100 evidence of IA; Fig. 1B, bottom trace) but their membrane potential trajectory ‘sagged’ 11 ± 4 101 mV (n = 9) in the direction of baseline when subjected to hyperpolarizing current steps from a 102 baseline membrane potential of -50 mV (i.e., evidence of Ih; Fig. 1C, bottom trace). 103 The disparities between delayed excitation and sag potentials measured in Type-1 and Type-2 104 neurons are unlikely to occur by random sampling from a single population with normally 105 distributed expression of IA and Ih with probabilities of pdelay = 0.0006 (t = 4.53, df = 13) and psag 106 = 0.0002 (t = 4.96, df = 14), respectively. Therefore, we reject the null hypothesis and reconfirm 107 that Type-1 and Type-2 are unique subpopulations of Dbx1 preBötC neurons13. 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.08.01.454659; this version posted August 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
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