Abstract
Retrograde tracing is an important method for dissecting neuronal connections and mapping neural circuits. Over the past decades, several virus-based retrograde tracers have been developed and have contributed to display multiple neural circuits in the brain. However, most of the previously widely used viral tools have focused on mono-transsynaptic neural tracing within the central nervous system, with very limited options for achieving polysynaptic tracing between the central and peripheral nervous systems. In this study, we generated a novel mouse line, GT mice, in which both glycoprotein (G) and ASLV-A receptor (TVA) were expressed throughout the body. Using this mouse model, in combination with the well-developed rabies virus tools (RABV-EnvA-ΔG) for monosynaptic retrograde tracing, polysynaptic retrograde tracing can be achieved. This allows functional forward mapping and long-term tracing. Furthermore, since the G-deleted rabies virus can travel upstream against the nervous system as the original strain, this mouse model can also be used for rabies pathological studies.
Graphical Abstract: Application of GT Mice
Similar content being viewed by others
Data Availability
The data and materials generated in this study is available upon reasonable request.
References
Axer M, Amunts K (2022) Scale matters: the nested human connectome. Sci (New York N Y) 378:500–504. https://doi.org/10.1126/science.abq2599
Beier KT, Kim CK, Hoerbelt P et al (2017) Rabies screen reveals GPe control of cocaine-triggered plasticity. Nature 549:345–350. https://doi.org/10.1038/nature23888
Brittle EE, Reynolds AE, Enquist LW (2004) Two modes of pseudorabies virus neuroinvasion and lethality in mice. J Virol 78:12951–12963. https://doi.org/10.1128/JVI.78.23.12951-12963.2004
Chatterjee S, Sullivan HA, MacLennan BJ et al (2018) Nontoxic, double-deletion-mutant rabies viral vectors for retrograde targeting of projection neurons. Nat Neurosci 21:638–646. https://doi.org/10.1038/s41593-018-0091-7
Craddock RC, Jbabdi S, Yan CG et al (2013) Imaging human connectomes at the macroscale. Nat Methods 10:524–539. https://doi.org/10.1038/nmeth.2482
Dietzschold B, Schnell M, Koprowski H (2005) Pathogenesis of rabies. Curr Top Microbiol Immunol 292:45–56. https://doi.org/10.1007/3-540-27485-5_3
Fisher CR, Streicker DG, Schnell MJ (2018) The spread and evolution of rabies virus: conquering new frontiers. Nature reviews. Microbiology 16:241–255. https://doi.org/10.1038/nrmicro.2018.11
Hannah R, Aron AR (2021) Towards real-world generalizability of a circuit for action-stopping. Nat Rev Neurosci 22:538–552. https://doi.org/10.1038/s41583-021-00485-1
He ZG, Wang Q, Xie RS et al (2018) Neuroanatomical autonomic substrates of brainstem-gut circuitry identified using transsynaptic tract-tracing with pseudorabies virus recombinants. Am J Clin experimental Immunol 7:16–24
Kelly RM, Strick PL (2000) Rabies as a transneuronal tracer of circuits in the central nervous system. J Neurosci Methods 103:63–71. https://doi.org/10.1016/s0165-0270(00)00296-x
Kim EJ, Jacobs MW, Ito-Cole T, Callaway EM (2016) Improved monosynaptic neural circuit tracing using Engineered rabies Virus Glycoproteins. Cell Rep 15:692–699. https://doi.org/10.1016/j.celrep.2016.03.067
Li X, Chen W, Pan K et al (2018) Serotonin receptor 2c-expressing cells in the ventral CA1 control attention via innervation of the Edinger-Westphal nucleus. Nat Neurosci 21:1239–1250. https://doi.org/10.1038/s41593-018-0207-0
Li X, Chen W, Huang X et al (2021a) Synaptic dysfunction of Aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors. Mol Neurodegener 16:73. https://doi.org/10.1186/s13024-021-00494-9
Li X, Chen W, Yu Q et al (2021b) A circuit of mossy cells controls the efficacy of memory retrieval by Gria2I inhibition of Gria2. Cell Rep 34:108741. https://doi.org/10.1016/j.celrep.2021.108741
Li X, Yu H, Zhang B et al (2022) Molecularly defined and functionally distinct cholinergic subnetworks. Neuron 110:3774–3788e3777. https://doi.org/10.1016/j.neuron.2022.08.025
Morimoto K, Hooper DC, Carbaugh H et al (1998) Rabies virus quasispecies: implications for pathogenesis. Proc Natl Acad Sci USA 95:3152–3156. https://doi.org/10.1073/pnas.95.6.3152
Ngai J (2022) BRAIN 2.0: transforming neuroscience. Cell 185:4–8. https://doi.org/10.1016/j.cell.2021.11.037
Oh SW, Harris JA, Ng L et al (2014) A mesoscale connectome of the mouse brain. Nature 508:207–214. https://doi.org/10.1038/nature13186
Pi HJ, Hangya B, Kvitsiani D et al (2013) Cortical interneurons that specialize in disinhibitory control. Nature 503:521–524. https://doi.org/10.1038/nature12676
Pomeranz LE, Reynolds AE, Hengartner CJ (2005) Molecular biology of pseudorabies virus: impact on neurovirology and veterinary medicine. Microbiol Mol Biol Rev 69:462–500. https://doi.org/10.1128/MMBR.69.3.462-500.2005
Prasad JA, Chudasama Y (2013) Viral tracing identifies parallel disynaptic pathways to the hippocampus. J Neurosci 33:8494–8503. https://doi.org/10.1523/jneurosci.5072-12.2013
Reardon TR, Murray AJ, Turi GF et al (2016) Rabies virus CVS-N2c(∆G) strain enhances Retrograde synaptic transfer and neuronal viability. Neuron 89:711–724. https://doi.org/10.1016/j.neuron.2016.01.004
Rossi LF, Harris KD, Carandini M (2020) Spatial connectivity matches direction selectivity in visual cortex. Nature 588:648–652. https://doi.org/10.1038/s41586-020-2894-4
Tang X, Jaenisch R, Sur M (2021) The role of GABAergic signalling in neurodevelopmental disorders. Nat Rev Neurosci 22:290–307. https://doi.org/10.1038/s41583-021-00443-x
Tervo DG, Hwang BY, Viswanathan S et al (2016) A designer AAV variant permits efficient Retrograde Access to Projection neurons. Neuron 92:372–382. https://doi.org/10.1016/j.neuron.2016.09.021
Tye KM, Prakash R, Kim SY et al (2011) Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 471:358–362. https://doi.org/10.1038/nature09820
Ugolini G (1995) Specificity of rabies virus as a transneuronal tracer of motor networks: transfer from hypoglossal motoneurons to connected second-order and higher order central nervous system cell groups. J Comp Neurol 356:457–480. https://doi.org/10.1002/cne.903560312
Vos A, Neubert A, Aylan O et al (1999) An update on safety studies of SAD B19 rabies virus vaccine in target and non-target species. Epidemiol Infect 123:165–175. https://doi.org/10.1017/s0950268899002666
Wee NKY, Lorenz MR, Bekirov Y, Jacquin MF, Scheller EL (2019) Shared Autonomic Pathways connect bone marrow and peripheral adipose tissues across the Central Neuraxis. Front Endocrinol 10:668. https://doi.org/10.3389/fendo.2019.00668
Wickersham IR, Lyon DC, Barnard RJ et al (2007) Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons. Neuron 53:639–647. https://doi.org/10.1016/j.neuron.2007.01.033
Wirblich C, Schnell MJ (2011) Rabies virus (RV) glycoprotein expression levels are not critical for pathogenicity of RV. J Virol 85:697–704. https://doi.org/10.1128/jvi.01309-10
Xie Z, Zhang X, Zhao M et al (2022) The gut-to-brain axis for toxin-induced defensive responses. Cell 185:4298–4316e4221. https://doi.org/10.1016/j.cell.2022.10.001
Xu L, Füredi N, Lutter C et al (2022) Leptin coordinates efferent sympathetic outflow to the white adipose tissue through the midbrain centrally-projecting Edinger-Westphal nucleus in male rats. Neuropharmacology 205:108898. https://doi.org/10.1016/j.neuropharm.2021.108898
Yang F, Liu Y, Chen S et al (2020) A GABAergic neural circuit in the ventromedial hypothalamus mediates chronic stress-induced bone loss. J Clin Investig 130:6539–6554. https://doi.org/10.1172/jci136105
Yao J, Zhang Q, Liao X et al (2018) A corticopontine circuit for initiation of urination. Nat Neurosci 21:1541–1550. https://doi.org/10.1038/s41593-018-0256-4
Yetman MJ, Washburn E, Hyun JH et al (2019) Intersectional monosynaptic tracing for dissecting subtype-specific organization of GABAergic interneuron inputs. Nat Neurosci 22:492–502. https://doi.org/10.1038/s41593-018-0322-y
Zeng WB, Jiang HF, Gang YD et al (2017) Anterograde monosynaptic transneuronal tracers derived from herpes simplex virus 1 strain H129. Mol Neurodegener 12:38. https://doi.org/10.1186/s13024-017-0179-7
Zhu X, Lin K, Liu Q et al (2020) Rabies virus pseudotyped with CVS-N2C glycoprotein as a powerful Tool for Retrograde neuronal network tracing. Neurosci Bull 36:202–216. https://doi.org/10.1007/s12264-019-00423-3
Acknowledgements
We would like to thank Dr. Hao Li and Tongmei Zhang for their help throughout the project.
Funding
This work was supported by the National Natural Science Foundation of China (Grants: 82271486 to XL; 81800133 to AH; 31721002 to YL).
Author information
Authors and Affiliations
Contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Yige Song, Lanfang Li, Tian Ma, Bing Zhang, Jing Wang and Xiaomei Tang. The project was administrated and supervised by Youming Lu, Aodi He and Xinyan Li. The first draft of the manuscript was written by Xinyan Li and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Ethics Approval
The ethical committee number for the study is SYXK-2021-0057.
Consent for Publication
Not applicable.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yige Song, Lanfang Li, Tian Ma and Bing Zhang contributed equally to this work.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Song, Y., Li, L., Ma, T. et al. A Novel Mouse Model for Polysynaptic Retrograde Tracing and Rabies Pathological Research. Cell Mol Neurobiol 43, 3743–3752 (2023). https://doi.org/10.1007/s10571-023-01384-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-023-01384-y