Abstract
The GABAergic neurons in the parafacial zone (PZ) play an important role in sleep-wake regulation and have been identified as part of a sleep-promoting center in the brainstem, but the long-range connections mediating this function remain poorly characterized. Here, we performed whole-brain mapping of both the inputs and outputs of the GABAergic neurons in the PZ of the mouse brain. We used the modified rabies virus EnvA-ΔG-DsRed combined with a Cre/loxP gene-expression strategy to map the direct monosynaptic inputs to the GABAergic neurons in the PZ, and found that they receive inputs mainly from the hypothalamic area, zona incerta, and parasubthalamic nucleus in the hypothalamus; the substantia nigra, pars reticulata and deep mesencephalic nucleus in the midbrain; and the intermediate reticular nucleus and medial vestibular nucleus (parvocellular part) in the pons and medulla. We also mapped the axonal projections of the PZ GABAergic neurons with adeno-associated virus, and defined the reciprocal connections of the PZ GABAergic neurons with their input and output nuclei. The newly-found inputs and outputs of the PZ were also listed compared with the literature. This cell-type-specific neuronal whole-brain mapping of the PZ GABAergic neurons may reveal the circuits underlying various functions such as sleep-wake regulation.
Similar content being viewed by others
References
Anaclet C, Lin JS, Vetrivelan R, Krenzer M, Vong L, Fuller PM, et al. Identification and characterization of a sleep-active cell group in the rostral medullary brainstem. J Neurosci 2012, 32: 17970–17976.
Jones BE. Modulation of cortical activation and behavioral arousal by cholinergic and orexinergic systems. Ann N Y Acad Sci 2008, 1129: 26–34.
Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron 2010, 68: 1023–1042.
Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW. Control of sleep and wakefulness. Physiol Rev 2012, 92: 1087–1187.
Zhan Y. Harnessing GABAergic transmission for slow oscillations. Neurosci Bull 2016, 32: 501–502.
Anaclet C, Ferrari L, Arrigoni E, Bass CE, Saper CB, Lu J, et al. The GABAergic parafacial zone is a medullary slow wave sleep–promoting center. Nat Neurosci 2014, 17: 1217–1224.
Schwartz MD, Kilduff TS. The neurobiology of sleep and wakefulness. Psychiatr Clin North Am 2015, 38: 615–644.
Brown RE, McKenna JT. Turning a negative into a positive: ascending GABAergic control of cortical activation and arousal. Front Neurol 2015, 6: 135.
Shammah-Lagnado SJ, Costa MS, Ricardo JA. Afferent connections of the parvocellular reticular formation: a horseradish peroxidase study in the rat. Neuroscience 1992, 50: 403–425.
Travers JB, Norgren R. Afferent projections to the oral motor nuclei in the rat. J Comp Neurol 1983, 220: 280–298.
Stanek E, Cheng S, Takatoh J, Han BX, Wang F. Monosynaptic premotor circuit tracing reveals neural substrates for oro-motor coordination. eLife 2014, 3: e02511.
Wickersham IR, Finke S, Conzelmann KK, Callaway EM. Retrograde neuronal tracing with a deletion-mutant rabies virus. Nat Methods 2007, 4: 47–49.
Han W, Tellez LA, Rangel MJ, Motta SC, Zhang X, Perez IO, et al. Integrated control of predatory hunting by the central nucleus of the amygdala. Cell 2017, 168: 311–324.
Ter Horst GJ, Copray JC, Liem RS, Van Willigen JD. Projections from the rostral parvocellular reticular formation to pontine and medullary nuclei in the rat: involvement in autonomic regulation and orofacial motor control. Neuroscience 1991, 40: 735–758.
Huang ZJ, Zeng H. Genetic approaches to neural circuits in the mouse. Annu Rev Neurosci 2013, 36: 183–215.
Callaway EM, Luo L. Monosynaptic circuit tracing with glycoprotein-deleted rabies viruses. J Neurosci 2015, 35: 8979–8985.
Osten P, Margrie TW. Mapping brain circuitry with a light microscope. Nat Methods 2013, 10: 515–523.
Oh SW, Harris JA, Ng L, Winslow B, Cain N, Mihalas S, et al. A mesoscale connectome of the mouse brain. Nature 2014, 508: 207–214.
Franklin KBJ, Paxinos G. The Mouse Brain in Stereotaxic Coordinates: Compact second Edition. Academic Press, 2001.
Wickersham IR, Lyon DC, Barnard RJO, Mori T, Finke S, Conzelmann KK, et al. Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons. Neuron 2007, 53: 639–647.
Miyamichi K, Amat F, Moussavi F, Wang C, Wickersham I, Wall NR, et al. Cortical representations of olfactory input by trans-synaptic tracing. Nature 2011, 472: 191–196.
Watabe-Uchida M, Zhu L, Ogawa SK, Vamanrao A, Uchida N. Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron 2012, 74: 858–873.
Wall NR, De La Parra M, Callaway EM, Kreitzer AC. Differential innervation of direct- and indirect-pathway striatal projection neurons. Neuron 2013, 79: 347–360.
Zhao F, Jiang HF, Zeng WB, Shu Y, Luo MH, Duan S. Anterograde trans-synaptic tagging mediated by adeno-associated virus. Neurosci Bull 2017, 33: 348–350.
Minkels RF, Jüch PJ, Ter Horst GJ, Van Willigen JD. Projections of the parvocellular reticular formation to the contralateral mesencephalic trigeminal nucleus in the rat. Brain Res 1991, 547: 13–21.
Sahara Y, Hashimoto N, Nakamura Y. Hypoglossal premotor neurons in the rostral medullary parvocellular reticular formation participate in cortically-induced rhythmical tongue movements. Neurosci Res 1996, 26: 119–131.
Parenti R, Cicirata F, Pantò MR, Serapide MF. The projections of the lateral reticular nucleus to the deep cerebellar nuclei. An experimental analysis in the rat. Eur J Neurosci 1996, 8: 2157–2167.
Anaclet C, Pedersen NP, Fuller PM, Lu J. Brainstem circuitry regulating phasic activation of trigeminal motoneurons during REM sleep. PLoS One 2010, 5: e8788.
Boissard R, Gervasoni D, Schmidt MH, Barbagli B, Fort P, Luppi PH. The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study. Eur J Neurosci 2002, 16: 1959–1973.
Weber F, Chung S, Beier KT, Xu M, Luo L, Dan Y. Control of REM sleep by ventral medulla GABAergic neurons. Nature 2015, 526: 435–438.
Morairty SR, Dittrich L, Pasumarthi RK, Valladao D, Heiss JE, Gerashchenko D, et al. A role for cortical nNOS/NK1 neurons in coupling homeostatic sleep drive to EEG slow wave activity. Proc Natl Acad Sci U S A 2013, 110: 20272–20277.
Hayashi Y, Kashiwagi M, Yasuda K, Ando R, Kanuka M, Sakai K, et al. Cells of a common developmental origin regulate REM/non-REM sleep and wakefulness in mice. Science 2015, 350: 957–961.
Gerashchenko D, Wisor JP, Burns D, Reh RK, Shiromani PJ, Sakurai T, et al. Identification of a population of sleep-active cerebral cortex neurons. Proc Natl Acad Sci U S A 2008, 105: 10227–10232.
Gong H, McGinty D, Guzman-Marin R, Chew KT, Stewart D, Szymusiak R. Activation of c-fos in GABAergic neurones in the preoptic area during sleep and in response to sleep deprivation. J Physiol 2004, 556: 935–946.
Alam MA, Kumar S, McGinty D, Alam MN, Szymusiak R. Neuronal activity in the preoptic hypothalamus during sleep deprivation and recovery sleep. J Neurophysiol 2014, 111: 287–299.
Kumar S, Rai S, Hsieh KC, McGinty D, Alam MN, Szymusiak R. Adenosine A(2A) receptors regulate the activity of sleep regulatory GABAergic neurons in the preoptic hypothalamus. Am J Physiol Regul Integr Comp Physiol 2013, 305: R31–41.
Xu M, Chung S, Zhang S, Zhong P, Ma C, Chang WC, et al. Basal forebrain circuit for sleep-wake control. Nat Neurosci 2015, 18: 1641–1647.
Qiu MH, Vetrivelan R, Fuller PM, Lu J. Basal ganglia control of sleep-wake behavior and cortical activation. Eur J Neurosci 2010, 31: 499–507.
Cho JR, Treweek JB, Robinson JE, Xiao C, Bremner LR, Greenbaum A, et al. Dorsal raphe dopamine neurons modulate arousal and promote wakefulness by salient stimuli. Neuron 2017, 94: 1205–1219.
Sun HX, Wang DR, Ye CB, Hu ZZ, Wang CY, Huang ZL, et al. Activation of the ventral tegmental area increased wakefulness in mice. Sleep Biol Rhythms 2017, 15: 107–115.
Cerri M, Del Vecchio F, Mastrotto M, Luppi M, Martelli D, Perez E, et al. Enhanced slow-wave EEG activity and thermoregulatory impairment following the inhibition of the lateral hypothalamus in the rat. PLoS One 2014, 9: e112849.
Acknowledgements
We thank Hui-Fang Lou and Li-Ya Zhu for technical support. This work was supported by the National Natural Science Foundation of China (31571090 and 31771167), the National Key Research and Development Program (2016YFC1306700), the National High Technology Research and Development Program (863 Program) of China (2015AA020512), and the Fundamental Research Funds for the Central Universities of China (2017FZA7003).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All authors claim that there are no conflicts of interest.
Rights and permissions
About this article
Cite this article
Su, YT., Gu, MY., Chu, X. et al. Whole-Brain Mapping of Direct Inputs to and Axonal Projections from GABAergic Neurons in the Parafacial Zone. Neurosci. Bull. 34, 485–496 (2018). https://doi.org/10.1007/s12264-018-0216-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12264-018-0216-8