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Distribution of corticotropin-releasing factor neurons in the mouse brain: a study using corticotropin-releasing factor-modified yellow fluorescent protein knock-in mouse

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Abstract

We examined the morphological features of corticotropin-releasing factor (CRF) neurons in a mouse line in which modified yellow fluorescent protein (Venus) was expressed under the CRF promoter. We previously generated the CRF-Venus knock-in mouse, in which Venus is inserted into the CRF gene locus by homologous recombination. In the present study, the neomycin phosphotransferase gene (Neo), driven by the pgk-1 promoter, was deleted from the CRF-Venus mouse genome, and a CRF-Venus∆Neo mouse was generated. Venus expression is much more prominent in the CRF-Venus∆Neo mouse when compared to the CRF-Venus mouse. In addition, most Venus-expressing neurons co-express CRF mRNA. Venus-expressing neurons constitute a discrete population of neuroendocrine neurons in the paraventricular nucleus of the hypothalamus (PVH) that project to the median eminence. Venus-expressing neurons were also found in brain regions outside the neuroendocrine PVH, including the olfactory bulb, the piriform cortex (Pir), the extended amygdala, the hippocampus, the neocortices, Barrington’s nucleus, the midbrain/pontine dorsal tegmentum, the periaqueductal gray, and the inferior olivary nucleus (IO). Venus-expressing perikarya co-expressing CRF mRNA could be observed clearly even in regions where CRF-immunoreactive perikarya could hardly be identified. We demonstrated that the CRF neurons contain glutamate in the Pir and IO, while they contain gamma-aminobutyric acid in the neocortex, the bed nucleus of the stria terminalis, the hippocampus, and the amygdala. A population of CRF neurons was demonstrated to be cholinergic in the midbrain tegmentum. The CRF-Venus∆Neo mouse may be useful for studying the structural and functional properties of CRF neurons in the mouse brain.

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Acknowledgments

This work was supported in part by the Research Grants from JSPS (K.I., K.S., M.W.), JST (K.I., K.S., M.W.), and Comprehensive Brain Research Network (K.I., K.S., M.W.). Anti-CRF antibodies were generously donated by Drs. Wylie Vale and Paul Sawchenko, Salk Institute, Ca, USA, and Dr. Tamotsu Shibasaki, Nippon Medical School, Tokyo, Japan. Anti-thyrotropin-releasing hormone antibody was a gift from Dr. Fekete, Hungarian Academy of Sciences. We thank Dr. Sadayoshi Ito, Tohoku University, and Shinji Ohara, Matsumoto Medical Center, for encouragements. Address any requests to K.I. for mice generated in his laboratory and presented in the present manuscript. The CRF-Venus mouse is also available from Experimental Animal Division, RIKEN BRC (Access Number: RBRC06519).

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    1. Laboratory of Information Biology, Graduate School of Information Sciences, Tohoku University, 6-3-09 Aramaki-aza, Aoba, Sendai, 980-8579, Japan

      Junko Kono, Ashraf Hossain Talukder, Toshimitsu Fuse, Katsuya Uchida & Keiichi Itoi

    2. Department of Neuroendocrinology, Graduate School of Medicine, Tohoku University, Sendai, 980-8579, Japan

      Keiichi Itoi

    3. Department of Anatomy, Hokkaido University School of Medicine, Sapporo, 060-8638, Japan

      Kohtarou Konno & Masahiko Watanabe

    4. Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan

      Manabu Abe & Kenji Sakimura

    5. Department of Pharmaceutical Information Science, Tokushima University, Tokushima, 770-8505, Japan

      Shuhei Horio

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    1. Junko Kono
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    All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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    J. Kono, K. Konno and A. H. Talukder contributed equally to this work.

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    Supplementary Fig. 1 Generation of the Actb-FLPe mouse by homologous recombination. The Actb-FLPe mouse was generated by inserting the CAG promoter-driven FLPe-IRES-Flag-EGFP-Neo construct, into the 3′ downstream region of the β-actin gene (Actb) by homologous recombination using RENKA embryonic stem cells, which are of C57BL6/N genetic background (Mishina and Sakimura 2007). The neomycin phosphotransferase gene (Neo), driven by the pgk-1 promoter, is flanked by loxP sites. The Actb gene locus, targeting vector for homologous recombination, and the targeted allele are shown schematically.

    Supplementary Fig. 2 Venus-expressing neurons in the cingulate cortex. An inverted monochrome image of Venus-expressing neurons in the cingulate cortex (Cg) is shown in a (immunofluorescence). A cresyl violet (Nissl) staining of the same section in a, is shown in a’. Venus-expressing neurons were observed mainly in layers 2/3 of the Cg. Scale bar = 200 μm.

    Supplementary Fig. 3 Venus-expressing neurons in the hippocampus. a-a’: an inverted monochrome image of Venus-expressing neurons and fibers in the dentate gyrus of the hippocampus is shown in a (immunofluorescence). A cresyl violet (Nissl) staining of the same section in a, is shown in a’. b-b’: most Venus-expressing neurons co-expressed glutamic acid decarboxylase 67 (GAD67) mRNA. A single image of GAD67 mRNA is shown in b’, and a merged image for Venus and GAD67 mRNA in b (dually stained cells are indicated by arrows). c–c’: Venus-containing puncta, which co-expressed vesicular inhibitory amino acid transporter (VIAAT) immunoreactivity, were observed in close proximity to the somata of granule cells (arrows). GrDG, granule cell layer of dentate gyrus; PoDG, polymorphic cell layer of the dentate gyrus. Scale bars = 200 μm for a-a’, 20 μm for b-b’, and 5 μm for c–c’.

    Supplementary Fig. 4 Venus-expressing neurons in the shell of the nucleus accumbens. An inverted monochrome image of Venus-expressing neurons in the nucleus accumbens is shown in a (immunofluorescence). A cresyl violet (Nissl) staining of the same section in a, is shown in a’. Venus-expressing neurons are present in the shell of the nucleus accumbens (AcbSh). aca, anterior part of the anterior commissure; Pir, piriform cortex. Scale bar = 200 μm.

    Supplementary Fig. 5 Venus-expressing neurons in the periaqueductal gray and mesencephalic reticular formation. Inverted monochrome images of Venus-expressing neurons in the periaqueductal gray (PAG) and the adjacent mesencephalic reticular formation (mRt) are shown in a and b, respectively (immunofluorescence). The same sections in a and b are stained with cresyl violet (Nissl) and shown in a’ and b’, respectively. In the PAG, Venus-expressing neurons and fibers tended to be localized in the ventral half of this structure (a-a’). Scale bars = 200 μm.

    Supplementary Fig. 6 Venus-expressing neurons in the interpeduncular nucleus and median raphe nucleus. a-a’, b-b’: inverted monochrome images of Venus-expressing neurons and fibers in the caudal subnucleus of interpeduncular nucleus (IPC) and the median raphe nucleus (MnR) are shown in a and b, respectively (immunofluorescence). The same sections in a and b are stained with cresyl violet (Nissl) and shown in a’ and b’, respectively. Numerous small-sized neurons expressed Venus in the IPC (a) and the MnR (b). c–c’: most Venus-expressing neurons co-expressed CRF mRNA in the MnR. A single image of CRF mRNA is shown in c’, and merged image for Venus and CRF mRNA in c. Arrows indicate the cells that co-express Venus and CRF mRNA. ml, medial lemniscus; PMnR, paramedian raphe nucleus; ts, tectospinal tract. Scale bars = 200 μm for a-a’ and b-b’, and 10 μm for c–c’.

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    Kono, J., Konno, K., Talukder, A.H. et al. Distribution of corticotropin-releasing factor neurons in the mouse brain: a study using corticotropin-releasing factor-modified yellow fluorescent protein knock-in mouse. Brain Struct Funct 222, 1705–1732 (2017). https://doi.org/10.1007/s00429-016-1303-0

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