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PreprintCited by 5Neurogenesis and neuroplasticity mechanismsLaser Applications in Dentistry and MedicineOptical Imaging and Spectroscopy Techniques

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Near-Infrared Light Induces Neurogenesis and Modulates Anxiety-like Behavior

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Qi, Xing, Xu, Zhiliang, Liu, Xingchen, Ren, Yanan, Jin, Yecheng, Sun, Wenjie, Li, Jiangxia, Liu, Duo, Liu, Shuwei, Liu, Qiji, Li, Xi·2024·Stem Cell Research & Therapy
DOI 10.21203/rs.3.rs-3918262/v1PMC PMC11662543

Preprint — published as 10.1186/s13287-024-04114-3 · Paper page

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Abstract

Background The hippocampus is associated with mood disorders, and the activation of quiescent neurogenesis has been linked to anxiolytic effects. Near-infrared (NIR) light has shown potential to improve learning and memory in human and animal models. Despite the vast amount of information regarding the effect of visible light, there is a significant gap in our understanding of the response of neural stem cells (NSCs) to NIR stimulation, particularly in anxiety-like behavior. The present study aimed to develop a new optical manipulation approach to stimulate hippocampal neurogenesis and understand the mechanisms underlying its anxiolytic effects. Methods We used 940 nm NIR (40 Hz) light exposure to stimulate hippocampal stem cells in C57BL/6 mice. The enhanced proliferation and astrocyte differentiation of NIR-treated NSCs were assessed using 5-Ethynyl-2’-deoxyuridine (EdU) incorporation and immunofluorescence assays. Additionally, we evaluated calcium activity of NIR light-treated astrocytes using GCaMP6f recording through fluorescence fiber photometry. The effects of NIR illumination of the hippocampus on anxiety-like behaviors were evaluated using elevated plus maze and open-field test. Results In vitro, the NIR light effectively promoted the NSC proliferation and astrocyte differentiation via the Opn4 photoreceptor. In vivo, the NIR stimulation significantly enhanced neurogenesis and calcium-dependent astrocytic activity. Moreover, activating hippocampal astrocytes with 40-Hz NIR light substantially improved anxiety-like behaviors in mice. Conclusions We found that flickering NIR (940 nm/40Hz) light illumination improved neurogenesis in the hippocampus with anxiolytic effects. This innovative approach holds promise as a novel preventive treatment for depression.

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Fig. 1 Behavioral test of CRS mice under NIR illumination. (A) Experimental scheme outlining the indicated treatments and behavioral experiments conducted. (B-D) Results of EPM (CON: n = 6; CRS: n = 6; CRS + NIR: n = 6. Values represent mean ± SEM, *p < 0.05 and **p < 0.01. (B) Representative locomotion trajectories of mice in the EPM. (C) Time spent by mice in the open arm of EPM. (D) Number of mice entering the open-arm in the EPM. (E-G) Results of OFT (CON: n = 6; CRS: n = 6; CRS + NIR: n = 6). Values represent mean ± SEM, *p < 0.05 and **p < 0.01. (E) Representative locomotion trajectories of mice in the OFT. (F) Time spent by mice in the central area of OFT. (G) Distance travelled by mice in the OFT
Fig. 1 Behavioral test of CRS mice under NIR illumination. (A) Experimental scheme outlining the indicated treatments and behavioral experiments conducted. (B-D) Results of EPM (CON: n = 6; CRS: n = 6; CRS + NIR: n = 6. Values represent mean ± SEM, *p < 0.05 and **p < 0.01. (B) Representative locomotion trajectories of mice in the EPM. (C) Time spent by mice in the open arm of EPM. (D) Number of mice entering the open-arm in the EPM. (E-G) Results of OFT (CON: n = 6; CRS: n = 6; CRS + NIR: n = 6). Values represent mean ± SEM, *p < 0.05 and **p < 0.01. (E) Representative locomotion trajectories of mice in the OFT. (F) Time spent by mice in the central area of OFT. (G) Distance travelled by mice in the OFTCC BY-NC-ND · PubMed Central
Fig. 2 Glial expression in the hippocampus of CRS mice after NIR treatment. (A) Representative image of immunohistochemical staining for PCNA in the non-stimulated and stimulated DG regions of CRS mice. (B) Relative intensity value of fluorescence after homogenization (CRS: n = 3; CRS + NIR: n = 3; two slices per mice). (C) Representative images of immunofluorescence staining of GFAP in the non-stimulated and stimulated DG regions of CRS mice. (D) Relative intensity value of fluorescence after homogenization (CRS: n = 3; CRS + NIR: n = 3; two slices per mice). (E) Representative image of immunohistochemical staining for S100 in the non-stimulated and stimulated DG regions of CRS mice. (F) Relative intensity value of fluorescence after homogenization (CRS: n = 3; CRS + NIR: n = 3; two slices per mice).Values represent mean ± SEM, ***p < 0.001. (G) Representative image of immunohistochemical staining for MAP2 in the non-stimulated and stimulated SGZ regions of CRS mice. (H) Relative intensity value of fluorescence after homogenization (CRS: n = 3; CRS + NIR: n = 3; two slices per mice).Values represent mean ± SEM, ***p < 0.001
Fig. 2 Glial expression in the hippocampus of CRS mice after NIR treatment. (A) Representative image of immunohistochemical staining for PCNA in the non-stimulated and stimulated DG regions of CRS mice. (B) Relative intensity value of fluorescence after homogenization (CRS: n = 3; CRS + NIR: n = 3; two slices per mice). (C) Representative images of immunofluorescence staining of GFAP in the non-stimulated and stimulated DG regions of CRS mice. (D) Relative intensity value of fluorescence after homogenization (CRS: n = 3; CRS + NIR: n = 3; two slices per mice). (E) Representative image of immunohistochemical staining for S100 in the non-stimulated and stimulated DG regions of CRS mice. (F) Relative intensity value of fluorescence after homogenization (CRS: n = 3; CRS + NIR: n = 3; two slices per mice).Values represent mean ± SEM, ***p < 0.001. (G) Representative image of immunohistochemical staining for MAP2 in the non-stimulated and stimulated SGZ regions of CRS mice. (H) Relative intensity value of fluorescence after homogenization (CRS: n = 3; CRS + NIR: n = 3; two slices per mice).Values represent mean ± SEM, ***p < 0.001CC BY-NC-ND · PubMed Central
Fig. 3 NIR stimulated hippocampal neurogenesis in vivo by nongenetic stimulation. (A) Schematic flowchart of nongenetic NIR stimulation experiment. (B) Immunofluorescence staining of EdU incorporation assay of NSCs in DG under NIR exposure. (C) Statistical analysis of EdU positive cells using Image-J software (n = 6 slices/3 mice/group, the left DG with only the optical fiber was used as a control after light stimulation for each animal) (D) Representative images of immunofluorescence staining of GFAP in the non-stimulated and stimulated DG regions as described in the experimental procedures. (E) Statistical analysis of immunosignals using Image-J software (n = 6 mice per group, the left DG with only the optical fiber was used as a control after light stimulation for each animal). (F) Representative images of immunofluorescence staining of NeuN in the non-stimulated and stimulated DG regions as described in the experimental procedures. (G) Statistical analysis of immunosignals using Image-J software (n = 7 mice per group, the left DG with only the optical fiber was used as a control after light stimulation for each animal).Values are presented as mean ± SEM. Values are presented as mean ± SEM. **p < 0.01, ***p < 0.001. (H) Equivalent amounts (30 µg) of tissue lysates were separated by SDS-PAGE and analyzed by immunoblotting with antibodies specific for the indicated proteins. GAPDH was used as a loading control (n = 3 mice per group, the left SGZ with only the optical fiber was used as a control after light stimulation for each animal). (I) Statistical analysis of immunosignals. Values are presented as mean ± SEM. *p < 0.05
Fig. 3 NIR stimulated hippocampal neurogenesis in vivo by nongenetic stimulation. (A) Schematic flowchart of nongenetic NIR stimulation experiment. (B) Immunofluorescence staining of EdU incorporation assay of NSCs in DG under NIR exposure. (C) Statistical analysis of EdU positive cells using Image-J software (n = 6 slices/3 mice/group, the left DG with only the optical fiber was used as a control after light stimulation for each animal) (D) Representative images of immunofluorescence staining of GFAP in the non-stimulated and stimulated DG regions as described in the experimental procedures. (E) Statistical analysis of immunosignals using Image-J software (n = 6 mice per group, the left DG with only the optical fiber was used as a control after light stimulation for each animal). (F) Representative images of immunofluorescence staining of NeuN in the non-stimulated and stimulated DG regions as described in the experimental procedures. (G) Statistical analysis of immunosignals using Image-J software (n = 7 mice per group, the left DG with only the optical fiber was used as a control after light stimulation for each animal).Values are presented as mean ± SEM. Values are presented as mean ± SEM. **p < 0.01, ***p < 0.001. (H) Equivalent amounts (30 µg) of tissue lysates were separated by SDS-PAGE and analyzed by immunoblotting with antibodies specific for the indicated proteins. GAPDH was used as a loading control (n = 3 mice per group, the left SGZ with only the optical fiber was used as a control after light stimulation for each animal). (I) Statistical analysis of immunosignals. Values are presented as mean ± SEM. *p < 0.05CC BY-NC-ND · PubMed Central
Fig. 4 In vivo calcium recordings in awake mice using optical fiber photometry. (A) Experimental protocol for calcium signal recording with optical fiber photometry in C57BL/6 mice. (B) Immunofluorescence image showing GCaMP6f expressed astrocytes in the DG. (C) Color plot depicting DG Ca2+ activity in the non-stimulated and stimulated mice. (D) Sample ΔF/F of GCaMP6f signals from the DG in non-stimulated and stimulated mice. (E) Bar graphs illustrating the peak valley of calcium signal in non-stimulated and stimulated mice DG regions as described in the experimental procedures (n = 6 mice per group). (F) Bar graphs showing the integration under the curve of calcium signal in non-stimulated and stimulated mice DG regions as described in the experimental procedures (n = 6 mice per group). (G) Experimental protocol for calcium signal recording with optical fiber photometry in CRS mice. (H) Sample ΔF/F of GCaMP6f signals from the DG in non-stimulated and stimulated CRS mice. (I) Bar graphs illustrating the peak valley of calcium signal in non-stimulated and stimulated CRS mice DG regions as described in the experimental procedures (n = 6 mice per group). (F) Bar graphs showing the integration under the curve of calcium signal in non-stimulated and stimulated CRS mice DG regions as described in the experimental procedures (n = 6 mice per group). Values are presented as mean ± SEM, *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 4 In vivo calcium recordings in awake mice using optical fiber photometry. (A) Experimental protocol for calcium signal recording with optical fiber photometry in C57BL/6 mice. (B) Immunofluorescence image showing GCaMP6f expressed astrocytes in the DG. (C) Color plot depicting DG Ca2+ activity in the non-stimulated and stimulated mice. (D) Sample ΔF/F of GCaMP6f signals from the DG in non-stimulated and stimulated mice. (E) Bar graphs illustrating the peak valley of calcium signal in non-stimulated and stimulated mice DG regions as described in the experimental procedures (n = 6 mice per group). (F) Bar graphs showing the integration under the curve of calcium signal in non-stimulated and stimulated mice DG regions as described in the experimental procedures (n = 6 mice per group). (G) Experimental protocol for calcium signal recording with optical fiber photometry in CRS mice. (H) Sample ΔF/F of GCaMP6f signals from the DG in non-stimulated and stimulated CRS mice. (I) Bar graphs illustrating the peak valley of calcium signal in non-stimulated and stimulated CRS mice DG regions as described in the experimental procedures (n = 6 mice per group). (F) Bar graphs showing the integration under the curve of calcium signal in non-stimulated and stimulated CRS mice DG regions as described in the experimental procedures (n = 6 mice per group). Values are presented as mean ± SEM, *p < 0.05, **p < 0.01, ***p < 0.001CC BY-NC-ND · PubMed Central
Fig. 5 NIR irradiation promoted NSC proliferation and astrocyte differentiation (A) Scheme of the experimental design. (B) shRNA-Opn4 injection down-regulated OPN4 and GFAP expression in the hippocampus of mice with NIR irradiation. (C) Immunofluorescence staining for GFAP in the control and shRNA-Opn4 group with NIR irradiation. (D) Quantitative data from immunofluorescence staining (5 slices from 3 mice for each group). Values are presented as mean ± SEM, ***p < 0.001. (E) Representative micrographs of NSC sphere formation after NIR irradiation and Opn4 inhibitor (AA92593) treatment. (F) Quantitative data from NSC sphere counts with the indicated treatment. The results from four repeat wells of a 24-well plate. Values are given as mean ± SEM. *p < 0.05. (G) Photographs of the EdU incorporation assay of NSCs under NIR exposure. (H) Quantitative data from NSC proliferation under illumination across 12–13 randomly selected view fields of the tested samples using ImageJ software. Values are given as mean ± SEM. *P < 0.05, and ***P < 0.001
Fig. 5 NIR irradiation promoted NSC proliferation and astrocyte differentiation (A) Scheme of the experimental design. (B) shRNA-Opn4 injection down-regulated OPN4 and GFAP expression in the hippocampus of mice with NIR irradiation. (C) Immunofluorescence staining for GFAP in the control and shRNA-Opn4 group with NIR irradiation. (D) Quantitative data from immunofluorescence staining (5 slices from 3 mice for each group). Values are presented as mean ± SEM, ***p < 0.001. (E) Representative micrographs of NSC sphere formation after NIR irradiation and Opn4 inhibitor (AA92593) treatment. (F) Quantitative data from NSC sphere counts with the indicated treatment. The results from four repeat wells of a 24-well plate. Values are given as mean ± SEM. *p < 0.05. (G) Photographs of the EdU incorporation assay of NSCs under NIR exposure. (H) Quantitative data from NSC proliferation under illumination across 12–13 randomly selected view fields of the tested samples using ImageJ software. Values are given as mean ± SEM. *P < 0.05, and ***P < 0.001CC BY-NC-ND · PubMed Central
Fig. 6 Schematic representation of our findings showing that NIR light irradiation improved neurogenesis in the hippocampus with anxiolytic effects. See the Discussion section for further details. The image was created using MedPeer.cn
Fig. 6 Schematic representation of our findings showing that NIR light irradiation improved neurogenesis in the hippocampus with anxiolytic effects. See the Discussion section for further details. The image was created using MedPeer.cnCC BY-NC-ND · PubMed Central

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Metadata

Authors
Qi, X., Xu, Z., Liu, X., Ren, Y., Jin, Y., Sun, W., Li, J., Liu, D., Liu, S., Liu, Q., & Li, X.
Affiliations
  • Shandong University (CN)
  • Shandong Sport University (CN)
Corresponding author
  • Liu, Duo
  • Liu, Shuwei
  • Liu, Qiji
  • Li, Xi
ORCID
Venue
Stem Cell Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2024-04-04
Volume
15
Issue
1
Pages
494-494
ISSN
1757-6512 (ISSN-L)
DOI
10.21203/rs.3.rs-3918262/v1
PMC
PMC11662543
OpenAlex
W4405624547
Cited by
5
References
1
Citations by year
2026: 3 · 2025: 2
FWCI
0.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cell Research & Therapy (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Shandong University
  • National Natural Science Foundation of China (32070586, 81873737)
  • Natural Science Foundation of Shandong Province (ZR2022LZL010)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Laser Applications in Dentistry and Medicine
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Optical Imaging and Spectroscopy Techniques
Keywords
near-infrared light, hippocampal neurogenesis, anxiety-like behavior, neural stem cells, astrocyte differentiation, anxiolytic effects, depression prevention, optical stimulation
MeSH terms
Animals, Anxiety, Astrocytes, Behavior, Animal, Cell Differentiation, Hippocampus, Infrared Rays, Male, Mice, Inbred C57BL, Cell Proliferation, Mice, Neurogenesis, Neural Stem Cells

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Qi, X., Xu, Z., Liu, X., Ren, Y., Jin, Y., Sun, W., Li, J., Liu, D., Liu, S., Liu, Q., & Li, X. (2024). Near-Infrared Light Induces Neurogenesis and Modulates Anxiety-like Behavior. Stem Cell Research & Therapy. https://doi.org/10.21203/rs.3.rs-3918262/v1