Terahertz photons promote neuron growth and synapse formation through cAMP signaling pathway

Yuan Zhong; Yun Yu; Yangmei Li; Junkai Yin; Yuankun Sun; Rundong Jiang; Chao Chang

doi:10.1186/s43074-025-00165-8

Article Contents

Article Navigation > PhotoniX > > Accepted Manuscript

Yuan Zhong, Yun Yu, Yangmei Li, Junkai Yin, Yuankun Sun, Rundong Jiang, Chao Chang. Terahertz photons promote neuron growth and synapse formation through cAMP signaling pathway[J]. PhotoniX. doi: 10.1186/s43074-025-00165-8

Citation:

PDF( 0 KB)

Terahertz photons promote neuron growth and synapse formation through cAMP signaling pathway

doi: 10.1186/s43074-025-00165-8

Yuan Zhong^{1, 2},
Yun Yu^{2, 3},
Yangmei Li²,
Junkai Yin²,
Yuankun Sun²,
Rundong Jiang²,
Chao Chang^{2, 4}

1.
Department of Engineering Physics, Tsinghua University, Beijing, 100084, China
2.
Innovation Laboratory of Terahertz Biophysics, National Innovation Institute of Defense Technology, Beijing, 100071, China
3.
School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, 710049, China
4.
School of Physics, Peking University, Beijing, 100081, China

Funds: We thank Prof. Guozhi Liu for providing invaluable advices and guidances for this work.

Received Date: 2024-11-21
Accepted Date: 2025-03-16
Rev Recd Date: 2025-02-08

Available Online: 2025-04-01

Abstract

Abstract

Neurite outgrowth and synapse formation constitute the cellular basis for the establishment and plasticity of neural networks, crucially involved in cognitive functions. However, the techniques currently available to effectively and specifically modulate these processes remain limited. In this work, we propose a non-drug and non-thermal terahertz (THz) photon modulation approach that enhances neuronal growth and synaptogenesis. Frequency screening experiments show that 34.5 THz photon stimulation could effectively promote neurite elongation and postsynaptic density protein 95 (PSD95) expression by 26.0% in rat hippocampal neurons. Subsequent cellular experiments reveal an upregulation of the cyclic adenosine monophosphate (cAMP) signaling pathway and adenylyl cyclase type 1 (AC1) activity after 34.5 THz photon irradiation. Molecular dynamics simulations suggest that 34.5 THz photons promote the binding between AC1 and ligand, accelerating cAMP generation. In vivo experiments further confirm an increase in hippocampal cAMP levels and dendritic spine density after THz photon stimulation, accompanied by a significant improvement in cognitive performance. Overall, our results suggest THz photon stimulation as an effective and specific method for neuromodulation, promising for future applications in the treatment of cognitive dysfunction.
- Engineering",
- Terahertz photons')">" data-track="click" data-track-action="view keyword" data-track-label="link">Terahertz photons,
- Engineering",
- Neuromodulation')">" data-track="click" data-track-action="view keyword" data-track-label="link">Neuromodulation,
- Engineering",
- Molecular dynamics')">" data-track="click" data-track-action="view keyword" data-track-label="link">Molecular dynamics,
- Engineering",
- cAMP signaling pathway')">" data-track="click" data-track-action="view keyword" data-track-label="link">cAMP signaling pathway

FullText(HTML)

References(65)

References

[1]	Eichenbaum H. A cortical-hippocampal system for declarative memory. Nat Rev Neurosci. 2000;1(1):41–50. https://doi.org/10.1038/35036213.
[2]	Morris RG, Garrud P, Rawlins JN, O’Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature. 1982;297(5868):681–3. https://doi.org/10.1038/297681a0.
[3]	Yang Y, Liu DQ, Huang W, Deng J, Sun Y, Zuo Y, et al. Selective synaptic remodeling of amygdalocortical connections associated with fear memory. Nat Neurosci. 2016;19(10):1348–55. https://doi.org/10.1038/nn.4370.
[4]	Jungenitz T, Beining M, Radic T, Deller T, Cuntz H, Jedlicka P, et al. Structural homo- and heterosynaptic plasticity in mature and adult newborn rat hippocampal granule cells. Proc Natl Acad Sci U S A. 2018;115(20):E4670–9. https://doi.org/10.1073/pnas.1801889115.
[5]	Lisman J, Cooper K, Sehgal M, Silva AJ. Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability. Nat Neurosci. 2018;21(3):309–14. https://doi.org/10.1038/s41593-018-0076-6.
[6]	Moser MB, Trommald M, Andersen P. An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses. Proc Natl Acad Sci U S A. 1994;91(26):12673–5. https://doi.org/10.1073/pnas.91.26.12673.
[7]	Schmidt-Hieber C, Jonas P, Bischofberger J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature. 2004;429(6988):184–7. https://doi.org/10.1038/nature02553.
[8]	Yang X, Gong R, Qin L, Bao Y, Fu Y, Gao S, et al. Trafficking of NMDA receptors is essential for hippocampal synaptic plasticity and memory consolidation. Cell Rep. 2022;40(7):111217. https://doi.org/10.1016/j.celrep.2022.111217.
[9]	Smith DL, Pozueta J, Gong B, Arancio O, Shelanski M. Reversal of long-term dendritic spine alterations in Alzheimer disease models. Proc Natl Acad Sci U S A. 2009;106(39):16877–82. https://doi.org/10.1073/pnas.0908706106.
[10]	Krauss JK, Lipsman N, Aziz T, Boutet A, Brown P, Chang JW, et al. Technology of deep brain stimulation: current status and future directions. Nat Rev Neurol. 2021;17(2):75–87. https://doi.org/10.1038/s41582-020-00426-z.
[11]	Zhang A, Mandeville ET, Xu L, Stary CM, Lo EH, Lieber CM. Ultraflexible endovascular probes for brain recording through micrometer-scale vasculature. Science. 2023;381(6655):306–12. https://doi.org/10.1126/science.adh3916.
[12]	Kim TI, McCall JG, Jung YH, Huang X, Siuda ER, Li Y, et al. Injectable, cellular-scale optoelectronics with applications for wireless optogenetics. Science. 2013;340(6129):211–6. https://doi.org/10.1126/science.1232437.
[13]	Chernov M, Roe AW. Infrared neural stimulation: a new stimulation tool for central nervous system applications. Neurophotonics. 2014;1(1):011011. https://doi.org/10.1117/1.NPh.1.1.011011.
[14]	Wu X, Jiang Y, Rommelfanger NJ, Yang F, Zhou Q, Yin R, et al. Tether-free photothermal deep-brain stimulation in freely behaving mice via wide-field illumination in the near-infrared-II window. Nat Biomed Eng. 2022;6(6):754–70. https://doi.org/10.1038/s41551-022-00862-w.
[15]	Wang P, Lou J, Fang G, Chang C. Progress on cutting-edge infrared-terahertz biophysics. IEEE Trans Microw Theory Tech. 2022;70(11):5117–40. https://doi.org/10.1109/TMTT.2022.3200333.
[16]	Sun Y, Geng J, Fan Y, Li Y, Zhong Y, Cai J, et al. A non-invasive and DNA-free approach to upregulate mammalian voltage-gated calcium channels and neuronal calcium signaling via terahertz stimulation. Adv Sci. 2024;11(47):e2405436. https://doi.org/10.1002/advs.202405436.
[17]	Lyu J, Shen S, Chen L, Zhu Y, Zhuang S. Frequency selective fingerprint sensor: the Terahertz unity platform for broadband chiral enantiomers multiplexed signals and narrowband molecular AIT enhancement. PhotoniX. 2023;4(1):28. https://doi.org/10.1186/s43074-023-00108-1.
[18]	Tian J, Cao W. Reconfigurable flexible metasurfaces: from fundamentals towards biomedical applications. PhotoniX. 2024;5(1):2. https://doi.org/10.1186/s43074-023-00116-1.
[19]	Liu B, Peng Y, Hao Y, Zhu Y, Chang S, Zhuang S. Ultra-wideband terahertz fingerprint enhancement sensing and inversion model supported by single-pixel reconfigurable graphene metasurface. PhotoniX. 2024;5(1):10. https://doi.org/10.1186/s43074-024-00129-4.
[20]	Lou J, Jiao Y, Yang R, Huang Y, Xu X, Zhang L, et al. Calibration-free, high-precision, and robust terahertz ultrafast metasurfaces for monitoring gastric cancers. Proc Natl Acad Sci U S A. 2022;119(43):e2209218119. https://doi.org/10.1073/pnas.2209218119.
[21]	Zhang J, Lou J, Wang Z, Liang J, Zhao X, Huang Y, et al. Photon-induced ultrafast multitemporal programming of terahertz metadevices. Adv Mater. 2024:e2410671. https://doi.org/10.1002/adma.202410671.
[22]	Liu G, Chang C, Qiao Z, Wu K, Zhu Z, Cui G, et al. Myelin sheath as a dielectric waveguide for signal propagation in the mid-infrared to terahertz spectral range. Adv Funct Mater. 2019;29(7):1807862. https://doi.org/10.1002/adfm.201807862.
[23]	Xiang Z, Tang C, Chang C, Liu G. A primary model of THz and far-infrared signal generation and conduction in neuron systems based on the hypothesis of the ordered phase of water molecules on the neuron surface I: signal characteristics. Sci Bull. 2020;65(4):308–17. https://doi.org/10.1016/j.scib.2019.12.004.
[24]	Wu K, Qi C, Zhu Z, Wang C, Song B, Chang C. Terahertz wave accelerates DNA unwinding: a molecular dynamics simulation study. J Phys Chem Lett. 2020;11(17):7002–8. https://doi.org/10.1021/acs.jpclett.0c01850.
[25]	Peng W, Zhu Z, Lou J, Chen K, Wu Y, Chang C. High-frequency terahertz waves disrupt Alzheimer’s β-amyloid fibril formation. eLight. 2023;3(1). https://doi.org/10.1186/s43593-023-00048-0.
[26]	Yin J, Wu K, Yu Y, Zhong Y, Song Z, Chang C, et al. Terahertz photons inhibit cancer cells long term by suppressing nano telomerase activity. ACS Nano. 2024;18(6):4796–810. https://doi.org/10.1021/acsnano.3c09216.
[27]	Romanenko S, Begley R, Harvey AR, Hool L, Wallace VP. The interaction between electromagnetic fields at megahertz, gigahertz and terahertz frequencies with cells, tissues and organisms: risks and potential. J R Soc Interface. 2017;14(137):20170585. https://doi.org/10.1098/rsif.2017.0585.
[28]	Song Z, Sun Y, Liu P, Ruan H, He Y, Yin J, et al. Terahertz wave alleviates comorbidity anxiety in pain by reducing the binding capacity of nanostructured glutamate molecules to GluA2. Research. 2024;7:0535. https://doi.org/10.34133/research.0535.
[29]	Li Y, Chang C, Zhu Z, Sun L, Fan C. Terahertz wave enhances permeability of the voltage-gated calcium channel. J Am Chem Soc. 2021;143(11):4311–8. https://doi.org/10.1021/jacs.0c09401.
[30]	Liu X, Qiao Z, Chai Y, Zhu Z, Wu K, Ji W, et al. Nonthermal and reversible control of neuronal signaling and behavior by midinfrared stimulation. Proc Natl Acad Sci U S A. 2021;118(10):e2015685118. https://doi.org/10.1073/pnas.2015685118.
[31]	Zhang J, He Y, Liang S, Liao X, Li T, Qiao Z, et al. Non-invasive, opsin-free mid-infrared modulation activates cortical neurons and accelerates associative learning. Nat Commun. 2021;12(1):2730. https://doi.org/10.1038/s41467-021-23025-y.
[32]	Yu Y, Wu K, Yang X, Long J, Chang C. Terahertz photons improve cognitive functions in posttraumatic stress disorder. Research. 2023;6:0278. https://doi.org/10.34133/research.0278.
[33]	Zhao X, Zhang M, Liu Y, Liu H, Ren K, Xue Q, et al. Terahertz exposure enhances neuronal synaptic transmission and oligodendrocyte differentiation in vitro. iScience. 2021;24(12):103485. https://doi.org/10.1016/j.isci.2021.103485.
[34]	Van Oostrum M, Blok TM, Giandomenico SL, Tom Dieck S, Tushev G, Furst N, et al. The proteomic landscape of synaptic diversity across brain regions and cell types. Cell. 2023;186(24):5411-27 e23. https://doi.org/10.1016/j.cell.2023.09.028.
[35]	Sadana R, Dessauer CW. Physiological roles for G protein-regulated adenylyl cyclase isoforms: insights from knockout and overexpression studies. Neurosignals. 2009;17(1):5–22. https://doi.org/10.1159/000166277.
[36]	Zhu Z, Zhao Y, Chang C, Yan S, Sun T, Gu S, et al. Design of artificial biomimetic channels with Na+ permeation rate and selectivity potentially outperforming the natural sodium channel. Nano Res. 2024;17(9):8638–46. https://doi.org/10.1007/s12274-024-6797-9.
[37]	Zhang QL, Zhou T, Chang C, Gu SY, Wang YJ, Liu Q, et al. Ultrahigh-flux water nanopumps generated by asymmetric terahertz absorption. Phys Rev Lett. 2024;132(18):184003. https://doi.org/10.1103/PhysRevLett.132.184003.
[38]	Liu Y, He Y, Tong J, Guo S, Zhang X, Luo Z, et al. Solvent-mediated analgesia via the suppression of water permeation through TRPV1 ion channels. Nat Biomed Eng. 2024. https://doi.org/10.1038/s41551-024-01288-2.
[39]	Khannpnavar B, Mehta V, Qi C, Korkhov V. Structure and function of adenylyl cyclases, key enzymes in cellular signaling. Curr Opin Struct Biol. 2020;63:34–41. https://doi.org/10.1016/j.sbi.2020.03.003.
[40]	Qi C, Lavriha P, Mehta V, Khanppnavar B, Mohammed I, Li Y, et al. Structural basis of adenylyl cyclase 9 activation. Nat Commun. 2022;13(1):1045. https://doi.org/10.1038/s41467-022-28685-y.
[41]	Zhang G, Liu Y, Ruoho AE, Hurley JH. Structure of the adenylyl cyclase catalytic core. Nature. 1997;386(6622):247–53. https://doi.org/10.1038/386247a0.
[42]	Mou TC, Masada N, Cooper DM, Sprang SR. Structural basis for inhibition of mammalian adenylyl cyclase by calcium. Biochemistry. 2009;48(15):3387–97. https://doi.org/10.1021/bi802122k.
[43]	Qi C, Sorrentino S, Medalia O, Korkhov VM. The structure of a membrane adenylyl cyclase bound to an activated stimulatory G protein. Science. 2019;364(6438):389–94. https://doi.org/10.1126/science.aav0778.
[44]	Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596(7873):583–9. https://doi.org/10.1038/s41586-021-03819-2.
[45]	Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, et al. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1–2:19–25. https://doi.org/10.1016/j.softx.2015.06.001.
[46]	Tesmer JJ, Sunahara RK, Johnson RA, Gosselin G, Gilman AG, Sprang SR. Two-metal-Ion catalysis in adenylyl cyclase. Science. 1999;285(5428):756–60. https://doi.org/10.1126/science.285.5428.756.
[47]	Hahn DK, Tusell JR, Sprang SR, Chu X. Catalytic mechanism of mammalian adenylyl cyclase: a computational investigation. Biochemistry. 2015;54(40):6252–62. https://doi.org/10.1021/acs.biochem.5b00655.
[48]	Ji Y, Pang PT, Feng L, Lu B. Cyclic AMP controls BDNF-induced TrkB phosphorylation and dendritic spine formation in mature hippocampal neurons. Nat Neurosci. 2005;8(2):164–72. https://doi.org/10.1038/nn1381.
[49]	Murphy DD, Segal M. Morphological plasticity of dendritic spines in central neurons is mediated by activation of cAMP response element binding protein. Proc Natl Acad Sci U S A. 1997;94(4):1482–7. https://doi.org/10.1073/pnas.94.4.1482.
[50]	Humeau Y, Choquet D. The next generation of approaches to investigate the link between synaptic plasticity and learning. Nat Neurosci. 2019;22(10):1536–43. https://doi.org/10.1038/s41593-019-0480-6.
[51]	Ritchie KP, Keller BM, Syed KM, Lepock JR. Hyperthermia (heat shock)-induced protein denaturation in liver, muscle and lens tissue as determined by differential scanning calorimetry. Int J Hyperthermia. 1994;10(5):605–18. https://doi.org/10.3109/02656739409022441.
[52]	Liu S, Bai S, Wen Y, Lou J, Jiang Y, Zhu Y, et al. Quadruple-band synglisis enables high thermoelectric efficiency in earth-abundant tin sulfide crystals. Science. 2025;387(6730):202–8. https://doi.org/10.1126/science.ado1133.
[53]	Zhang Z, Wang Z, Zhang C, Yao Z, Zhang S, Wang R, et al. Advanced terahertz refractive sensing and fingerprint recognition through metasurface-excited surface waves. Adv Mater. 2024;36(14):e2308453. https://doi.org/10.1002/adma.202308453.
[54]	Peng Y, Shi C, Zhu Y, Gu M, Zhuang S. Terahertz spectroscopy in biomedical field: a review on signal-to-noise ratio improvement. PhotoniX. 2020;1(1):12. https://doi.org/10.1186/s43074-020-00011-z.
[55]	Peng Y, Huang J, Luo J, Yang Z, Wang L, Wu X, et al. Three-step one-way model in terahertz biomedical detection. PhotoniX. 2021;2(1):12. https://doi.org/10.1186/s43074-021-00034-0.
[56]	Xiao T, Wu K, Wang P, Ding Y, Yang X, Chang C, et al. Sensory input-dependent gain modulation of the optokinetic nystagmus by mid-infrared stimulation in pigeons. Elife. 2023;12:12. https://doi.org/10.7554/eLife.78729.
[57]	Zhou Z, Okamoto K, Onodera J, Hiragi T, Andoh M, Ikawa M, et al. Astrocytic cAMP modulates memory via synaptic plasticity. Proc Natl Acad Sci U S A. 2021;118(3):e2016584118. https://doi.org/10.1073/pnas.2016584118.
[58]	Ferguson GD, Storm DR. Why calcium-stimulated adenylyl cyclases? Physiology. 2004;19:271–6. https://doi.org/10.1152/physiol.00010.2004.
[59]	Wong ST, Athos J, Figueroa XA, Pineda VV, Schaefer ML, Chavkin CC, et al. Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP. Neuron. 1999;23(4):787–98. https://doi.org/10.1016/s0896-6273(01)80036-2.
[60]	Brust TF, Alongkronrusmee D, Soto-Velasquez M, Baldwin TA, Ye Z, Dai M, et al. Identification of a selective small-molecule inhibitor of type 1 adenylyl cyclase activity with analgesic properties. Sci Signal. 2017;10(467):eaah5381. https://doi.org/10.1126/scisignal.aah5381.
[61]	Pierre S, Eschenhagen T, Geisslinger G, Scholich K. Capturing adenylyl cyclases as potential drug targets. Nat Rev Drug Discov. 2009;8(4):321–35. https://doi.org/10.1038/nrd2827.
[62]	Zhang J, Zhang M, Wang Q, Wen H, Liu Z, Wang F, et al. Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits. Nat Struct Mol Biol. 2023;30(5):629–39. https://doi.org/10.1038/s41594-023-00959-z.
[63]	Karakas E, Furukawa H. Crystal structure of a heterotetrameric NMDA receptor ion channel. Science. 2014;344(6187):992–7. https://doi.org/10.1126/science.1251915.
[64]	Jo S, Kim T, Iyer VG, Im W. CHARMM-GUI: a web-based graphical user interface for CHARMM. J Comput Chem. 2008;29(11):1859–65. https://doi.org/10.1002/jcc.20945.
[65]	Kumari R, Kumar R, Open Source Drug Discovery C, Lynn A. g_mmpbsa- -a GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model. 2014;54(7):1951-62. https://doi.org/10.1021/ci500020m.