Effects of 40 Hz light flicker stimulation on hippocampal-prefrontal neural activity characteristics during working memory tasks in Alzheimer’s disease model rats_Journal of Biomedical Engineering

Authors：

LIU Suhong ^1,2,3 , WANG Longlong ^2,3 ,  LI Shuangyan ^1,2,3 , XU Guizhi ^1,2,3

1. School of Health Science and Biomedical Engineering, Hebei University of Technology, Tianjin 300130, P. R. China;
2. Hebei Key Laboratory of Bioelectromagnetic and Neural Engineering, Hebei University of Technology, Tianjin 300130, P. R. China;
3. The State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300130, P. R. China;

Corresponding?author：

LI Shuangyan, Email: yujichj@163.com

Keywords：

40 Hz light flicker; Alzheimer’s disease; Neural electrical activity characteristics; Working memory; Hippocampus; Prefrontal lobe

DOI：

10.7507/1001-5515.202503009

Video：

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40 Hz light flicker stimulation is deemed to hold considerable promise in the treatment of Alzheimer’s disease (AD). However, whether its long-term effect can improve working memory and its related mechanisms remains to be further explored. In this study, 21 adult Wistar rats were randomly divided into the AD light-stimulation group, the AD group and the control group. AD models were established in the first two of these groups, with the light-stimulation group receiving long-term 40 Hz light flicker stimulation. Working memory performance across groups was subsequently evaluated using the T-maze task. To investigate the potential neural mechanisms underlying the effects of 40 Hz light stimulation on working memory, we examined changes in neuronal excitability within the hippocampus (HPC) and medial prefrontal cortex (mPFC), as well as alterations in inter-regional synchronization of neural activity. The findings demonstrated that prolonged 40 Hz light stimulation significantly improved working memory performance in AD model rats. Furthermore, the intervention enhanced the synchronization of neural activity between the hippocampus (HPC) and medial prefrontal cortex (mPFC), as well as the efficiency of information transfer, primarily mediated by theta and low-frequency gamma oscillations. This study provides theoretical support for exploring the mechanisms of 40 Hz light flicker stimulation and its further clinical application in the prevention and treatment of Alzheimer’s disease.

1.	Li A, Wei X, Xie Y, et al. Light exposure and its applications in human health. J Biophotonics, 2024, 17(5): e202400023.
2.	Li C, Managi S. Inappropriate nighttime light reduces living comfort. Environ Pollut, 2023, 334: 122173.
3.	Lee K, Park Y, Suh S W, et al. Optimal flickering light stimulation for entraining gamma waves in the human brain. Sci Rep, 2021, 11(1): 16206.
4.	Dima R, Francio V T, Towery C, et al. Review of literature on low-level laser therapy benefits for nonpharmacological pain control in chronic pain and osteoarthritis. Altern Ther Health Med, 2017, 24(5): 8-10.
5.	Li D, Liu S, Yu T, et al. Photostimulation of brain lymphatics in male newborn and adult rodents for therapy of intraventricular hemorrhage. Nat Commun, 2023, 14(1): 6104.
6.	Semyachkina-Glushkovskaya O, Kurths J, Blokhina I, et al. Night photostimulation of clearance of beta-amyloid from mouse brain: new strategies in preventing Alzheimer’s disease. Cells, 2021, 10(12): 3289.
7.	Iaccarino H F, Singer A C, Martorell A J, et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature, 2016, 540(7632): 230-235.
8.	Singer A C, Martorell A J, Miller D J, et al. Noninvasive 40-Hz light flicker to recruit microglia and reduce amyloid beta load. Nat Protoc, 2018, 13(8): 1850-1868.
9.	Park S S, Park H S, Kim C J, et al. Physical exercise during exposure to 40-Hz light flicker improves cognitive functions in the 3xTg mouse model of Alzheimer’s disease. Alzheimers Res Ther, 2020, 12(1): 62.
10.	Huang F, Huang Q, Zheng L, et al. Effect of 40Hz light flicker on behaviors of adult C57BL/6J mice. Brain Res, 2023, 1814: 148441.
11.	Rajasethupathy P, Sankaran S, Marshel J H, et al. Projections from neocortex mediate top-down control of memory retrieval. Nature, 2015, 526(7575): 653-659.
12.	Zheng L, Yu M, Lin R, et al. Rhythmic light flicker rescues hippocampal low gamma and protects ischemic neurons by enhancing presynaptic plasticity. Nat Commun, 2020, 11(1): 3012.
13.	Lin Z, Hou G, Yao Y, et al. 40-Hz blue light changes hippocampal activation and functional connectivity underlying recognition memory. Front Hum Neurosci, 2021, 15: 739333.
14.	Mamashli F, Khan S, Hamalainen M, et al. Synchronization patterns reveal neuronal coding of working memory content. Cell Rep, 2021, 36(8): 109566.
15.	Gordon J A. Oscillations and hippocampal-prefrontal synchrony. Curr Opin Neurobiol, 2011, 21(3): 486-491.
16.	Jones M W, Wilson M A. Theta rhythms coordinate hippocampal–prefrontal interactions in a spatial memory task. PLoS Biol, 2005, 3(12): e402.
17.	Samant N P, Gupta G L. Avicularin attenuates memory impairment in rats with amyloid beta-induced Alzheimer's disease. Neurotox Res, 2022, 40(1): 140-153.
18.	Dudchenko P A. An overview of the tasks used to test working memory in rodents. Neurosci Biobehav Rev, 2004, 28(7): 699-709.
19.	Colgin L L. Mechanisms and functions of theta rhythms. Annu Rev Neurosci, 2013, 36: 295-312.
20.	Buzsaki G. Theta oscillations in the hippocampus. Neuron, 2002, 33(3): 325-340.
21.	Ray S, Maunsell J H R, Ungerleider L. Different origins of gamma rhythm and high-gamma activity in macaque visual cortex. PLoS Biol, 2011, 9(4): e1000610.
22.	Adhikari A, Sigurdsson T, Topiwala M A, et al. Cross-correlation of instantaneous amplitudes of field potential oscillations: a straightforward method to estimate the directionality and lag between brain areas. J Neurosci Methods, 2010, 191(2): 191-200.
23.	Ahnaou A, Moechars D, Raeymaekers L, et al. Emergence of early alterations in network oscillations and functional connectivity in a tau seeding mouse model of Alzheimer’s disease pathology. Sci Rep, 2017, 7(1): 14189.
24.	Funane T, Jun H, Sutoko S, et al. Impaired sharp-wave ripple coordination between the medial entorhinal cortex and hippocampal CA1 of knock-in model of Alzheimer’s disease. Front Syst Neurosci, 2022, 16: 955178.
25.	Tomoaki N, Lam T N, Patel A Y, et al. Impaired in vivo gamma oscillations in the medial entorhinal cortex of knock-in Alzheimer model. Front Syst Neurosci, 2017, 11: 48.
26.	Sun Q, Zhang J, Li A, et al. Acetylcholine deficiency disrupts extratelencephalic projection neurons in the prefrontal cortex in a mouse model of Alzheimer's disease. Nat Commun, 2022, 13(1): 998.
27.	Bazzigaluppi P, Beckett T L, Koletar M M, et al. Early-stage attenuation of phase-amplitude coupling in the hippocampus and medial prefrontal cortex in a transgenic rat model of Alzheimer’s disease. J Neurochem, 2018, 144(5): 669-679.
28.	Milan S, Craig K, Horvath T L, et al. Neurophysiological signals as predictive translational biomarkers for Alzheimer's disease treatment: effects of donepezil on neuronal network oscillations in TgF344-AD rats. Alzheimers Res Ther, 2018, 10(1): 105.
29.	Bitarafan S, Pybus A F, Rivera Moctezuma F G, et al. Frequency and duration of sensory flicker controls astrocyte and neuron specific transcriptional profiles in 5xFAD mice. bioRxiv, 2024. DOI: 10.1101/2024.05.20.594705.
30.	Hu H, Pang Y, Luo H, et al. Noninvasive light flicker stimulation promotes optic nerve regeneration by activating microglia and enhancing neural plasticity in zebrafish. Invest Ophthalmol Vis Sci, 2024, 65(5): 3.
31.	Vivekananda U, Bush D, Bisby J A, et al. Theta power and theta-gamma coupling support long-term spatial memory retrieval. Hippocampus, 2021, 31(2): 213-220.
32.	Mysin I, Shubina L. From mechanisms to functions: the role of theta and gamma coherence in the intrahippocampal circuits. Hippocampus, 2022, 32(5): 342-358.

1. Li A, Wei X, Xie Y, et al. Light exposure and its applications in human health. J Biophotonics, 2024, 17(5): e202400023.
2. Li C, Managi S. Inappropriate nighttime light reduces living comfort. Environ Pollut, 2023, 334: 122173.
3. Lee K, Park Y, Suh S W, et al. Optimal flickering light stimulation for entraining gamma waves in the human brain. Sci Rep, 2021, 11(1): 16206.
4. Dima R, Francio V T, Towery C, et al. Review of literature on low-level laser therapy benefits for nonpharmacological pain control in chronic pain and osteoarthritis. Altern Ther Health Med, 2017, 24(5): 8-10.
5. Li D, Liu S, Yu T, et al. Photostimulation of brain lymphatics in male newborn and adult rodents for therapy of intraventricular hemorrhage. Nat Commun, 2023, 14(1): 6104.
6. Semyachkina-Glushkovskaya O, Kurths J, Blokhina I, et al. Night photostimulation of clearance of beta-amyloid from mouse brain: new strategies in preventing Alzheimer’s disease. Cells, 2021, 10(12): 3289.
7. Iaccarino H F, Singer A C, Martorell A J, et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature, 2016, 540(7632): 230-235.
8. Singer A C, Martorell A J, Miller D J, et al. Noninvasive 40-Hz light flicker to recruit microglia and reduce amyloid beta load. Nat Protoc, 2018, 13(8): 1850-1868.
9. Park S S, Park H S, Kim C J, et al. Physical exercise during exposure to 40-Hz light flicker improves cognitive functions in the 3xTg mouse model of Alzheimer’s disease. Alzheimers Res Ther, 2020, 12(1): 62.
10. Huang F, Huang Q, Zheng L, et al. Effect of 40Hz light flicker on behaviors of adult C57BL/6J mice. Brain Res, 2023, 1814: 148441.
11. Rajasethupathy P, Sankaran S, Marshel J H, et al. Projections from neocortex mediate top-down control of memory retrieval. Nature, 2015, 526(7575): 653-659.
12. Zheng L, Yu M, Lin R, et al. Rhythmic light flicker rescues hippocampal low gamma and protects ischemic neurons by enhancing presynaptic plasticity. Nat Commun, 2020, 11(1): 3012.
13. Lin Z, Hou G, Yao Y, et al. 40-Hz blue light changes hippocampal activation and functional connectivity underlying recognition memory. Front Hum Neurosci, 2021, 15: 739333.
14. Mamashli F, Khan S, Hamalainen M, et al. Synchronization patterns reveal neuronal coding of working memory content. Cell Rep, 2021, 36(8): 109566.
15. Gordon J A. Oscillations and hippocampal-prefrontal synchrony. Curr Opin Neurobiol, 2011, 21(3): 486-491.
16. Jones M W, Wilson M A. Theta rhythms coordinate hippocampal–prefrontal interactions in a spatial memory task. PLoS Biol, 2005, 3(12): e402.
17. Samant N P, Gupta G L. Avicularin attenuates memory impairment in rats with amyloid beta-induced Alzheimer's disease. Neurotox Res, 2022, 40(1): 140-153.
18. Dudchenko P A. An overview of the tasks used to test working memory in rodents. Neurosci Biobehav Rev, 2004, 28(7): 699-709.
19. Colgin L L. Mechanisms and functions of theta rhythms. Annu Rev Neurosci, 2013, 36: 295-312.
20. Buzsaki G. Theta oscillations in the hippocampus. Neuron, 2002, 33(3): 325-340.
21. Ray S, Maunsell J H R, Ungerleider L. Different origins of gamma rhythm and high-gamma activity in macaque visual cortex. PLoS Biol, 2011, 9(4): e1000610.
22. Adhikari A, Sigurdsson T, Topiwala M A, et al. Cross-correlation of instantaneous amplitudes of field potential oscillations: a straightforward method to estimate the directionality and lag between brain areas. J Neurosci Methods, 2010, 191(2): 191-200.
23. Ahnaou A, Moechars D, Raeymaekers L, et al. Emergence of early alterations in network oscillations and functional connectivity in a tau seeding mouse model of Alzheimer’s disease pathology. Sci Rep, 2017, 7(1): 14189.
24. Funane T, Jun H, Sutoko S, et al. Impaired sharp-wave ripple coordination between the medial entorhinal cortex and hippocampal CA1 of knock-in model of Alzheimer’s disease. Front Syst Neurosci, 2022, 16: 955178.
25. Tomoaki N, Lam T N, Patel A Y, et al. Impaired in vivo gamma oscillations in the medial entorhinal cortex of knock-in Alzheimer model. Front Syst Neurosci, 2017, 11: 48.
26. Sun Q, Zhang J, Li A, et al. Acetylcholine deficiency disrupts extratelencephalic projection neurons in the prefrontal cortex in a mouse model of Alzheimer's disease. Nat Commun, 2022, 13(1): 998.
27. Bazzigaluppi P, Beckett T L, Koletar M M, et al. Early-stage attenuation of phase-amplitude coupling in the hippocampus and medial prefrontal cortex in a transgenic rat model of Alzheimer’s disease. J Neurochem, 2018, 144(5): 669-679.
28. Milan S, Craig K, Horvath T L, et al. Neurophysiological signals as predictive translational biomarkers for Alzheimer's disease treatment: effects of donepezil on neuronal network oscillations in TgF344-AD rats. Alzheimers Res Ther, 2018, 10(1): 105.
29. Bitarafan S, Pybus A F, Rivera Moctezuma F G, et al. Frequency and duration of sensory flicker controls astrocyte and neuron specific transcriptional profiles in 5xFAD mice. bioRxiv, 2024. DOI: 10.1101/2024.05.20.594705.
30. Hu H, Pang Y, Luo H, et al. Noninvasive light flicker stimulation promotes optic nerve regeneration by activating microglia and enhancing neural plasticity in zebrafish. Invest Ophthalmol Vis Sci, 2024, 65(5): 3.
31. Vivekananda U, Bush D, Bisby J A, et al. Theta power and theta-gamma coupling support long-term spatial memory retrieval. Hippocampus, 2021, 31(2): 213-220.
32. Mysin I, Shubina L. From mechanisms to functions: the role of theta and gamma coherence in the intrahippocampal circuits. Hippocampus, 2022, 32(5): 342-358.

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