| It is a rapidly developing biomedical engineering technology to therapy brain diseases and improve the quality of life for patients with neural modulation.Multi-modulation techniques,such as drug,electric,magnetic,optical,and heat stimulation have been proven to be effective in regulating neural activity,and have been applied in neuropsychiatric diseases,including but not limited to the depression,sleep disorders,Alzheimer’s disease,and Parkinson’s disease.In particular,noninvasive electrical stimulation,magnetic stimulation and optical stimulation without surgical intervention are of high safety,low cost and suitable for a variety of nervous system diseases,which have crucial clinical application value.However,there are still many problems in the application of neural modulation technology.The reason is that the exact mechanism underlying neural modulation remain unclear.On the one hand,in addition to synapses and neuronal populations activities profoundly affect the stimulation effect,the larger number of non-neuronal cells may also be the potential effector of neural stimulation.On the other hand,due to the differences of anatomy and the complexity of nervous system,these bring great challenges to investigate the mechanism of neural modulation.Computational neuroscience provides a new insight for clarifying the law of neural regulation and achieving precise determination of brain stimulation.Computational neuroscience is a multi-disciplinary new discipline,which integrates the research findings of cognitive science,information science,mathematics,physics and biomedicine.Multi-disciplinary concepts and tools are utilized to study the working principle of the brain and explain a series of phenomena related to the nervous system.In this paper,we focus on the role of non-neuronal cells,network effect and individual differences in multi-neural modulations,and study multi-neural modulation from the perspectives of computational neural modeling and biological experiments.The innovative work of the paper is described as follows:1.Based on tight morphological arrangement of the astrocytes and neurons,named "tripartite synapses",we implemented a biophysically neuron-astrocyte computational network model.And then adding different concentrations of exogenous GABA(0,1,5 and 10μM)to the network model,we investigate the regulation of neuronal excitability by the gliotransmitter glutamate released from astrocytes under inhibitory stimulation.The result demonstrated that exogenous GABA significantly inhibit neuronal and synaptic activities.Astrocytes can be activated by GABA and presynaptic glutamate at the same time,and then promote the release of presynaptic neurotransmitters through astrocyte-derived glutamate.The slow inward currents(SICs)evoked by gliotransmitter enhance postsynaptic excitatory currents and modulate neuronal excitability to counteract the inhibitory effect of exogenous GABA,suggesting that astrocytes are key factors in the excitatory-inhibitory balance of neural networks.2.Based on the anatomical features of the hippocampal CA region,we developed a computational model of neuro-glial microcircuit to elucidate the effects of magnetic stimulation on different types of neurons and astrocytes by loading magnetic field parameters at different frequencies(1-50Hz).The results showed that different types of neurons have different response modes to magnetic field due to the difference of activation threshold,and the coupled intensity of inhibitory neurons and excitatory neurons has an important influence on magnetic stimulation effect.Furthermore,astrocytes respond to magnetic stimulation with higher amplitude and shorter period than spontaneous calcium oscillations.Astrocyte regulates neuronal activity through SICs evoked by gliotransmitter to maintain the stability of excitatory and inhibitory neurons,preventing over excitation or inhibition under magnetic stimulation.3.Based on the response law of cortical neuron membrane capacitance current and ion channel current to optical stimulation,this paper constructed a neuronal network computational model with the treatment of near-infrared laser to provide a novel insight for the design of biological experimental stimulation schemes.The temperature rise curves of 808 nm and 1550 nm near-infrared lasers at different powers were established by experimental methods,and the temperature rise gradients in the calculation model were screened.We modified the membrane capacitance current and ion channel current of Hodgkin-Huxley neuronal model to respond to photothermal stimulation.And then we investigated the effects of photothermal effect on the activities of single neuron,synapse and neuronal network at different temperatures.These results showed a dose-dependent biphasic cellular response,i.e.,low dose promotion and high dose inhibition.In addition,we expanded the single-scale study of optical modulation,and constructed a dual-grid mesh-based Monte Carlo algorithm by considering the individual characteristics of human brain.By applying laser stimulation at630 nm,810 nm,980 nm and 1064 nm,we quantified the distribution dose of photon flux in cerebral cortex under different wavelengths of optical source.We found that the modulation effects of different wavelengths have great differences,among which red light at 630 nm and near infrared at 810 nm have the best penetration and stability.4.Using Gel MA/Alg MA bioinks and 3D bio-printing technology,we constructed engineered neural tissues in vitro.Based on the tissues model,we investigate the mechanism of optical stimulation on neural stem cell differentiation by mitochondrial membrane potential,protein and gene expression detection.Compared with two-dimensional cell culture in vitro and complex models in vivo,engineered neural tissue not only preserves the microenvironment in vivo,but also enables intuitive detection of cells.In this paper,we firstly characterized the rheological properties,optical properties and biocompatibility of bioinks materials.These results indicate that the physical and chemical properties of the materials are suitable for the growth of neural stem cells.Furthermore,neural stem cells were stimulated by low-intensity near-infrared laser(808 nm),and the expression of related proteins and genes in differentiated neural cells were detected.The results showed that low-intensity laser stimulation can induce neural stem cells into neurons,in which the response of mitochondria to optical stimulation plays a key role in this process. |
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