The Study On The Circuit Mechanism Of Epilepsy Induced Mental Disorder

At present,the medical cost of treating neuropsychiatric diseases,including schizophrenia,Parkinson's disease,depression,epilepsy,and drug addiction,accounts for 13%of the global medical burden.Epilepsy is a chronic brain disease caused by unexpected abnormal neural discharges,which affects about 1%of the global population and has been attracting more and more attentions.Because seizures are frequently occurred and nearly unpredictable,epilepsy not only seriously affects patients'daily lives and work,but also may endanger their lives,and ultimately brings great pressure and burden on patients,their families and society.Worse still,the harm of epilepsy is far more than its clinical attack.Recent studies have found that patients with epilepsy are susceptible to emotional disorders,which significantly increases the risk of unexpected death.The possible cause of this phenomenon is that the recurrence of epilepsy leads to the abnormal function of the neural circuit of emotion,which interferes with the accurate processing and evaluation of risky information.To date,the intervention mechanism of epilepsy is still under debate,and little is known about the characteristics of epileptic neural circuit and the causes of emotional disorders,which seriously affects the more comprehensive treatment of epilepsy.In order to solve the above problems,we have developed tools for the regulation and analysis of neural circuits based on optogenetics and electrophysiology,which mainly includes:?1?the development of a multifunctional optrode array suitable for real-time drug delivery in vivo,multi-region optogenetic regulation and multi-channel electrophysiological recordings;?2?the development of a novel neural electrode interfaces based on conductive polymers and bioactive materials,which improved the electrochemical performance and biocompatibility of the electrode interface;?3?the design and development of a self-spreadable electrode array,which significantly reduced tissue damage and inflammatory response at the electrode/neural interface,and achieved long-term stable electrophysiological recordings in vivo;?4?the development of a flexible and stretchable hydrogel optical fiber,which matched the mechanical properties of neural tissue,and significantly reduced the inflammatory response at the fiber/neural interface.With the aid of the developed tools described above,we first accurately analyzed the propagating direction of epileptic seizures in the hippocampal-entorhinal cortex structures.We implanted optrode arrays in the hippocampus and entorhinal cortex of kainic acid-induced epileptic mice,and preformed electrophysiological analysis across the brain regions.We found that the main propagating direction of epileptic seizures are from the hippocampus to the entorhinal cortex,and the interneurons in the hippocampal dentate gyrus/hilus?DGH?region are potential intervention targets for epilepsy.Subsequently,we demonstrated that cyclic optogenetic activation of the DGH interneurons has a long-lasting inhibitory effect on the hyper-activated neurons and behavioral seizures in epileptic mice.It should be mentioned that,we observed that mice with chronic epilepsy?inter-seizure period?have exhibited abnormal responses to innate fear,evidenced by weakened defensive behavior.The experimental results of c-fos mapping experiment indicate that the mouse hippocampal neuron activity is significantly increased,while the downstream regions?including the amygdala,hypothalamus,etc.?are significantly decreased.Based on the above results,we focused on the neural circuit mechanism of hyper-activated hippocampus affecting innate fear.Combining neural circuit tracing,in situ hybridization,optogenetics,and electrophysiological techniques,we have confirmed the structural and functional connection of the dHPC^Glu-dLS^GABA-DMH circuit.We also found that selectively activating the dHPC^Glu-dLS and dLS^GABA-DMH circuits can both significantly reduced the defense responses of mice in the presence of predator.Therefore,the activation of dHPC^Glu and dLS^GABA neurons inhibited the activity of DMH neurons,which may be responsible for the abnormally suppressed fear of the experimental subjects.In addition,we also found that activation of dHPC^Glu neurons can inhibit anxiety-like behaviors in mice,which is evidenced by the increased entries into and time spent in the open arms during the elevated plus-maze test.Interestingly,activation of the dHPC^Glu-dLS projections can significantly inhibit anxiety-like behaviors,but activation of the dLS^GABA-DMH projections did not result a similar effect,suggesting that the aforementioned neural circuit is not involved in the regulation of anxiety.To explain this phenomenon,we combined behavioral,c-fos mapping,neural tracing,optogenetics,and in-vivo electrophysiological techniques,and found a dHPC^Glu-dLS^GABA-CeA circuit.We confirmed the structural and functional connections of this neural circuit,as well as their regulatory effects on anxiety behaviors.These results suggest that the activation of dHPC^Glu and dLS^GABAABA neurons caused the inhibition of CeA neurons,which may subsequently lead to an anxiolytic effect on mice.In summary,we have developed new tools for in vivo neural circuit dissection and modulations,and clarified the propagating direction of seizures and intervention mechanism of temporal lobe epilepsy.Besides,we have also revealed the neural circuit mechanisms of hyper-activation of the dorsal hippocampus inducing negative emotion?innate fear and anxiety?abnormalities.These works not only provide an experimental and theoretical basis for the clinical treatment of epilepsy,but also has important reference significance for the study of other neuropsychiatric diseases.