The Mechanistic Study Of DOI On Gamma Oscillations In TRN Mediated Corticothalamic Circuit

Objective:Hallucinogens are a kind of psychoactive substances that can cause changes in perception,thinking and emotion,the neural mechanism of hallucinogenic behavior induced by hallucinogens is not known.Gamma oscillations regulate various cognitive processes through regulating the transmission of information between different brain regions,including sensation,attention,learning and memory.Recent studies have shown that 40 Hz gamma oscillations in the thalamocortical circuit are involved in the formation of hallucinations in schizophrenic positive patients.In this study,serotonergic hallucinogen 2,5-dimethoxy-4-iodoamphetamine（DOI）was used as a drug model to explore the role of 40 Hz gamma oscillation in regulating hallucinogenic head twitch response（HTR）behavior induced by DOI,and to explore the role of corticothalamic circuit mediated by the thalamic reticular nucleus（TRN）in it,in order to reveal the pathogenesis of hallucinatory related schizophrenia and provide new ideas for clinical treatment of schizophrenia.Methods:（1）We used immunofluorescence technique to identify the position of electrode in limbic TRN brain region.（2）We used in vivo electrophysiological technique to research the effects of DOI on gamma oscillations and neuronal spike frequency in limbic TRN of freely moving mouse.（3）We used immunofluorescence technique to identify the position of virus expression.（4）We used optogenetic activation or inhibition of parvalbumin（PV）neurons to study the effect of hallucinogen on HTR behavior induced by DOI in limbic TRN brain region.（5）We used optogenetic activation or inhibition of glutamate circuit in cingulate cortex（Cg）→limbic TRN to study the effect of hallucinogen on HTR behavior induced by DOI.（6）We used optogenetic activation or inhibition of PV circuit in limbic TRN→inter-mediodorsal thalamic nucleus（IMD）to study the effect of hallucinogen on HTR behavior induced by DOI.Results:The results of in vivo electrophysiology showed that（1）The 40 Hz gamma oscillations power spectra were decreased by DOI（2mg/kg）in limbic TRN,compared with vehicle.（2）5-Hydroxytryptaime 2A(5-HT_2A)receptor selective antagonist MDL-100907（0.3mg/kg）reversed the 40 Hz gamma oscillations power spectra in limbic TRN brain that had been decreased by DOI（2mg/kg）,while the 40 Hz gamma oscillations power spectra were not affected by DOI（2mg/kg）in limbic TRN brain,compared with vehicle.（3）The 40 Hz gamma oscillations power spectra were affected by non-hallucinogenic 5-HT_2A receptor agonist lisuride（0.1mg/kg）in limbic TRN brain,compared with vehicle.（4）The neuronal cluster analysis showed that spike frequency of gamma-aminobutyric acid（GABA）ergic interneurons were decreased by DOI（2mg/kg）in limbic TRN brain,compared with vehicle.These results were suggested that DOI（2mg/kg）reduced the spike frequency of GABAergic interneurons and 40 Hz gamma oscillations power spectra by activating 5-HT_2A receptors on GABAergic interneurons in limbic TRN brain region.The results of optogenetic regulation combined with HTR behavior showed that（5）40 Hz（but not 80 Hz）optogenetic activation of PV neurons decreased DOI-induced HTR behavior in limbic TRN brain,while optogenetic inhibition of PV neurons increased DOI-induced HTR behavior in limbic TRN brain,it suggested that 40 Hz optogenetic stimulation of PV neurons can specifically regulate DOI-induced HTR behavior in limbic TRN brain.（6）The 40 Hz（but not 80 Hz）optogenetic activation of glutamate circuit of Cg→limbic TRN reduced DOI-induced HTR behavior.The optogenetic inhibition of glutamate circuit of Cg→limbic TRN increased DOI-induced HTR behavior,it suggested that 40 Hz optogenetic stimulation of glutamate circuit of Cg→limbic TRN can specifically regulate DOI-induced HTR behavior.（7）The 40 Hz（but not 80 Hz）optogenetic activation of PV circuit of limbic TRN→IMD reduced DOI-induced HTR behavior,while optogenetic inhibition of PV circuit of limbic TRN→IMD increased DOI-induced HTR behavior,it suggested that 40 Hz optogenetic stimulation of PV circuit of limbic TRN→IMD can specifically regulate DOI-induced HTR behavior.These results were suggested that 40 Hz optogenetic stimulation of limbic TRN mediated Cg→limbic TRN→IMD circuit can specifically regulate DOI-induced HTR behavior.Conclusion:The 40 Hz gamma oscillations regulate DOI-induced hallucinatory HTR behavior through limbic TRN mediated Cg→limbic TRN→IMD circuit and DOI may be involved in the hallucinatory effect by reducing the 40 Hz gamma oscillations power spectra in limbic TRN brain region.