Generation And Modulation Of Auditory Gating In The Posterior Parietal Cortex Of Awake Mice

Objective:Auditory gating(AG)is an important regulatory mechanism of biological function,which is mainly manifested in the gradual reduced responsiveness to redundant sound stimuli.Maintaining a robust AG of the central nervous system(CNS)can effectively filter out the transmission of redundant information to the higher-order brain regions and protect the information processing capacity of CNS.The auditory cognitive network is mainly composed of two auditory signal transmission pathways.One pathway is called the specific auditory thalamocortical pathway: Acoustic information is projected from the medial geniculate body(MGB)to the ipsilateral primary auditory cortex(AC),and then transmitted to the higher-order brain regions such as posterior parietal cortex(PPC)and medial prefrontal cortex(m PFC)via cortico-cortical pathway.Another pathway is called the non-specific auditory thalamocortical pathway: Acoustic information can through thalamo-cortical pathway directly projected from the medial dorsal thalamic nucleus(MD)to PPC and m PFC.However,the difference of AG in these two pathways and their changes in the auditory cognitive network are still unclear.Previous studies have shown that neural activity in PPC plays a crucial role in the transmission of auditory information between the thalamus and cortex.The PPC neurons can respond to visual,auditory,vestibular,and somatosensory stimuli,thereby pooling,processing and filtering multisensory information.As a key hub of the auditory pathway,the PPC neurons can simultaneously receive auditory information from MD and AC.Therefore,depth-investigating the role of auditory information from different sources in the generation of AG in PPC will facilitate to understand the potential neural circuit mechanisms of multisensory integration.It has been reported that the abnormal function of thalamocortical transmission can contribute to the occurrence of various neuropsychiatric diseases,such as schizophrenia(SZ).SZ is a severe psychiatric disorder with high prevalence and disability,usually manifested as disturbances in perception,thinking,emotion,and behavior,as well as incoordination between mental activities and the environment.Clinical evidence shows that patients with SZ often have abnormalities in sensory gating such as prepulse inhibition(PPI)deficits.The brain of SZ patients is overwhelmed and overloaded by too many sensory information,which causes the abnormalities of cognitive functions such as attention and orientation,and eventually leads to mental symptoms such as hallucinations and delirium.In addition,SZ patients showed disruptions in motor control and motor imagery in behavioral tasks which indicate PPC dysfunction.However,whether there are abnormal changes in AG of PPC in SZ patients is still unclear.Therefore,we firstly applied the electrophysiological recordings to measure AG in each brain region of abovementioned auditory pathway and in each layer of PPC in our study.Combining with optogenetics,we established the MD/AC-PPC neural network model to comprehensively reveal the underlying neural circuit mechanism of AG in PPC.Then,we build a model mouse of SZ,combining with the hypothesis of the generation mechanism of AG in PPC,to explore whether there are AG deficits in PPC of SZ patients and reveal the possible reasons,which providing a new insight to finding potential therapeutic targets for SZ.Methods:1.We conducted the synchronous electrophysiological recordings in m PFC,PPC,AC,MD and MGB of normal mice.The AG in different brain regions were measured and evaluated by local field potential(LFP)and single unit activity(SUA)evoked by conditioning-test sound stimuli paradigm.2.Analyzing the correlation between the degree of AG and the response latency of sound-evoked LFP in different brain regions to evaluate whether AG has the characteristics of gradual enhancement during the sound information transmitted from the first-primary to the higher-order brain regions.3.Electrophysiological recordings with multi-channel probes were performed in vivo to measure the paired-tone stimuli evoked responses in PPC.We identify the layer of PPC by the results of current source density(CSD),and then investigate the differences in the degree of AG between different layers in PPC.4.MD and AC excitatory neurons express red fluorescent protein m Cherry through injecting the AAV-Camk IIα-Ch R2-m Cherry virus in these two areas.Evaluate the differences in projection of terminal fibers from MD and AC in PPC using nerve tracing techniques.5.We performed an optogenetic method to selectively activate GABAergic neurons in VGAT-Ch R2-EYFP mice,evaluated their effects on local excitatory neurons,and try to find an effective way to optogenetically manipulate the activity of specific brain regions.6.Using the optogenetic strategy in step 5,we optogenetic inactivating MD and AC respectively,and evaluated their regulatory effect on AG of different layers in PPC.In addition,the optogenetic vector virus AAV-Camk IIα-Ch R2-m Cherry was injected into MD and AC respectively,so that make the excitatory neurons in these two regions express the light-sensitive channel protein Ch R2.We used the paired pulsed light stimulation to activate the nerve terminals projected from MD or AC,and recorded the light-evoked responses of each layer in PPC to evaluate the contribution of the MD/ACPPC pathway activity on the formation of AG in PPC.7.The SZ mice model was built by administering NMDA receptor blocker(MK-801)during the critical period of nervous system development(PND7-11),and the modeling effectiveness was evaluated by open field test(OFT),startle reflex test(SR)and prepulse inhibition test(PPI).8.The AG in each layer of PPC and in MD and AC of SZ model mice were recorded to evaluate whether there were gating deficits.Combined with the hypothesis of the formation mechanism of AG in PPC obtained from the previous experiments,we try to find the main reasons for the abnormal AG in PPC of SZ patients.Results:1.In the specific auditory pathway,the degree of AG in MGB and AC was weak,in the non-specific auditory pathway,MD and m PFC demonstrated the strong AG,and the AG in PPC was moderate.The level of AG was gradually increased with the prolongation of the response latency among recorded brain regions.2.There are significant differences in AG levels between different layers in PPC,among which the degree of AG in G layer is the strongest,followed by I layer,and the weakest in P/S layer.3.The nerve fibers from MD mainly projected to G layer of PPC,while the nerve fibers from AC mainly arrived at the P/S layer of PPC.Selectively optogenetic inactivation of neuronal activity in MD can lead to a decrease of AG in all layers of PPC,while optogenetic inactivation of AC result in an increase of AG in G layer and I layer,while the AG in P/S layer was unchanged.4.Optogenetic activation of MD/AC-projected nerve terminals in PPC can drive LFP and SUA responses across all layer of PPC.Activating the nerve terminals of MD projecting to PPC induce the strongest response in G layer,while activating the nerve terminals of AC projecting to PPC induce the strongest response in P/S layer of PPC.However,optogenetic activation of these two projection pathways could not trigger the generation of AG in PPC.5.Administration of MK-801 on postnatal 7-11 days can lead to hyperlocomotion(increase in total distance and velocity of movement in open field test),abnormally increased SR and PPI deficits in adulthood.Compared with normal mice,SZ model mice showed a weakened AG in all layers of PPC and MD,but no significant changes in AC.Conclusion:1.The degree of AG was gradually enhanced in the auditory thalamocortical pathway.Among them,the level of AG in non-specific auditory pathway was stronger than in specific auditory pathway.The PPC showed significant differences in AG of each layer,in which the AG was the strongest in G layer,intermediated in I layer,and the weakest in P/S layer.2.The AG of PPC was mainly inherited from MD and AC.The strong AG signal derived from MD was mainly transmitted to G layer of PPC;while the weak AG signal from AC was predominantly delivered to P/S layer of PPC.These two different sources of AG information were gradually mixed and superimposed with each other,finally generating a laminar-specific AG in PPC.3.According to the hypothesis of the formation mechanism of AG in PPC,which obtained from the previous experiments,the dysfunction of MD may result in the disrupted AG in all layers of PPC in SZ model mice.