The Role Of Lateral Parabrachial Nucleus To Ventral Tegmental Area Neural Circuit In Anorexia Nervosa

Anorexia nervosa(AN)patients exhibit some symptoms,such as selfstarvation,low body weight,etc.These core symptoms have huge serious effects on patients' living quality and work efficiency,and may eventually lead to death.The pathological mechanism of this disease is not clear,and the treatment is mainly inpatient nursing or outpatient psychotherapy without any effective drugs.Some studies have found abnormalities in the dopamine system in patients with AN,however,the exact changes are not clear.In this research,based on the activity-based anorexia(ABA)animal model,we recorded and manipulated brain areas in the dopamine system(lateral parabrachial nucleus(LPBN)and ventral tegmental area(VTA))by using in vivo electrophysiology,in vitro electrophysiology,optogenetics,chemogenetics,fiber photometry to illustrate the pathological mechanism of the anorexia nervosa.Some researchers hold the perspective that the patients in AN can reinforce their anorexia behaviors in the area of anorexia nervosa.We verified whether the neural circuit of LPBN to VTA possess the reinforcement and self-starvation behaviors simultaneously or not by manipulating this neural circuit.We found that activation of this neural circuit could induce self-starvation behaviors and inhibition of this neural circuit could increase feeding behaviors in mouse using chemogenetics.In the real-time place preference test,we found that activation of this neural circuit could increase the entries into the stimulated chamber,which means the mouse exhibited a reinforcement behavior.However,inhibition of this neural circuit could induce aversive behavior eventually.These results indicated that the neural circuit of LPBN to VTA play role in self-starvation and reinforcement behaviors simultaneously.Based on the ABA animal model,We observed the hyperactivation in the neural circuit of LPBN to VTA using in vitro electrophysiology.By inhibiting this hyperactive neural circuit during the development of ABA by chemogenetics,We found the enhanced survival rates in AN mouse.We found that this neural circuit was mainly glutamatergic projection by combing optogenetic and in vitro electrophysiology.Activation of this neural circuit using optogenetics could inhibit dopamine release into the medial nucleus accumbens shell by using dopamine sensor.These results indicated that this glutamatergic projection targets onto VTA inhibitory interneurons,and thus have inhibitory effects on VTA dopamine neurons.By using in vivo electrophysiology,we recorded the local field potential in VTA and found decreased theta-band(4-12Hz)power in AN mouse.Using cellattached recording,we found decreased spontaneously firing frequency on VTA dopamine neurons in AN mouse.By analyzing the waveforms of the action potential,we found some changed parameters which indicated the alteration of high-conductance calcium-and voltage-dependent potassium channel(BK channel).Thus,we tested the BK channel currents on VTA dopamine neurons and found decreased BK current density in the AN mouse.Furthermore,the BK channel agonist could restore the decreased firing rates in AN mouse.In summary,in our results,we found that the neural circuit of LPBN to VTA play role in reinforcement and self-starvation behaviors.This neural circuit is mainly glutamatergic projection targets onto VTA inhibitory interneurons to inhibit VTA dopamine neurons ultimately.In AN mouse,this glutamatergic neural circuit is overactivated,and the firing rates of VTA dopamine neurons are thus attenuated.The decreased firing rates can be restored by BK channels agonist in AN mouse.During the development of the animal model,inhibition of this neural circuit can enhance survival rates in AN mouse.This therapeutic effect may be the result that inhibition of this glutamatergic neural circuit can induce disinhibition onto VTA dopamine neurons via inhibitory interneurons in VTA,thus activating the decreased firing rates of VTA dopamine neurons in AN mouse and then enhancing the survival rates of AN mouse.Our research explored the neural circuit mechanism in anorexia nervosa,the results may support the development of drugs and treatment in the future.