Study On The Effect And Mechanism Of The Lateral Habenula Nucleus In The Pathogenesis Of Schizophrenia

Schizophrenia is one of the most intractable psychiatric diseases,especially the negative symptoms and cognitive disorder.It has been said that the dysfunction of dopamine(DA)and serotonin(5-HT)system is involved in the two symptoms.The habenular,especially the lateral part,is one of few regions in the central nervous system that influence both the DA and serotonin systems.The lateral habenula(LHb)is involved in the regulation to nociception,cognition,sleep and circadian rhythms,and emotion.It is unknown the role of the LHb in schizophrenia.The aim of the present study is to investigate the relationship of the LHb and schizophrenia.First of all,quantitative cytochrome-c oxidase histochemistry was used to detect the activity of LHb neurons in MK801 schizophrenia model.In the saline group,the cytochrome-c oxidase activity is 0.0009265±0.00008127,while the COX activity of the MK801 group is 0.0004798 ± 0.00009389.There is significant difference between the two groups(P=0.0074).It is suggested that the LHb is hypofunction in the MK801 group.Electrophysiology study indicated that the firing activity of LHb neurons can be disrupted by MK801.Saline injections didn't change the firing rate of LHb neurons.MK801 administration(0.5mg/kg,i.p.)evoked three types of responses.52.5%percent of the neurons decreased their firing rate whereas 12.5%percent of recorded neurons increased their firing rate after MK801,and the rest were unaffected.These data suggest that the pathology of LHb may be involved in schizophrenia.In the second,electrolytic lesions of the LHb was performed to examine whether any behavioural changes resembling those of schizophrenia was caused.The disruption of social interaction,impaired of learning and memory,and hedonistic-like behavior which resembling negative symptoms and cognitive dysfunction of schizophrenia were emerged after the LHb damaged.However,hyperlocomotion and stereotype which represent the positive symptoms were not shown.These behavioural data indicate that the negative symptoms and cognitive disorder can be induced after the LHb damage.As we know,the medial prefrontal cortex(mPFC)is a key region in the pathology of negative and cognitive symptoms of schizophrenia.Interesting,western blot analysis showing amount of dopamine receptor D1 and tyrosine hydroxylase which is the rate-limit enzyme in the synthesis of DA is decreased in the mPFC after the LHb lesion.The activity of neurons in the mPFC is also lower in the LHb lesion group compare the sham group.The tyrosine hydroxidase2 which is the rate-limit enzyme of serotonin is increased in the mPFC in the lesion group,indicating the hyperfunction of serotonin system in the cortex.Compelling electrophysiological and neurochemical data show that serotonin exert an inhibitory effect on the mesocortical DA system.It can be conclude that the LHb lesion can induce negative and cognitive symptoms of schizophrenia through downregulating dopamine transmission in the mPFC.