The Role Of Lateral Habenula In Depressive-like Behavior Of Rats Induced By Hypothyroidism And The Underlying Mechanisms

Thyroid hormone plays an important role in the development,metabolism and function of most organs,and the disturbance of thyroid function could result in dysfunction of many organs.It has been reported that hypothyroidism has a close relationship with psychiatric disorders such as depression.The patients with hypothyroidism usually present with various kinds of depression-like behavior as cognitive dysfunction,apathy,dull reaction and poor sociability,which severely affects the life quality and its prognosis.While,some depression patients are more prone to suffer from hypothyroidism,which might be an important risk factor in the development of depression.So,there will be an important clinical significance to find out the mechanism of depression that induced by hypothyroidism,which could be beneficial for the prevention and treatment of the patient with hypothyroidism-induced depression.The pathogenesis of depression is complicated,it might closely related to monoamine neurotransmitter disorder,social environment,individual characteristic,endocrine changes and mental diseases.The deficiency of monoamine neurotransmitter,especially serotonin(5-hydroxytryptamine,5-HT),is focused on because of its important role in the onset of depression.It is reported that 5-HT levels in serum and cerebrospinal fluid declines in depression patients,serotonin uptake inhibitor has already been used as anti-depressive treatment in clinic,which undoubtly demonstrates that the 5-HT plays a key role in depression,and other factors related to depression also work via affecting the 5-HT system.Other studies argue there has a close functional interaction between hypothalamus-pituitary-thyroid(HPT)axis and serotonin system.5-HT levels could be elevated by thyroid hormone by inhibiting 5-HT 1A receptors in dorsal rapheal nuclei(DRN).Monoamine neurotransmitter is lower in serum and some brain region of rats with hypothyroidism induced by Propylthiouracil.Decreased serum 5-HT levels could also be found in hypothyroidism with depressive-like behavior,which indicates the depressive-like behavior resulting from hypothyroidism is associated with the declined central serotonin neurotransmitter.But the mechanism underlying the effects of thyroid disorders on the central serotonin system is unknown and the key region that connects the HPT axis and serotonin systems has yet not to be identified.DRN is the principal part of the 5-HT synthesis and release,DRN lesion could result in significant decreased central 5-HT levels.The key region that controls the DRN is lateral habenular nucleus(LHb).Neuron activity in DRN could be inhibited by electrical stimulation on LHb,and there exists a complicated functional projection between them.Lots of evidence show that LHb acts as a key point in depression both in experimental animals and in clinical patients.Activity of LHb is obviously increased in the four different animal models of depression.Other research indicates depressive-like behavior could be improved by the increased 5-HT levels induced by LHb lesion.What's more,there exits a close functional connection between LHb and thyroid,an enlarged LHb size could be detected in hypothyroidism rats induced by the excision of cervical neural ganglion.Dynaprin could exert an antidepressive effect on depressive rats by decreasing the metabolism of LHb,Other studies show that the thyroid hormone receptors exist in LHb,which indicates LHb may involved in the pathogenesis of depression resulting from hypothyroidism by mediating the effect of hypothalamus-pituitary-thyroid axis on 5-HT system in DRN.In our work,we used behavior tests,histochemistry,high efficiency liquid chromatography and Western blot to measure depressive behavior of thyroidectomy(TD)rats,and then,to observe the changes of depressive-like behavior,neural activity of LHb and DRN,5-HT levels in DRN after LHb lesion and thyroid hormone supplement on TD rats,further to discuss the role of LHb in depressive-like behavior of rats induced by hypothyroidism and the underlying mechanism.The results are list as follow:1.The behavior test showed depressive-like behavior was obvious in TD rats with prolonged immobility time and decreased climbing time in 'force swimming test(FST).The movement distance was also declined in TD rats comparing with the sham rats in open-field test(OST).High efficiency liquid chromatography showed the 5-HT levels of DRN were decreased in TD rats compared with the sham.It reveals that the depressive-like behavior could be induced by hypothyroidism in TD rats.2.Histochemistry manifested the COX activity in LHb of TD rats was much higher than that of the sham,which could be restored after thyroid hormone supplement of TD rats.Western blot showed the expression of thyroid hormone receptor ?(THR)and ? calcium/calmodulin-dependent protein kinase ?(?CaMK-?)were up regulated.These changes could recovered by thyoird hormone supply.3.After LHb lesion or thyroid hormone supplement,the depressive-like behavior of TD rats were improved.In FST,the climbing time was increased and the time spent immobile was decreased compared with the sham,and the mobile distance was increased in OFT.4.The COX activity in DRN of TD rats was decreased compared with the sham,which could be reversed after thyroid hormone supplement.High efficiency liquid chromatography showed 5-HT levels of DRN in TD rats were increased after LHb lesion.According to our results,we conclude that depressive like behavior could be induced by hypothyroidism in TD rats,which results from the decreased 5-HT level of DRN that was attributed to the inhibitory effect from the excited LHb.