【作者】 李华丽；

【导师】 赵华；

【作者基本信息】 吉林大学 ， 生理学， 2009， 博士

【摘要】 目前我国的抑郁症患者已高达2600万,大量的研究资料显示,女性抑郁症的发病率是男性的两倍以上。女性抑郁症患者大多伴有雌激素缺乏,研究发现,无论是更年期抑郁,还是产后抑郁,雌激素水平低下是其病因的内在病理生理基础。国内外许多研究证明,脑内5-羟色胺水平降低是导致抑郁的直接原因,中缝背核是5-羟色胺的主要生成部位,抑郁时中缝背核被抑制与缰核兴奋有关。缰核不仅与中缝背核有密切的纤维和功能联系,而且与蓝斑核、海马和杏仁核等与情绪相关的中枢核团也具有密切的联系,在抑郁症发病及治疗机制中具有重要的意义。缰核尤其是外侧缰核上有大量的雌激素受体,卵巢摘除后4周,外侧缰核内的雌激素受体发生代偿性上调,证明外侧缰核在母性行为和情绪调节中具有重要作用。本研究课题主要从行为学、分子生物学、高效液相色谱分析学及电生理学等方面证明了抑制外侧缰核可通过提高中缝背核内谷氨酸和5-羟色胺水平来改善更年期抑郁大鼠的抑郁行为。17β-雌二醇可通过降低外侧缰核内谷氨酸的水平,即抑制外侧缰核神经元兴奋性来提高中缝背核内5-羟色胺能神经元的放电频率,增加更年期抑郁大鼠脑内5-羟色胺水平,发挥其抗抑郁作用。更多还原

【Abstract】 Menopausal depression occurred in women are the most common clinical cases. It is reported that women entering menopause, about 46% of people suffering from this disease, significantly higher than other age groups. The main performance for depression is, fatigue weakness, loss of confidence in the life, self-evaluation is too low, feel that the days going on like years, while others have antifeedant and suicidal behavior. Menopausal depression have a huge impact on women’s physical and mental health, direct impact on the quality of life in old age and length of life, and it has long been attached great importance to the medical profession. It is the current problems and the major disease affecting life quality of menopausal women.On the pathophysiological basis incidence of menopausal depression, the majority of people think that the menopausal ovary of women is no longer ovulation, estrogen levels plummeted, leading to the brain and emotion-related decline in neurotransmitter levels, and then induced depression. Norepinephrine (NE), serotonin (5-HT), dopamine (DA), glutamate,γ-aminobutyric acid (GABA) and other neurotransmitters involved in the pathogenesis of depression. Many studies show that the incidence of climacteric depression with brain 5-HT reduction has a close relationship. Clinical application of 5-HT reuptake inhibitors, enhance the level of central 5-HT, antidepressant effect can be achieved. Dorsal raphe nucleus (DRN) is one of the main gathering nucleus of the 5-HT neurons in the brain, and is the the main generating site of central 5-HT, the nerve fibers uplink projected onto the forebrain and lot parts of the cerebral cortex. There is great significance of DRN for the maintenance of central 5-HT levels in a stable situation. DRN function of the brain can be inhibited, and the 5-HT content significantly decreased, indicating that the DRN neuron excitability change in the incidence of depression and treatment of depression play an important role. Habenular nucleus (Hb) is the part of limbic system neural loop, and is the relay station which contacts the edge of forebrain and the dorsal brain stem descending pathway, and behavioral and emotional related. Hb, especially the lateral habenular nucleus (LHb), there is mutual projection fibers between the LHb and DRN, the two affect each other in a way. Electrical stimulation LHb inhibit 5-HT neuronal activity of the DRN indirectly through exciting GABA neurons, which can reduce the release of 5-HT and the central 5-HT level. In addition, LHb contains many estrogen receptor expression, and estrogen receptor expression was compensatory increased after ovariectomy, suggesting that the antidepressant effect of estrogen are achieved probably by inhibiting the over-excitement of LHb. Its mechanism is probably by the inhibition of LHb and indirectly exciting the 5-HT neurons activity of the DRN, increasing the release of 5-HT and the central 5-HT level. This study mainly conduct behavior study, molecular biology techniques, high-performance liquid chromatography analysis and electrophysiology techniques, from the point of view of the behavior and neurotransmitter changes in the content, revealed the role of LHb at the incidence and treatment of menopausal depression in rats, and proved LHb as one of the important antidepressant central target mediated the antidepressant effect of estrogen.The research findings show:(1) Using ovariectomized rat to preparation the model of menopausal depression, 4 weeks after OVX, the body weight of ovariectomized rats increased significantly compared with the body weight of control group and sham group (compared with the control group: P<0.001; compared with the sham group: P<0.001)(2) The immobile time of ovariectomized rats was increased significantly in the FST compared with the control group and sham group (compared with the control group: P<0.001; compared with the sham group: P<0.01), and the climbing time was significantly reduced (compared with the control group: P<0.001; compared with the sham group: P<0.01).(3) Electrical lesion LHb of menopause depression rats the immobile time was significantly shorten in the FST (t=3.75,P<0.01), and the climbing time was significantly prolonged (t=3.24,P<0.01), and the depressive behavior of rats has been significantly improved. False lesion LHb of menopausal depression rats the immobile time and climbing time have been no significant change compared with the former before LHb lesion (P>0.05).(4) LHb microinjection of sesame oil (0.2μl) in menopausal depression model rats had no effect on the immobile time and climbing time in the FST (P>0.05). LHb microinjection of 17β-estradiol (1μg / 0.2μl) in menopause depression rats had significantly been reduced the immobile time (t=2.81, P<0.05), and the climbing time had been significantly prolonged (t=3.44, P<0.01). The depressive behavior in menopausal depression rats had been significantly improved.(5) LHb and hippocampus C1 region of control group rats has estrogenαreceptor expression, and there was no estrogenβreceptor expression in the LHb. There was neither estrogenαnorβreceptor expression in the MHb. Estrogenαreceptor expression of LHb compensatory increase in the ovariectomized group compared with the control group.(6) The levels of Glu, GABA and the ratio of Glu to GABA in the DRN of ovariectomized rats was significantly reduced compared with control group (The level of Glu:t=7.55,P<0.001;The level of GABA:t=2.56,P<0.05;The ratio of Glu to GABA:t=2.4,P<0.05).The levels of Glu, GABA and the ratio of Glu to GABA in the DRN of ovariectomy + LHb lesion rats was significantly increased compared with the ovariectomized rats (The level of Glu:t=7.3,P<0.001;The level of GABA:t=4.66,P<0.01;The ratio of Glu to GABA:t=2.34,P<0.05).The levels of Glu, GABA and the ratio of Glu to GABA in the DRN of ovariectomy + LHb lesion rats was significantly increased compared with the ovariectomized + LHb sham lesion rats (The level of Glu:t=3.1,P<0.05;The level of GABA:t=2.06,P>0.05;The ratio of Glu to GABA :t=2.44,P<0.05). The results showed that female rats with a reduction in the level of glutamic acid of DRN, 4 weeks after ovariectomy, and the excitatory neurons reduced. Damaging LHb in menopausal rats with depression can increase glutamic acid levels in rats DRN, and enhance neuronal excitability in DRN.(7) The 5-HT level in DRN of ovariectomized rats was significantly decreased compared with the control group (t=2.27,P<0.05).The 5-HT level in DRN of ovariectomized + LHb lesion rats was significantly increased compared with the ovariectomized group (t=3.63,P<0.01), and with the ovariectomized + LHb sham lesion group (t=3.55,P<0.01). There was no significant difference between the ovariectomized + LHb lesion group and the control group (t=0.44,P>0.05). The results showed that ovariectomy can reduced the 5-HT level of DRN in the female rats, and damaging LHb can improve the 5-HT level of DRN in the menopausal rats with depression.(8) The levels of Glu, GABA and the ratio of Glu to GABA in the DRN of ovariectomized + LHb microinjection of 17β-estradiol was significantly increased compared with the ovariectomized group (The level of Glu:t=7.02,P<0.001;The level of GABA:t=5.17,P<0.01;The ratio of Glu to GABA:t=2.34,P<0.05).The levels of Glu, GABA and the ratio of Glu to GABA in the DRN of ovariectomized + LHb microinjection of 17β-estradiol was significantly increased compared with the ovariectomized + LHb microinjection of sesame group too (The level of Glu:t=2.88,P<0.05;The level of GABA:t=2.37,P<0.05;The ratio of Glu toGABA:t=0.46,P>0.05). The results showed that LHb microinjection of 17β-estradiol (1μg/0.2μl) in ovariectomized rats can increase the glutamic acid level of the DRN nucleus, and improve the excitability of DRN neuron.(9) The 5-HT level in DRN of ovariectomized rats was significantly decreased compared with the control group (t=2.27,P<0.05).The 5-HT level in DRN of ovariectomized + LHb microinjection of 17β-estradiol was significantly increased compared with the ovariectomized group ((t=3.32,P<0.01). The results showed that LHb microinjection of 17β-estradiol (1μg/0.2μl) increased the 5-HT level in DRN in ovariectomized rats.(10) The levels of Glu, GABA and the ratio of Glu to GABA in the LHb of ovariectomized rats was significantly increased compared with the control group (The level of Glu:t=4.26,P<0.01;The level of GABA:t=3.3.,P<0.05;The ratio of Glu to GABA:t=4.37,P<0.01).The levels of Glu and the ratio of Glu to GABA in the LHb of ovariectomized + LHb microinjection of 17β-estradiol was significantly decreased compared with the ovariectomized group (The level of Glu:t=2.6,P<0.05;The ratio of Glu to GABA:t=3.88,P<0.01). There was no significant difference in the level of GABA (t=1.35,P>0.05). The results showed that the level of Glu of LHb in the ovariectomized female rats was increased, and the excitability of neurons was inceased too. LHb microinjection of 17β-estradiol can reduce the Glu level of LHb in menopausal rats with depression, and inhibit the excitability of LHb neurons.(11) Microinjection of 17β-estradiol (3 nM) into LHb can increase the firing rate of 5-HT neurons in DRN (t=7.74,P <0.001). The results showed that 17β-estradiol can change the electric activity of the 5-HT neurons in DRN by affecting the activity of neurons in LHb.According to these results, we can draw the following conclusions:(1) From the view of behavior demonstrated that the depression behavior can be induced from the ovariectomized rats, confirmed that the rat model of menopausal depression was reliability, but also proved once again that the ovariectomized rats are the ideal model of studying the mechanism of menopausal depression which are used to study the incidence and treatment of menopausal depression.(2) LHb lesion can enhance the neuronal excitability and 5-HT levels of DRN, which improve the depressive behavior of the rat model of menopausal depression. It noted that LHb activity enhanced played an important role in the incidence of the menopausal depression.(3) 17β-estradiol can inhibit the neuronal activity of LHb, thereby enhancing the excitibility in DRN neurons and 5-HT levels to improve the depressive behavior of menopausal depression in rats. It showed that LHb is an important central target point for estrogen exerting its antidepressant effects.更多还原