甲状腺素对大鼠抑郁和焦虑样行为以及背景恐惧记忆的影响

发布时间：2018-03-20 15:34

本文选题：甲状腺功能减退症　切入点：甲状腺功能亢进症　出处：《云南大学》2015年博士论文　论文类型：学位论文

【摘要】：本文包括两部分内容：第一部分,甲减和甲亢双向作用于SD大鼠的抑郁和焦虑样行为；第二部分,SD大鼠海马内高甲状腺素损伤背景恐惧记忆的巩固。第一部分：甲状腺素异常经常与抑郁症相关,长期以来这方面已受到关注,但它们间的具体因果关系一直保持着争议。为了说明甲状腺功能(甲功)异常与抑郁症之间的因果关系,我们用给SD大鼠灌胄(I.G)1引碘(131I)以造模甲状腺功能减退症(甲减)大鼠,给SD大鼠腹腔注射(I.P.)注射左旋甲状腺素(LT4)以造模甲状腺功能亢进症(甲亢)大鼠。单次给SD大鼠胃内注入(I.G.)131I(5mCi/kg body weight),9天后其血清游离四碘甲状腺原氨酸(FT4)和游离三碘甲状腺原氨酸(FT3)将长期低于正常水平。这些大鼠在强迫游泳(FST)和糖水偏爱实验中,表现为降低的抑郁样行为,在高架十字迷宫(EPM)中表现为抗焦虑样行为。和对照组大鼠(胃内灌相同体积的生理盐水NS)相比,甲减大鼠大脑内的五羟色胺(5-HT)水平显著降低,但海马内的脑源性神经营养因子(BDNF)表达水平显著升高。在甲减大鼠腹腔内注入LT4将逆转降低的血清甲状腺素,并逆转其抗抑郁样行为。相反,在大鼠腹腔内每周注射LT4(15μg/kg body weight),将导致大鼠血清的FT4和FT3比对照组大鼠(腹腔内注入相同体积的NS)高出10多倍。甲亢大鼠在FST中表现为抑郁样行为,在EPM中表现为焦虑样行为,比对照组在大脑内有更高的5-HT,在海马内有显著降低的BDNF表达。用抗抑郁药丙咪嗪(15mg/kg)注入甲亢大鼠腹腔,将显著降低血清的FT4,也随之降低其抑郁和焦虑样行为,但相对于对照组和甲减组大鼠,其导致脑内的5.HT进一步升高。总之,我们的结果提示了甲减和甲亢将双向调节大鼠的焦虑和抑郁样行为,可能是通过调节海马内的BDNF水平起作用的。这些数据为今后更深入的临床研究打下了基础。第二部分：甲状腺素在大脑许多正常功能中起着关键作用,其中包括认知功能。本研究主要用背景条件性恐惧记忆研究四碘甲状腺原氨酸(T4)在情绪学习和记忆中的作用。在背景条件性恐惧记忆训练前24小时和训练后立即、2小时后、23.5小时时等四个时间点,分别在不同雄性SD大鼠的背侧海马(DH)内微量注入左旋甲状腺素(LT4,0.4μg/μl×1ul/lateral×2laterals, LT4-注射组)或生理盐水NS (vehicle,1μl/lateral×2laterals对照组)。在训练时(DO)、训练后24小时(D1)、7天(D7)、14天(D14),在相同的恐惧性记忆训练箱中分别记录大鼠不动时间占每次实验观察时间的百分比,以此作为反映大鼠对厌恶刺激的记忆强度。在恐惧性记忆训练箱中,厌恶刺激为电刺激(0.8mA×2Seconds/time×5times)大鼠足部。DH内(I.H.)注入LT4后的3天内,海马内的游离四碘甲状腺原氨酸(FT4)显著高于对照组,但海马内的游离三三碘甲状腺原氨酸(FT3)以及前额叶(PFC)和血液中的FT4和FT3均不高于对照组。在连续6个试验,每个试验2分钟,共12分钟的背景条件性恐惧记忆训练中,训练前24小时DH内LT4-注射组的不动时间百分比与对照组比较无显著差异,提示学习能力并未显著受损。在背景条件性恐惧记忆训练后D1、D7、D14共三天,每天5分钟的背景条件恐惧记忆提取中,训练后立即或2小时后于DH内LT4-注射组的不动时间百分比比对照组显著减少,提示长期记忆(LTM)显著受损；但训练后23.5小时LT4.注射组的不动时间百分比与对照组比较在训练后上述3天均无显著差异,提示LTM未显著受损。训练后立即或2小时后于DH内LT4-注射组受损的LTM类似于条件性恐惧记忆训练后立即腹腔内注入(I.P.) LT4(15μg/kg)后在D1、D7、D14的LTM显著受损。腹腔内注入LT4后的2小时时海马内的FT4而不是FT3显著升高,24小时时海马内的脑源性神经营养因子(BDNF)显著降低。以上结果提示海马内高T4显著损伤背景条件性恐惧记忆是有时间限制的,其机制至少是通过显著降低海马内BDNF来实现的。本研究首次揭示海马内注入LT4仅显著损伤雄性SD大鼠背景条件性恐惧记忆的巩固期,而不显著损伤学习期和记忆提取。这为今后有针对性地研究和更好地选择治疗甲亢记忆受损的治疗方案提供了参考。
[Abstract]:This paper includes two parts: the first part is hypothyroidism and hyperthyroidism on the two-way action of depression and anxiety like behavior in SD rats; the second part is the consolidation of background fear memory of hyperthyroxine in SD rats.
The first part: the thyroid abnormalities often associated with depression, a long time it has been paid attention, but the specific causal relationship between them has remained controversial. In order to illustrate the thyroid function (a function) the causal relationship between abnormal and depression, we use Guan Zhou to SD rats (I.G) 1 (131I) of iodine die hypothyroidism (hypothyroidism) rats, SD rats by intraperitoneal injection (I.P.) injection of levothyroxine (LT4) in the model of hyperthyroidism (hyperthyroidism) rats. Single injection to SD rat stomach (I.G.) 131I (5mCi/ kg body weight), four thyroid ammonia after 9 days of free acid (FT4) and serum free triiodothyronine three (FT3) will be lower than the normal level. The rats in forced swimming (FST) and sucrose preference test, performance for depression like behavior to reduce, in the elevated plus maze (EPM) is in the form of anti anxiety like behavior. And the rats in the control group (normal saline NS gastric irrigation of the same volume) compared to hypothyroid rats in the brains of five hydroxytryptamine (5-HT) levels were significantly reduced, but the brain derived neurotrophic factor in the hippocampus (BDNF) expression level was significantly increased in hypothyroidism rats. Intraperitoneal injection of LT4 in the inverse transfer of serum thyroxine reduce, and reverse the anti depressive like behavior. On the contrary, in rats after intraperitoneal injection of LT4 per week (15 g/kg body weight), will result in the serum of rats FT4 and FT3 rats than in the control group (intraperitoneal injection of the same volume of NS) of more than 10 times higher. Hyperthyroid rats in FST performance as the depression like behavior in EPM showed anxiety like behavior than the control group, with higher 5-HT in the brain, have reduced the expression of BDNF in hippocampus. With antidepressant imipramine (15mg/kg) intraperitoneal injection of hyperthyroid rats, significantly reduced serum FT4, with reducing the depression and anxiety like But, compared with the control group and hypothyroidism group rats, resulting in brain 5.HT increased further. In conclusion, our results suggest that the hypothyroid and hyperthyroid rats will regulate anxiety and depression like behavior, it may regulate the level of BDNF in the hippocampus plays a role. These data for future clinical research deep foundation.
The second part: thyroid hormone plays a key role in many normal brain functions, including cognitive function. This research mainly used the research background of conditioned fear memory four triiodothyronine (T4) in emotional learning and memory function. In the background of conditioned fear memory training 24 hours before and immediately after training, after 2 hours 23.5 hours, four time points respectively in the dorsal hippocampus of different male SD rats (DH) microinjection of levothyroxine (LT4,0.4 g/ L * 1ul/lateral * 2laterals, LT4- injection group) or saline (NS vehicle, 1 l/lateral * 2laterals control group. (in training) DO), 24 hours after the training (D1), 7 days (D7), 14 days (D14), in fear of the same memory training box in the immobility time of the rats were recorded for each experiment to observe the percentage of time, so as to reflect on rat memory strength aversive stimuli. In Fear memory training box, aversive stimuli into electrical stimulation (0.8mA * 2Seconds/time * 5times) rat foot.DH (I.H.) LT4 within 3 days after the injection, four free triiodothyronine (FT4) in the hippocampus was significantly higher than the control group, but 33 free triiodothyronine in hippocampus (FT3) and the prefrontal cortex (PFC) and FT4 in blood and FT3 were not significantly higher than the control group. In 6 consecutive tests, each test 2 minutes, 12 minutes of conditioned fear memory training, training 24 hours before DH in LT4- injection group, the immobility time and the percentage of the control group showed no significant difference that suggests that learning ability does not significantly damaged. In the background of conditioned fear memory after training, D1, D7, D14 a total of three days, every 5 minutes of background extraction of fear memory, immediately after training or 2 hours after LT4- injection in DH group significantly decreased the immobility time percentage than the control group. In the long-term memory (LTM) significantly impaired; but the training 23.5 hours after LT4. injection group of real time compared with the control group in the 3 day after the training had no significant difference, suggesting that LTM was not significantly impaired. Immediately after training or after 2 hours in the DH group were injected with LT4- damaged LTM similar to the conditioned fear memory immediately after training injection intraperitoneal (I.P.) LT4 (15 g/kg) in D1, D7, D14, LTM were significantly damaged. Intraperitoneal injection 2 hours after LT4 FT4 in the hippocampus is not FT3 significantly increased at 24 h in the hippocampus brain derived neurotrophic factor (BDNF) decreased significantly. These results suggest that hippocampal T4 damage significantly high background of conditioned fear memory is a time limit, the mechanism is at least through significantly decreased in hippocampus of BDNF. This is the first study to show hippocampal injection of LT4 in the only significant damage in male SD rats background of conditioned fear memory Consolidation period does not significantly damage learning period and memory retrieval. This provides a reference for targeted research and better choice of treatment regimens for hyperthyroidism memory impairment.

【学位授予单位】：云南大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R749

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