小脑间位核调节免疫功能的作用途径研究
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摘要
目的：
我们实验室以往的研究表明小脑间位核可调节免疫功能。由于小脑与免疫系统之间没有直接的结构上的联系，因此阐明小脑调节免疫功能的信息传递途径对于更好地理解小脑的免疫调节功能具有重要作用。本研究以小脑—下丘脑的神经投射为切入点来揭示其在传递小脑免疫调节信息中的作用，为小脑神经免疫调节提供新的资料，有助于拓宽小脑功能的知识，促进临床上对小脑神经免疫调节异常疾病的思考和研究。
方法：
1.在一侧小脑间位核内微量注射顺行神经束路追踪剂葡聚糖-德克萨斯红（dextran-texas red, dextran-TR），观察小脑间位核至下丘脑神经投射的路径及终止部位。
2.在一侧下丘脑外侧区（顺行追踪显示下丘脑内终止纤维最丰富的区域）微量注射逆行神经束路追踪剂红色荧光金（fluoro-ruby, FR），观察小脑间位核内FR逆行标记的神经元，同时，结合谷氨酸荧光免疫组织化学法探讨小脑间位核投射至下丘脑的神经元中是否存在谷氨酸能神经元。
3.在双侧小脑间位核内微量注射谷氨酰胺酶抑制剂6-重氮-5-氧代-L-正亮氨酸（6-diazo-5-oxo-L-norleucine, DON），以抑制间位核内谷氨酸能神经元合成谷氨酸，并以双侧小脑间位核内注射等量生理盐水及未经任何处理的动物作为对照。在上述三组（未处理对照组、生理盐水对照组、DON组）大鼠的单侧下丘脑外侧区微量注射逆行神经束路追踪剂FR，5天后，在双侧小脑间位核内注射DON或生理盐水，3天后，同一层面的间位核脑片应用谷氨酸荧光免疫组织化学技术，观察小脑间位核—下丘脑外侧区谷氨酸能神经投射的数量变化。
4.在双侧小脑间位核内注射DON后第3天，用高效液相色谱法（high performanceliquid chromatography, HPLC）测定下丘脑内谷氨酸含量的变化。
5.在双侧小脑间位核内注射DON后第3天，用血细胞计数法检测动物外周血白细胞中淋巴细胞百分比的变化；用羧基二乙酸荧光素琥珀酰亚胺酯（carboxyfluorescein diacetate succinimidyl ester, CFSE）和结合PE的抗大鼠CD3抗体双标肠系膜淋巴结细胞，流式细胞仪检测T淋巴细胞对刀豆蛋白A（concanavalinA,Con A）刺激的增殖能力的变化；用酶联免疫吸附测定法（enzyme-linked immunosorbentassay, ELISA）检测血清中抗绵羊红细胞IgM抗体水平的变化。
结果：
1.小脑间位核内微量注射dextran-TR后示踪可见间位核神经元发出离核纤维，行走于同侧小脑上脚中，经小脑上脚交叉到达对侧，然后继续走行于小脑上脚中，进入下丘脑后较多纤维终止于下丘脑外侧区，少数纤维终止于下丘脑室旁核和下丘脑后区。说明小脑间位核神经元发出纤维直接投射至下丘脑（主要是外侧区）。
2.下丘脑外侧区内微量注射FR后可逆行追踪到对侧小脑间位核具有FR标记的神经元，这进一步证明了小脑间位核与下丘脑之间存在直接的神经投射；利用谷氨酸荧光免疫组织化学法染色小脑间位核，发现这些FR标记的神经元中有许多谷氨酸阳性神经元。表明小脑间位核投射至下丘脑外侧区的神经纤维中有谷氨酸能神经。
3.双侧小脑间位核内注射DON（50mM）后第3天，间位核内FR和谷氨酸双标神经元的数目明显少于生理盐水对照组和未处理对照组，而两组对照之间无明显差异，说明小脑间位核DON注射减少了小脑间位核—下丘脑外侧区的谷氨酸能神经投射。
4.双侧小脑间位核内注射DON（50mM）后第3天，下丘脑内谷氨酸含量显著低于生理盐水对照组和未处理对照组，而两组对照之间无显著性差异。双侧小脑间位核内注射低剂量DON（5mM）后，下丘脑内谷氨酸含量没有明显改变。此结果进一步证明双侧小脑间位核内注射DON（50mM）减少了小脑—下丘脑的谷氨酸能神经投射。
5.在小脑间位核—下丘脑谷氨酸能神经投射减少的同时，即在双侧小脑间位核内注射DON（50mM）后的第3天，动物外周血中淋巴细胞的百分比、淋巴结T细胞对Con A的增殖能力和血清中抗绵羊红细胞的IgM抗体水平均显著降低，而两组对照（生理盐水对照和未处理对照）之间无显著性差异。然而，低剂量的DON（5mM）注射没有明显改变上述免疫功能。说明减少小脑间位核—下丘脑的谷氨酸能神经投射可导致免疫功能减弱。
6.在小脑皮质内注射DON（50mM），没有改变下丘脑内谷氨酸的含量也不影响外周血中淋巴细胞百分比、淋巴结T细胞对Con A的增殖能力和血清中抗绵羊红细胞的IgM抗体水平。这一阴性结果进一步证明上述免疫功能的变化确实由小脑间位核—下丘脑的谷氨酸能神经投射所介导。
结论：
1.小脑间位核至下丘脑外侧区存在直接的谷氨酸能神经投射。
2.小脑间位核内注射DON减弱了间位核至下丘脑的谷氨酸能神经投射。
3.减弱小脑间位核—下丘脑的谷氨酸能神经投射导致免疫功能的抑制，提示小脑的免疫调节信息由小脑间位核—下丘脑的谷氨酸能神经投射所传递。
第二部分小脑间位核GABA能神经投射调节免疫功能的途径
目的：
我们在本文的第一部分研究中已说明小脑间位核—下丘脑的谷氨酸能神经投射可调节免疫功能。在这部分工作中，我们探讨小脑间位核的另一传出途径——GABA能神经投射对免疫功能的影响，以更深层次地理解和解释小脑间位核调节免疫功能的作用途径。
方法：
1.在一侧下丘脑外侧区微量注射逆行神经束路追踪剂FR，观察小脑间位核内FR逆行标记的神经元，同时，结合GABA荧光免疫组织化学法探讨小脑间位核投射至下丘脑的神经元中是否存在GABA能神经元。
2.双侧小脑间位核内分别微量注射GABA合成酶抑制剂3-巯基丙酸（3-mercaptopropionic acid,3-MP）、GABA转氨酶抑制剂氨己烯酸（vigabatrin, VGB）以分别减弱或增强间位核的GABA能神经投射，并以双侧小脑间位核内注射等量生理盐水及未经任何处理的动物作为对照。同时，腹腔注射小牛血清白蛋白（bovineserum albumin, BSA）免疫大鼠。术后第3天，流式细胞仪检测动物外周血单个核细胞中T和B淋巴细胞百分比的变化；用CFSE和结合PE的抗大鼠CD3抗体双标肠系膜淋巴结细胞，流式细胞仪检测T淋巴细胞对ConA刺激的增殖能力的变化；ELISA检测血清中抗BSAIgM抗体水平的变化。
3.双侧小脑间位核注射3-MP或VGB后第3天，HPLC测定下丘脑内GABA、淋巴结和脾脏中去甲肾上腺素（norepinephrine, NE）含量的变化。
4.双侧小脑间位核注射3-MP或VGB后第3天，ELISA试剂盒检测血清中促肾上腺皮质激素（adrenocorticotropic hormone, ACTH）、皮质醇（cortisol）、促甲状腺激素（thyroid stimulating hormone, TSH）、三碘甲状腺原氨酸（3,5,3’–triiodothyronine,T3）、四碘甲状腺原氨酸（3,5,3’,5’–tetraiodothyronine, T4）水平的变化。
结果：
1.下丘脑外侧区微量注射FR后逆行追踪至对侧小脑间位核，可见到FR标记的神经元；利用GABA荧光免疫组织化学法染色小脑间位核，发现这些FR标记的神经元中存在GABA阳性神经元，此结果证明小脑间位核与下丘脑外侧区之间存在直接的GABA能神经投射。
2.双侧小脑间位核内注射3-MP后第3天，外周血单个核细胞中的T和B淋巴细胞百分比、淋巴结T细胞对ConA的增殖能力、血清中抗BSA的IgM抗体水平均较两组对照显著升高；而双侧小脑间位核内注射VGB后第3天，外周血单个核细胞中的T和B淋巴细胞百分比、淋巴结T细胞对ConA的增殖能力、血清中抗BSA的IgM抗体水平均较两组对照显著降低。在两组对照之间，即双侧间位核内注射生理盐水的对照组和未作任何处理的对照组之间，上述免疫指标无显著性差异。这些结果表明减弱小脑间位核的GABA能神经投射促进了T和B细胞的功能，而增强小脑间位核的GABA能神经投射则抑制了T和B细胞的功能。
3.在免疫功能发生变化的同时，即在双侧小脑间位核内注射3-MP后第3天，下丘脑内GABA含量明显降低；而注射VGB后第3天，下丘脑内GABA含量显著升高。在两组对照之间，下丘脑内的GABA含量无显著性差异。这些结果表明间位核内注射3-MP减弱了间位核—下丘脑的GABA能神经投射，而间位核内注射VGB则增强了间位核—下丘脑的GABA能神经投射。因此提示，上述间位核内注射3-MP或VGB导致的免疫功能改变可由间位核—下丘脑的GABA能神经投射介导。
4.在免疫功能发生变化的同时，即在双侧小脑间位核内注射3-MP后的第3天，肠系膜淋巴结和脾脏中的NE含量降低，而注射VGB后的第3天，肠系膜淋巴结和脾脏中的NE含量升高，两对照组之间无显著性差异。这些结果表明，间位核内注射3-MP或VGB导致的免疫功能改变可由交感神经这一外周途径介导。
5.在免疫功能发生变化的同时，即在双侧小脑间位核内注射3-MP或VGB后的第3天，血清中的ACTH、皮质醇、TSH、T3和T4的水平与两对照组相比无显著性差异，说明腺垂体—肾上腺皮质/甲状腺途径可能不参与介导小脑间位核GABA能神经投射的免疫调节作用。
结论：
1.小脑间位核至下丘脑外侧区存在直接的GABA能神经投射。
2.小脑间位核的GABA能神经投射可调节T和B细胞的功能，其作用是负性调节这些细胞的功能。
3.小脑间位核GABA能神经投射通过下丘脑—交感神经的途径实现其免疫调节作用。
Objective:
Our previous work has shown that lesions of the cerebellar interposed nuclei (IN)suppress immune cell functions. Since there is no direct structural connection between thecerebellum and immune system, we explored the pathway mediating the cerebellarimmunomodulation at the profile of cerebellohypothalamic projections to understand thismodulation.
Methods:
1. Anterograde tracing of nerve tracts was conducted by injection of anterogradetracer dextran-texas red (dextran-TR) in the cerebellar IN to observe travelling routes andending locations of neuronal projections from the cerebellar IN to the hypothalamus.
2. Retrograde tracing of nerve tracts from the lateral hypothalamic area (LHA) to thecerebellar IN was conducted by injection of retrograde tracer fluoro-ruby (FR) in the LHA,and fluorescent immunohistochemistry for glutamate was used to identify neurotransmitterof the cerebellar IN projecting to the LHA.
3. A glutaminase inhibitor,6-diazo-5-oxo-L-norleucine (DON), was microinjectedinto the bilateral IN. The rats infused with same volume of saline in the bilateral IN andwith intact IN were used as control. FR had been infused in the LHA5days earlier. On day3following the DON injection, the cerebellar sections at the same plane were measured forglutamate-immunoreactive positive neurons by the fluorescent immunohistochemistry. Thenumber of FR-glutamate double-labeled neurons was compared among the DON, salineand intact groups.
4. On the3rd day after DON injection in bilateral cerebellar IN, high performanceliquid chromatography (HPLC) analysis was used to determine glutamate content in thehypothalamus.
5. On the3rd day after DON injection in bilateral cerebellar IN, lymphocytepercentage in the peripheral blood leukocyte was measured by a complete blood cell count;T lymphocyte proliferation induced by concanavalin A (Con A) was double labelled bycarboxyfluorescein diacetate succinimidyl ester (CFSE) and anti-rat CD3antibody anddetected by a flow cytometer; anti-sheep red blood cell (SRBC) IgM antibody in the serumwas determined by enzyme-linked immunosorbent assay (ELISA).
Results:
1. Dextran-TR-labeled nerve fibers, which were sent by cerebellar IN neurons,traveled through the ipsilateral superior cerebellar peduncle (SCP), crossed in SCPdecussation, penetrated the contralateral SCP, and entered the hypothalamus. In thehypothalamus, the fibers mostly terminated in the LHA, and less in the paraventricularnuclei and the posterior hypothalamus area.
2. Retrograde tracing by injection of retrograde tracer FR in the LHA found that theFR-labeled nerve fibers retrogradely traveled in the SCP decussation, and FR-labeledneurons appeared in contralateral cerebellar IN. Fluorescent immunohistochemistryshowed that a large number of glutamate-immunoreactive neurons (blue) were seen on thecerebellar IN section. Merging the red FR-labeled neurons and the blue glutamate-positiveneurons in the cerebellar IN, many carmine neurons which represented glutamatergicneurons projecting to the LHA were observed on the section.
3. On the3rd day after DON injection in bilateral cerebellar IN, the double-labeledneurons were significantly lower for their percentage in FR single-stained neurons inDON-injected IN than in intact or saline-treated IN. This indicated that DON infusion inbilateral cerebellar IN reduced glutamatergic projections from the cerebellar IN to theLHA.
4. Compared with intact or saline-injected rats, the DON-treated rats weresignificantly decreased in glutamate content in the hypothalamus. Between the two groupsof control rats, no significant difference was found. Glutamate content in the hypothalamusdid not change after DON treatment at a lower dose. These data further demonstrated thatDON injection in bilateral cerebellar IN reduced cerebellohypothalamic glutamatergicprojections.
5. DON injection in bilateral cerebellar IN led to a decrease in lymphocyte percentagein peripheral white blood cells, a suppression of T cell proliferative response to Con A, and a diminishment of serum specific anti-SRBC IgM antibody. But DON injection at a lowerdose in bilateral cerebellar IN did not affect the immune parameters.
6. To confirm that these immune changes were caused by decrease in cerebellarIN-hypothalamic glutamatergic projections, we injected the same dose of DON in thecerebellar cortex. DON injection in the cerebellar cortex neither altered glutamate contentin the hypothalamus nor affected immune function (lymphocyte percentage in peripheralwhite blood cells, T cell proliferative response to Con A, and the level of serum specificanti-SRBC IgM antibody).
Conclusions:
1. A direct glutamatergic projection originates from neurons of the cerebellar IN andterminates mainly in the LHA.
2. DON injection in the bilateral cerebellar IN effectively reduces thecerebellohypothalamic glutamatergic projections.
3. The reduced cerebellohypothalamic glutamatergic projection leads to the inhibitionof immune function, which suggests that cerebellohypothalamic glutamatergic projectionstransmit cerebellar immunomodulation.
Part Two: Pathways of Immunomodulation by GABAergic ProjectionsDeriving from the Cerebellar Interposed Nuclei
Objective:
Our work in the first part has shown that cerebellohypothalamic glutamatergicprojection is actively implicated in regulation of immune function. To obtain acomprehensive understanding of the pathways and mechanisms of regulating immunefunction by the cerebellar IN, in the present study, we expored the immune function of theother nerve projection, cerebellohypothalamic GABAergic projections, and its pathways oftransmitting this information.
Methods:
1. Retrograde tracing of nerve tracts from LHA to the cerebellar IN was conducted byinjection of FR in the LHA, and fluorescent immunohistochemistry for GABA was used toidentify neurotransmitter of the cerebellar IN projecting to the LHA.
2. A GABA synthetase inhibitor,3-mercaptopropionic acid (3-MP), and GABAtransaminase inhibitor, vigabatrin (VGB) were respectively microinjected into the bilateral IN. The rats infused with same volume of saline in the bilateral IN and with intact IN wereused as control. Meanwhile, rats were immuned by bovine serum albumin (BSA)intraperitoneal injection. On the3rd day after3-MP and VGB injection in bilateralcerebellar IN, lymphocyte percentage in the peripheral blood mononuclear cells wasmeasured by flow cytometry; T lymphocyte proliferation induced by Con A was doublelabelled by CFSE and anti-rat CD3antibody and detected by a flow cytometer; anti-BSAIgM antibody in the serum was determined by ELISA.
3. On the3rd day after3-MP and VGB injection in bilateral cerebellar IN, HPLCanalysis was used to determine GABA content in the hypothalamus and norepinephrine(NE) content in the lymph node and spleen.
4. On the3rd day after3-MP and VGB injection in bilateral cerebellar IN,adrenocorticotropic hormone (ACTH), cortisol, thyroid stimulating hormone (TSH),3,5,3’–triiodothyronine (T3) and3,5,3’,5’–tetraiodothyronine (T4) in the serum weredetected by ELISA.
Results:
1. Retrograde tracing by injection of retrograde tracer FR in the LHA found that theFR-labeled nerve fibers retrogradely traveled in the SCP decussation, and FR-labeledneurons appeared in contralateral cerebellar IN. Fluorescent immunohistochemistryshowed that GABA-immunoreactive neurons (green) were seen on the cerebellar INsection. Merging the red FR-labeled neurons and the green GABA-positive neurons in thecerebellar IN, some yellow neurons which represented GABAergic neurons projecting tothe LHA were observed on the section.
2. On the3rd day after3-MP injection in bilateral cerebellar IN, T and B lymphocytepercentage in the peripheral blood mononuclear cells were increased, T cell proliferativeresponse to Con A was enhanced, and serum specific anti-BSA IgM antibody level waselevated; on the other hand, when VGB was applied, all the parameters (lymphocytepercentage in the peripheral blood mononuclear cells, T cell proliferative response to ConA, and serum specific anti-BSA IgM antibody level) were suppressed. Between the twogroups of control rats, no significant difference was found.
3. On the3rd day after3-MP and VGB injection in bilateral cerebellar IN, comparedwith intact or saline-injected rats, the3-MP-treated rats were notably decreased in GABAcontent in the hypothalamus, but the VGB-treated rats were significantly increased. Between the two groups of control rats, no significant difference was found. These datademonstrated that3-MP and VGB injection in bilateral cerebellar IN effectively changedcerebellohypothalamic GABAergic projections.
4. On the3rd day after3-MP and VGB injection in bilateral cerebellar IN, HPLCresult showed that NE content was decreased in the lymph node and spleen when rats weretreated by3-MP and NE content was increased when rats were treated by VGB. Betweenthe two groups of control rats, no significant difference was found. These data showed thatcerebellohypothalamic GABAergic projection regulated immune function by the pathwayof sympathetic nerve-lymphoid organs.
5. On the3rd day after3-MP and VGB injection in bilateral cerebellar IN, ELISAresult displayed that the levels of ACTH, cortisol, TSH, T3, and T4in the serum did notalter after3-MP and VGB treatment compared with the two control groups. The datadisplayed that the pathway of pituitary-adrenal/thyroid gland-lymphoid organs did notmediate cerebellohypothalamic GABAergic projection regulating immune function.
Conclusions:
1. There is a direct cerebellohypothalamic GABAergic projection.
2. The cerebellar IN GABAergic projection is actively implicated in regulation ofimmune system function including lymphocyte percentage in the peripheral bloodmononuclear cells, T cell proliferative response to Con A, and B cell antibody response tospecific antigen.
3. The cerebellar IN GABAergic projection regulates immune function by thepathway of hypothalamus-sympathetic nerve-lymphoid organs.
我们实验室以往的研究表明小脑间位核可调节免疫功能。由于小脑与免疫系统之间没有直接的结构上的联系，因此阐明小脑调节免疫功能的信息传递途径对于更好地理解小脑的免疫调节功能具有重要作用。本研究以小脑—下丘脑的神经投射为切入点来揭示其在传递小脑免疫调节信息中的作用，为小脑神经免疫调节提供新的资料，有助于拓宽小脑功能的知识，促进临床上对小脑神经免疫调节异常疾病的思考和研究。
方法：
1.在一侧小脑间位核内微量注射顺行神经束路追踪剂葡聚糖-德克萨斯红（dextran-texas red, dextran-TR），观察小脑间位核至下丘脑神经投射的路径及终止部位。
2.在一侧下丘脑外侧区（顺行追踪显示下丘脑内终止纤维最丰富的区域）微量注射逆行神经束路追踪剂红色荧光金（fluoro-ruby, FR），观察小脑间位核内FR逆行标记的神经元，同时，结合谷氨酸荧光免疫组织化学法探讨小脑间位核投射至下丘脑的神经元中是否存在谷氨酸能神经元。
3.在双侧小脑间位核内微量注射谷氨酰胺酶抑制剂6-重氮-5-氧代-L-正亮氨酸（6-diazo-5-oxo-L-norleucine, DON），以抑制间位核内谷氨酸能神经元合成谷氨酸，并以双侧小脑间位核内注射等量生理盐水及未经任何处理的动物作为对照。在上述三组（未处理对照组、生理盐水对照组、DON组）大鼠的单侧下丘脑外侧区微量注射逆行神经束路追踪剂FR，5天后，在双侧小脑间位核内注射DON或生理盐水，3天后，同一层面的间位核脑片应用谷氨酸荧光免疫组织化学技术，观察小脑间位核—下丘脑外侧区谷氨酸能神经投射的数量变化。
4.在双侧小脑间位核内注射DON后第3天，用高效液相色谱法（high performanceliquid chromatography, HPLC）测定下丘脑内谷氨酸含量的变化。
5.在双侧小脑间位核内注射DON后第3天，用血细胞计数法检测动物外周血白细胞中淋巴细胞百分比的变化；用羧基二乙酸荧光素琥珀酰亚胺酯（carboxyfluorescein diacetate succinimidyl ester, CFSE）和结合PE的抗大鼠CD3抗体双标肠系膜淋巴结细胞，流式细胞仪检测T淋巴细胞对刀豆蛋白A（concanavalinA,Con A）刺激的增殖能力的变化；用酶联免疫吸附测定法（enzyme-linked immunosorbentassay, ELISA）检测血清中抗绵羊红细胞IgM抗体水平的变化。
结果：
1.小脑间位核内微量注射dextran-TR后示踪可见间位核神经元发出离核纤维，行走于同侧小脑上脚中，经小脑上脚交叉到达对侧，然后继续走行于小脑上脚中，进入下丘脑后较多纤维终止于下丘脑外侧区，少数纤维终止于下丘脑室旁核和下丘脑后区。说明小脑间位核神经元发出纤维直接投射至下丘脑（主要是外侧区）。
2.下丘脑外侧区内微量注射FR后可逆行追踪到对侧小脑间位核具有FR标记的神经元，这进一步证明了小脑间位核与下丘脑之间存在直接的神经投射；利用谷氨酸荧光免疫组织化学法染色小脑间位核，发现这些FR标记的神经元中有许多谷氨酸阳性神经元。表明小脑间位核投射至下丘脑外侧区的神经纤维中有谷氨酸能神经。
3.双侧小脑间位核内注射DON（50mM）后第3天，间位核内FR和谷氨酸双标神经元的数目明显少于生理盐水对照组和未处理对照组，而两组对照之间无明显差异，说明小脑间位核DON注射减少了小脑间位核—下丘脑外侧区的谷氨酸能神经投射。
4.双侧小脑间位核内注射DON（50mM）后第3天，下丘脑内谷氨酸含量显著低于生理盐水对照组和未处理对照组，而两组对照之间无显著性差异。双侧小脑间位核内注射低剂量DON（5mM）后，下丘脑内谷氨酸含量没有明显改变。此结果进一步证明双侧小脑间位核内注射DON（50mM）减少了小脑—下丘脑的谷氨酸能神经投射。
5.在小脑间位核—下丘脑谷氨酸能神经投射减少的同时，即在双侧小脑间位核内注射DON（50mM）后的第3天，动物外周血中淋巴细胞的百分比、淋巴结T细胞对Con A的增殖能力和血清中抗绵羊红细胞的IgM抗体水平均显著降低，而两组对照（生理盐水对照和未处理对照）之间无显著性差异。然而，低剂量的DON（5mM）注射没有明显改变上述免疫功能。说明减少小脑间位核—下丘脑的谷氨酸能神经投射可导致免疫功能减弱。
6.在小脑皮质内注射DON（50mM），没有改变下丘脑内谷氨酸的含量也不影响外周血中淋巴细胞百分比、淋巴结T细胞对Con A的增殖能力和血清中抗绵羊红细胞的IgM抗体水平。这一阴性结果进一步证明上述免疫功能的变化确实由小脑间位核—下丘脑的谷氨酸能神经投射所介导。
结论：
1.小脑间位核至下丘脑外侧区存在直接的谷氨酸能神经投射。
2.小脑间位核内注射DON减弱了间位核至下丘脑的谷氨酸能神经投射。
3.减弱小脑间位核—下丘脑的谷氨酸能神经投射导致免疫功能的抑制，提示小脑的免疫调节信息由小脑间位核—下丘脑的谷氨酸能神经投射所传递。
第二部分小脑间位核GABA能神经投射调节免疫功能的途径
目的：
我们在本文的第一部分研究中已说明小脑间位核—下丘脑的谷氨酸能神经投射可调节免疫功能。在这部分工作中，我们探讨小脑间位核的另一传出途径——GABA能神经投射对免疫功能的影响，以更深层次地理解和解释小脑间位核调节免疫功能的作用途径。
方法：
1.在一侧下丘脑外侧区微量注射逆行神经束路追踪剂FR，观察小脑间位核内FR逆行标记的神经元，同时，结合GABA荧光免疫组织化学法探讨小脑间位核投射至下丘脑的神经元中是否存在GABA能神经元。
2.双侧小脑间位核内分别微量注射GABA合成酶抑制剂3-巯基丙酸（3-mercaptopropionic acid,3-MP）、GABA转氨酶抑制剂氨己烯酸（vigabatrin, VGB）以分别减弱或增强间位核的GABA能神经投射，并以双侧小脑间位核内注射等量生理盐水及未经任何处理的动物作为对照。同时，腹腔注射小牛血清白蛋白（bovineserum albumin, BSA）免疫大鼠。术后第3天，流式细胞仪检测动物外周血单个核细胞中T和B淋巴细胞百分比的变化；用CFSE和结合PE的抗大鼠CD3抗体双标肠系膜淋巴结细胞，流式细胞仪检测T淋巴细胞对ConA刺激的增殖能力的变化；ELISA检测血清中抗BSAIgM抗体水平的变化。
3.双侧小脑间位核注射3-MP或VGB后第3天，HPLC测定下丘脑内GABA、淋巴结和脾脏中去甲肾上腺素（norepinephrine, NE）含量的变化。
4.双侧小脑间位核注射3-MP或VGB后第3天，ELISA试剂盒检测血清中促肾上腺皮质激素（adrenocorticotropic hormone, ACTH）、皮质醇（cortisol）、促甲状腺激素（thyroid stimulating hormone, TSH）、三碘甲状腺原氨酸（3,5,3’–triiodothyronine,T3）、四碘甲状腺原氨酸（3,5,3’,5’–tetraiodothyronine, T4）水平的变化。
结果：
1.下丘脑外侧区微量注射FR后逆行追踪至对侧小脑间位核，可见到FR标记的神经元；利用GABA荧光免疫组织化学法染色小脑间位核，发现这些FR标记的神经元中存在GABA阳性神经元，此结果证明小脑间位核与下丘脑外侧区之间存在直接的GABA能神经投射。
2.双侧小脑间位核内注射3-MP后第3天，外周血单个核细胞中的T和B淋巴细胞百分比、淋巴结T细胞对ConA的增殖能力、血清中抗BSA的IgM抗体水平均较两组对照显著升高；而双侧小脑间位核内注射VGB后第3天，外周血单个核细胞中的T和B淋巴细胞百分比、淋巴结T细胞对ConA的增殖能力、血清中抗BSA的IgM抗体水平均较两组对照显著降低。在两组对照之间，即双侧间位核内注射生理盐水的对照组和未作任何处理的对照组之间，上述免疫指标无显著性差异。这些结果表明减弱小脑间位核的GABA能神经投射促进了T和B细胞的功能，而增强小脑间位核的GABA能神经投射则抑制了T和B细胞的功能。
3.在免疫功能发生变化的同时，即在双侧小脑间位核内注射3-MP后第3天，下丘脑内GABA含量明显降低；而注射VGB后第3天，下丘脑内GABA含量显著升高。在两组对照之间，下丘脑内的GABA含量无显著性差异。这些结果表明间位核内注射3-MP减弱了间位核—下丘脑的GABA能神经投射，而间位核内注射VGB则增强了间位核—下丘脑的GABA能神经投射。因此提示，上述间位核内注射3-MP或VGB导致的免疫功能改变可由间位核—下丘脑的GABA能神经投射介导。
4.在免疫功能发生变化的同时，即在双侧小脑间位核内注射3-MP后的第3天，肠系膜淋巴结和脾脏中的NE含量降低，而注射VGB后的第3天，肠系膜淋巴结和脾脏中的NE含量升高，两对照组之间无显著性差异。这些结果表明，间位核内注射3-MP或VGB导致的免疫功能改变可由交感神经这一外周途径介导。
5.在免疫功能发生变化的同时，即在双侧小脑间位核内注射3-MP或VGB后的第3天，血清中的ACTH、皮质醇、TSH、T3和T4的水平与两对照组相比无显著性差异，说明腺垂体—肾上腺皮质/甲状腺途径可能不参与介导小脑间位核GABA能神经投射的免疫调节作用。
结论：
1.小脑间位核至下丘脑外侧区存在直接的GABA能神经投射。
2.小脑间位核的GABA能神经投射可调节T和B细胞的功能，其作用是负性调节这些细胞的功能。
3.小脑间位核GABA能神经投射通过下丘脑—交感神经的途径实现其免疫调节作用。
Objective:
Our previous work has shown that lesions of the cerebellar interposed nuclei (IN)suppress immune cell functions. Since there is no direct structural connection between thecerebellum and immune system, we explored the pathway mediating the cerebellarimmunomodulation at the profile of cerebellohypothalamic projections to understand thismodulation.
Methods:
1. Anterograde tracing of nerve tracts was conducted by injection of anterogradetracer dextran-texas red (dextran-TR) in the cerebellar IN to observe travelling routes andending locations of neuronal projections from the cerebellar IN to the hypothalamus.
2. Retrograde tracing of nerve tracts from the lateral hypothalamic area (LHA) to thecerebellar IN was conducted by injection of retrograde tracer fluoro-ruby (FR) in the LHA,and fluorescent immunohistochemistry for glutamate was used to identify neurotransmitterof the cerebellar IN projecting to the LHA.
3. A glutaminase inhibitor,6-diazo-5-oxo-L-norleucine (DON), was microinjectedinto the bilateral IN. The rats infused with same volume of saline in the bilateral IN andwith intact IN were used as control. FR had been infused in the LHA5days earlier. On day3following the DON injection, the cerebellar sections at the same plane were measured forglutamate-immunoreactive positive neurons by the fluorescent immunohistochemistry. Thenumber of FR-glutamate double-labeled neurons was compared among the DON, salineand intact groups.
4. On the3rd day after DON injection in bilateral cerebellar IN, high performanceliquid chromatography (HPLC) analysis was used to determine glutamate content in thehypothalamus.
5. On the3rd day after DON injection in bilateral cerebellar IN, lymphocytepercentage in the peripheral blood leukocyte was measured by a complete blood cell count;T lymphocyte proliferation induced by concanavalin A (Con A) was double labelled bycarboxyfluorescein diacetate succinimidyl ester (CFSE) and anti-rat CD3antibody anddetected by a flow cytometer; anti-sheep red blood cell (SRBC) IgM antibody in the serumwas determined by enzyme-linked immunosorbent assay (ELISA).
Results:
1. Dextran-TR-labeled nerve fibers, which were sent by cerebellar IN neurons,traveled through the ipsilateral superior cerebellar peduncle (SCP), crossed in SCPdecussation, penetrated the contralateral SCP, and entered the hypothalamus. In thehypothalamus, the fibers mostly terminated in the LHA, and less in the paraventricularnuclei and the posterior hypothalamus area.
2. Retrograde tracing by injection of retrograde tracer FR in the LHA found that theFR-labeled nerve fibers retrogradely traveled in the SCP decussation, and FR-labeledneurons appeared in contralateral cerebellar IN. Fluorescent immunohistochemistryshowed that a large number of glutamate-immunoreactive neurons (blue) were seen on thecerebellar IN section. Merging the red FR-labeled neurons and the blue glutamate-positiveneurons in the cerebellar IN, many carmine neurons which represented glutamatergicneurons projecting to the LHA were observed on the section.
3. On the3rd day after DON injection in bilateral cerebellar IN, the double-labeledneurons were significantly lower for their percentage in FR single-stained neurons inDON-injected IN than in intact or saline-treated IN. This indicated that DON infusion inbilateral cerebellar IN reduced glutamatergic projections from the cerebellar IN to theLHA.
4. Compared with intact or saline-injected rats, the DON-treated rats weresignificantly decreased in glutamate content in the hypothalamus. Between the two groupsof control rats, no significant difference was found. Glutamate content in the hypothalamusdid not change after DON treatment at a lower dose. These data further demonstrated thatDON injection in bilateral cerebellar IN reduced cerebellohypothalamic glutamatergicprojections.
5. DON injection in bilateral cerebellar IN led to a decrease in lymphocyte percentagein peripheral white blood cells, a suppression of T cell proliferative response to Con A, and a diminishment of serum specific anti-SRBC IgM antibody. But DON injection at a lowerdose in bilateral cerebellar IN did not affect the immune parameters.
6. To confirm that these immune changes were caused by decrease in cerebellarIN-hypothalamic glutamatergic projections, we injected the same dose of DON in thecerebellar cortex. DON injection in the cerebellar cortex neither altered glutamate contentin the hypothalamus nor affected immune function (lymphocyte percentage in peripheralwhite blood cells, T cell proliferative response to Con A, and the level of serum specificanti-SRBC IgM antibody).
Conclusions:
1. A direct glutamatergic projection originates from neurons of the cerebellar IN andterminates mainly in the LHA.
2. DON injection in the bilateral cerebellar IN effectively reduces thecerebellohypothalamic glutamatergic projections.
3. The reduced cerebellohypothalamic glutamatergic projection leads to the inhibitionof immune function, which suggests that cerebellohypothalamic glutamatergic projectionstransmit cerebellar immunomodulation.
Part Two: Pathways of Immunomodulation by GABAergic ProjectionsDeriving from the Cerebellar Interposed Nuclei
Objective:
Our work in the first part has shown that cerebellohypothalamic glutamatergicprojection is actively implicated in regulation of immune function. To obtain acomprehensive understanding of the pathways and mechanisms of regulating immunefunction by the cerebellar IN, in the present study, we expored the immune function of theother nerve projection, cerebellohypothalamic GABAergic projections, and its pathways oftransmitting this information.
Methods:
1. Retrograde tracing of nerve tracts from LHA to the cerebellar IN was conducted byinjection of FR in the LHA, and fluorescent immunohistochemistry for GABA was used toidentify neurotransmitter of the cerebellar IN projecting to the LHA.
2. A GABA synthetase inhibitor,3-mercaptopropionic acid (3-MP), and GABAtransaminase inhibitor, vigabatrin (VGB) were respectively microinjected into the bilateral IN. The rats infused with same volume of saline in the bilateral IN and with intact IN wereused as control. Meanwhile, rats were immuned by bovine serum albumin (BSA)intraperitoneal injection. On the3rd day after3-MP and VGB injection in bilateralcerebellar IN, lymphocyte percentage in the peripheral blood mononuclear cells wasmeasured by flow cytometry; T lymphocyte proliferation induced by Con A was doublelabelled by CFSE and anti-rat CD3antibody and detected by a flow cytometer; anti-BSAIgM antibody in the serum was determined by ELISA.
3. On the3rd day after3-MP and VGB injection in bilateral cerebellar IN, HPLCanalysis was used to determine GABA content in the hypothalamus and norepinephrine(NE) content in the lymph node and spleen.
4. On the3rd day after3-MP and VGB injection in bilateral cerebellar IN,adrenocorticotropic hormone (ACTH), cortisol, thyroid stimulating hormone (TSH),3,5,3’–triiodothyronine (T3) and3,5,3’,5’–tetraiodothyronine (T4) in the serum weredetected by ELISA.
Results:
1. Retrograde tracing by injection of retrograde tracer FR in the LHA found that theFR-labeled nerve fibers retrogradely traveled in the SCP decussation, and FR-labeledneurons appeared in contralateral cerebellar IN. Fluorescent immunohistochemistryshowed that GABA-immunoreactive neurons (green) were seen on the cerebellar INsection. Merging the red FR-labeled neurons and the green GABA-positive neurons in thecerebellar IN, some yellow neurons which represented GABAergic neurons projecting tothe LHA were observed on the section.
2. On the3rd day after3-MP injection in bilateral cerebellar IN, T and B lymphocytepercentage in the peripheral blood mononuclear cells were increased, T cell proliferativeresponse to Con A was enhanced, and serum specific anti-BSA IgM antibody level waselevated; on the other hand, when VGB was applied, all the parameters (lymphocytepercentage in the peripheral blood mononuclear cells, T cell proliferative response to ConA, and serum specific anti-BSA IgM antibody level) were suppressed. Between the twogroups of control rats, no significant difference was found.
3. On the3rd day after3-MP and VGB injection in bilateral cerebellar IN, comparedwith intact or saline-injected rats, the3-MP-treated rats were notably decreased in GABAcontent in the hypothalamus, but the VGB-treated rats were significantly increased. Between the two groups of control rats, no significant difference was found. These datademonstrated that3-MP and VGB injection in bilateral cerebellar IN effectively changedcerebellohypothalamic GABAergic projections.
4. On the3rd day after3-MP and VGB injection in bilateral cerebellar IN, HPLCresult showed that NE content was decreased in the lymph node and spleen when rats weretreated by3-MP and NE content was increased when rats were treated by VGB. Betweenthe two groups of control rats, no significant difference was found. These data showed thatcerebellohypothalamic GABAergic projection regulated immune function by the pathwayof sympathetic nerve-lymphoid organs.
5. On the3rd day after3-MP and VGB injection in bilateral cerebellar IN, ELISAresult displayed that the levels of ACTH, cortisol, TSH, T3, and T4in the serum did notalter after3-MP and VGB treatment compared with the two control groups. The datadisplayed that the pathway of pituitary-adrenal/thyroid gland-lymphoid organs did notmediate cerebellohypothalamic GABAergic projection regulating immune function.
Conclusions:
1. There is a direct cerebellohypothalamic GABAergic projection.
2. The cerebellar IN GABAergic projection is actively implicated in regulation ofimmune system function including lymphocyte percentage in the peripheral bloodmononuclear cells, T cell proliferative response to Con A, and B cell antibody response tospecific antigen.
3. The cerebellar IN GABAergic projection regulates immune function by thepathway of hypothalamus-sympathetic nerve-lymphoid organs.
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