三种复方对慢性应激模型大鼠海马CREB、BDNF基因表达的影响

 目的:探讨慢性应激肝郁模型大鼠海马CREB、BDNF基因表达及疏肝、疏肝健脾与健脾3种方剂的效应。方法:SD雄性大鼠40只,用随机区组设计的方法分为对照组、模型组、四逆散组、逍遥散组和四君子汤组,多种应激处理共21 d后,测定1%蔗糖水摄取率和强迫游泳中累计不动时间,用RT-PCR的方法检测海马CREB和BDNF mRNA表达。结果:与对照组比较,模型组大鼠1%蔗糖水摄取率明显降低,强迫游泳中累计不动时间明显延长,海马CREB、BDNF mRNA表达明显降低;与模型组比较,四逆散组、逍遥散组的1%蔗糖水摄取率明显升高,强迫游泳中累计不动时间明显缩短,CREB、BDNF mRNA表达均明显升高;四君子汤组各行为学指标及BDNF表达与模型组相比没有差异,仅CREB表达升高。结论:慢性应激肝郁模型大鼠海马CREB、BDNF的mRNA表达降低,具有疏肝作用的方剂四逆散和逍遥散可以对抗这种降低,而健脾方剂四君子汤无明显效应。     

解郁丸对WKY大鼠的抑郁样行为及海马和前额叶皮层BDNF表达的影响

目的:观察解郁丸对Wistar-Kyoto(WKY)大鼠抑郁样行为及脑源性神经营养因子(BDNF)在海马和前额叶皮层表达的影响,探讨其抗抑郁作用及相关机制。方法:成年雄性WKY大鼠为内源性抑郁动物模型,选取同品系Wistar大鼠作为空白对照组,WKY大鼠随机分为模型组、西酞普兰组和解郁丸组,分别灌胃给药21 d后,用糖水偏好实验及强迫游泳实验观察各组大鼠抑郁行为变化;采用免疫荧光法和Western blot法检测海马及前额叶皮层BDNF表达水平的变化。结果:WKY大鼠表现出明显的抑郁样行为,海马及前额叶皮层的BDNF表达量显著下降,且海马区神经元轴突减少(P0.01);在药物治疗后,WKY大鼠的抑郁样行为明显减少,BDNF在海马及前额叶皮层中的表达增加,且轴突数目也增加(P0.01)。结论:解郁丸能有效减少WKY大鼠的抑郁样行为;BDNF是其抗抑郁作用发挥的关键因子。本研究也进一步验证BDNF参与抑郁的发生发展过程。     

米诺环素对CCI大鼠抑郁样行为的影响及机制研究

目的:观察海马CA1区注射米诺环素对坐骨神经慢性缩窄性损伤(CCI)大鼠的抑郁样行为、海马和前额叶皮层小胶质细胞激活的影响并分析其机制。方法:成年SD雄性大鼠随机分为:对照组、假手术组、CCI模型组、CCI+米诺环素组。糖水偏好及旷场实验检测大鼠抑郁样行为;免疫组化观察海马以及前额叶皮层Iba-1表达;取海马以及前额叶皮层组织,real-time PCR观察Iba-1、NLRP3和caspase1 mRNA表达,ELISA测定IL-1β和IL-18含量。结果:与假手术组相比,CCI大鼠7、10 d和14 d的糖水偏好明显降低(P 0. 05),旷场中央活动距离和中央活动时间明显减少(P 0. 05);与CCI组相比,CA1区注射米诺环素后CCI大鼠7 d和14 d的糖水偏好明显升高(P 0. 05),旷场中央活动距离和中央活动时间明显增加(P 0. 05)。与假手术组相比,CCI组大鼠海马CA1、CA3及DG区和前额叶皮层Iba-1阳性细胞数目显著增多(P 0. 05),Iba-1、NLRP3和caspase1 mRNA表达明显上调; IL-1β和IL-18含量也明显升高(P 0. 05)。与CCI组相比,注射米诺环素后,CCI大鼠海马CA1、CA3及DG区和前额叶皮层Iba-1阳性细胞数目减少(P 0. 05),Iba-1、NLRP3和caspase1 mRNA表达降低(P 0. 05),IL-1β和IL-18含量降低(P 0. 05)。结论:海马CA1区注射米诺环素明显抑制CCI大鼠的抑郁样行为;其机制可能是抑制海马和前额叶皮层小胶质细胞激活,下调NLRP3和caspase1表达,从而使IL-1β和IL-18产生减少。     

侧脑室注射PP2对慢性复合应激大鼠学习记忆功能和海马内Fyn、BDNF和TrkB表达的影响

为了探讨酪氨酸激酶抑制剂PP2对慢性复合应激性学习记忆增强大鼠的学习记忆功能和海马内非受体酪氨酸激酶(Fyn)、脑源性神经营养因子(BDNF)和Trk酪氨酸激酶B(TrkB)表达的影响,本实验将成年雄性大鼠22只,随机分为三组:即慢性复合应激组(对照组)、慢性复合应激+注射盐水组(盐水组)和慢性复合应激+注射PP2组(PP2组)。全部动物暴露于复合应激原中6周后,盐水组和PP2组动物分别侧脑室注射生理盐水或PP2(1次/d,共11d)。实验结束后,用Morris水迷宫测试大鼠的空间学习记忆成绩;采用免疫组织化学方法检测Fyn、BDNF和TrkB在海马内蛋白表达的变化。结果显示:与对照组和盐水组相比,PP2组动物的学习与记忆成绩明显下降(P<0.05);海马内Fyn和BDNF蛋白阳性表达减弱(P<0.05);但3组动物海马内TrkB的蛋白表达无显著性差异(P>0.05)。上述结果表明:侧脑室注射PP2可抑制大鼠慢性复合应激性学习记忆能力的增强作用,下调Fyn和BDNF在海马内的表达;提示Fyn和BDNF/TrkB信号转导途径在慢性复合应激增强大鼠学习记忆能力的过程中发挥重要作用。     

慢性脑缺血大鼠海马CA_1区中的BDNF表达

为了观察慢性脑缺血时海马CA1区中BDNF的表达变化,探讨缺血性脑损伤及修复机制。我们将Wistar大鼠双侧颈总动脉结扎制成慢性脑缺血动物模型。分为三组:正常对照组、慢性脑缺血30d和120d组。分别于术后30d和120d处死动物,行BDNF免疫组化染色,计数各组大鼠海马CA1区中的阳性神经元数。结果显示:(1)在对照组的海马CA1区可见BDNF较强的表达;(2)在慢性脑缺血30d时,海马CA1区BDNF的表达高于缺血120d组及对照组(P<0.05)。而120d时,海马CA1区BDNF的表达与对照组无显著性差异(P>0.05)。结果提示:(1)在正常大鼠海马CA1区有BDNF表达,能维持神经元的存活;(2)慢性脑缺血时,BDNF在海马CA1区的表达先升后降。     

酒精处理影响青春期大鼠海马CA1区BDNF和TrkB的表达

为探讨青春期饮酒致学习记忆力下降的可能机制,本研究观察了青春期大鼠酒精处理后海马CA1区脑源性神经营养因子(BDNF)和酪氨酸激酶受体B(TrkB)的表达变化。实验选用30d龄SD雄性大鼠,以25%的酒精按8g/kg/d灌胃,连续灌7d,动物分别在停酒后0d,3d,7d和14d处死;对照组以等量生理盐水代替酒精按同样方法处理。用免疫组织化学方法(ABC法)检测海马CA1区BDNF和TrkB的表达,Motic3.2图像分析系统测定免疫阳性产物的平均灰度值。结果显示,BDNF的表达在停酒后0d和14d,实验组与相应对照组相比差异无显著性(P>0.05);3d显著升高(P<0.05);7d明显下降(P<0.05)。TrkB的表达在停酒后0d,3d,7d,实验组与相应对照组相比差异无显著性(P>0.05);14d显著下降(P<0.05)。以上结果提示,BDNF表达的相对不足可能是青春期饮酒致学习记忆力持续性下降的原因之一。     

脑卒中后抑郁大鼠海马BDNF及其受体TrkB蛋白的表达变化

目的:探讨脑卒中后抑郁(PSD)大鼠海马脑源性神经营养因子(BDNF)及其高亲和力受体酪氨酸激酶B(TrkB)蛋白的表达变化。方法:24只雌性SD大鼠随机分为正常组、抑郁组、脑卒中组及PSD组,每组6只。采用线栓法建立局灶性脑缺血(卒中)模型;采用孤养方法建立抑郁模型;局灶性脑缺血模型加以慢性不可预见的中等应激刺激和孤养法建立PSD模型;并设正常组做为正常对照。应用免疫组化检测各组大鼠造模后第29天大鼠海马BDNF和TrkB免疫阳性细胞数的表达变化。结果:PSD组海马BDNF免疫阳性细胞数最少[(8.56±1.67)个/视野]。PSD组、抑郁组及脑卒中组与正常对照组相比BDNF阳性细胞数均明显减少(P0.05);PSD组海马TrkB免疫阳性细胞数最少[(6.44±1.13)个/视野],与各对照组相比,差异均有统计学意义(P0.05)。结论:PSD大鼠海马BDNF及其高亲和力受体TrkB蛋白表达减少可能在PSD发病过程中发挥了一定的作用。     

西酞普兰对慢性应激大鼠海马CA1、CA3区神经细胞凋亡的影响

目的：探讨西酞普兰对慢性应激大鼠海马CA1、CA3神经细胞凋亡的影响。方法: 将40只雄性SD大鼠随机分为空白、对照（生理盐水灌胃）、实验1-3组（分别以8 mg·kg-1·d-1、4 mg·kg-1·d-1、1 mg·kg-1·d-1氢溴酸西酞普兰灌胃），每组8只，采用强迫游泳制造慢性应激大鼠模型，用大鼠悬尾实验、力竭实验观察行为学，苏木素伊红（HE）染色观察CA1、CA3神经细胞凋亡，脱氧核糖核苷酸末端转移酶介导的缺口末端标记法(TUNEL)检测和尼康图像分析（NIS BR）软件测量CA1、CA3神经细胞凋亡数量及积分吸光度值。结果: 对照组静止不动时间延长、挣扎次数减少，实验组静止不动时间缩短、力竭时间延长、挣扎次数增多；对照组CA1、CA3区阳性细胞增多,CA3区阳性细胞积分吸光度值变小；各实验组阳性细胞数量减少，实验1、3组CA1、CA3区阳性细胞积分吸光度值增大。结论: 西酞普兰对慢性应激大鼠海马CA1、CA3神经细胞具有保护作用，提示西酞普兰对慢性应激引起的神经精神疾病的治疗机制，可能是通过拮抗CA1、CA3区神经细胞凋亡而起作用。     

血管性痴呆大鼠海马synapsinⅠ及其磷酸化水平的动态变化

目的：观察血管性痴呆大鼠海马区突触结构和突触蛋白synapsin I及其磷酸化水平的变化，探讨血管性痴呆大鼠突触传递障碍的可能机制。方法: 采用双侧颈总动脉夹闭再灌注同时腹腔注射硝普纳建立血管性痴呆模型，在15 d、1月、2月和4月等时点，电镜观察大鼠海马CA1区突触结构的病理改变，应用免疫组织化学染色法测定血管性痴呆大鼠海马synapsinⅠ及其磷酸化水平的变化。结果: 假手术组大鼠海马CA1区未见明显病理改变，突触前小泡聚集成簇，模型组突触前后膜界限不清，突触后致密物减少，突触前囊泡分布分散、聚集囊泡簇减少，并随造模时间的延长，病理改变加重；模型组大鼠海马CA1区synapsin I阳性产物表达明显减少(P<0.01)，DG区分子层无明显变化(P>0.05)；模型组大鼠海马磷酸化synapsin I（p-synapsin I）阳性细胞明显减少(P<0.01,P<0.05)，15 d和1月时点大鼠海马DG区和CA1区p-synapsin I阳性细胞表达较假手术组增强(P<0.01)，2月和4月时点CA1区p-synapsin I阳性细胞表达较假手术组减弱(P<0.01)，而DG区无明显变化(P>0.05)。结论: VD模型大鼠海马突触结构受损，突触小泡簇减少；synapsinⅠ及其磷酸化水平表达降低，突触传递前机制受损可能是VD突触传递障碍的机制之一。     

水合橙皮内酯通过BDNF/TrkB/CREB信号通路对阿尔兹海默症的保护作用

目的 探究水合橙皮内酯对阿尔兹海默症大鼠的保护作用及可能机制。方法 SD大鼠随机分为假手术组（Sham组）、阿尔兹海默症组（AD组）和水合橙皮内酯组（MH组）,每组10只。水迷宫实验检测大鼠空间学习记忆能力;HE染色观察大鼠海马组织病理学变化;尼氏染色观察大鼠海马组织神经元存活;ELISA方法检测大鼠海马组织神经递质及相关因子水平;TUNEL实验检测大鼠海马组织细胞凋亡;Western blot检测大鼠海马组织BDNF、TrkB和p-CREB蛋白表达水平。结果 水合橙皮内酯降低阿尔兹海默症大鼠逃避潜伏期,增加大鼠穿越平台次数和海马组织神经元细胞数,降低大鼠海马组织TUNEL阳性细胞数,增加大鼠海马组织BDNF、TrkB和p-CREB蛋白表达水平。结论 水合橙皮内酯通过激活BDNF/TrkB/CREB信号通路改善AD大鼠学习记忆能力。     

Deprived of habitual running, rats downregulate BDNF and TrkB messages in the brain.

To study possible effects of physical training on the expression of neurotrophic factors and their receptors in the brain, we used a rat strain (spontaneously hypertensive rat, SHR), known to spontaneously run up to 20 km/night. We show that such long-distance running affects the brain-derived neurotrophic factor (BDNF) and TrkB system in hippocampus, and in particular that abrupt deprivation of habitual running leads to long-lasting decreases of BDNF/TrkB expression in hippocampus. Quantitative in situ hybridization demonstrates that running increases the expression of mRNA coding for BDNF and its high affinity receptor TrkB in hippocampus in a running length dependent manner. In addition, we show that an abrupt interruption of prolonged spontaneous exercise decrease expression of mRNA encoding BDNF and TrkB in certain hippocampal areas and that this decrease lasts at least 10 days. This down-regulation was most prominent in medial cornu ammonis 3 (CA3M). Several other trophic factors and receptors were investigated, including NGF, NT3, GDNF, trkC and p75. For these other probes investigated, no robust changes in mRNA expression were noted. Areas examined included sensorimotor cortex and hippocampus. For RET, p75, NT3, TrkB and BDNF we also examined the spinal cord without detecting any robust changes. We conclude that spontaneous running as well as its abrupt termination, leads to area-specific and trophic factor-specific changes in hippocampus.     

Modulation of BDNF and TrkB expression in rat hippocampus in response to acute neurotoxicity by diethyldithiocarbamate

In this study, we examined the expression profile of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in adult rat hippocampus following acute administration of diethyldithiocarbamate (DDTC), a neurotoxic compound which was previously shown to induce microglia activation and cell death. Semiquantitative RT-PCR analysis detected significant variations of BDNF mRNA levels in whole hippocampus homogenates, with a peak at 24h after DDTC injection. Increased BDNF protein expression was demonstrated by immunohistochemistry in various hippocampal subfields. The most relevant increase was observed in the hilus of the dentate gyrus where BDNF levels at 120h were found to be almost four times those of basal levels. Full-length TrkB (TrkB.FL) encoding mRNA was also shown to undergo an earlier increase in the hippocampus of DDTC-treated rats. TrkB immunostaining with an antibody binding both full-length and truncated (TrkB.T) isoforms was found to increase at 120h in the hippocampal CA2 and CA3 regions. These results demonstrate that DDTC modulates the expression of BDNF and its receptor in the adult rat hippocampus and suggest a possible involvement of this neurotrophin in the protective response to DDTC-induced neuronal damage.     

Effects of chronic forced swim stress on hippocampal brain-derived neutrophic factor (BDNF) and its receptor (TrkB) immunoreactive cells in juvenile and aged rats

A type of stress stimulation and age are claimed to affect the expression of brain-derived neurotrophic factor (BDNF) and its receptor - tyrosine kinase B (TrkB) in the hippocampal regions differentially. This study aimed to explore the influence of chronic (15 min daily for 21 days) forced swim stress (FS) exposure on the BDNF and TrkB containing neurons in the hippocampal CA1, CA3 pyramidal cell layers and dentate gyrus (DG) granule cell layer in juvenile (P28) and aged (P360) rats. An immunofluorescence (-ir) method was used to detect BDNF-ir and TrkB-ir cells. Under chronic FS exposure, in the group of juvenile rats a significant decrease in the density of BDNF immunoreactive neurons was observed in CA1 and DG (P less than <0.001), unlike CA3, where it remained unaltered just as the density of TrkB-ir cells in CA1 and DG, but in CA3 the number of TrkB-ir cells was found to grow (P less than 0.05) in comparison with control groups. After chronic FS exposure of aged (P360) rats, the density of BDNF-ir and TrkB-ir cells did not decline in any of the subregions of the hippocampus. In all subfields of the hippocampus, the denseness of BDNF-positive neurons was significantly higher in P360 stressed group, compared with P28 stressed group, but the density of TrkB-ir fell more markedly in P360 than in P28. In conclusion, chronic FS stress influenced the number of BDNF and TrkB immunoreactive neurons only in juvenile animals. The age of rats tested in the chronic forced swim test was a decisive factor determining changes in the density of BDNF-ir and TrkB-ir in the hippocampal structures.     

BDNF Up-Regulates TrkB Protein and Prevents the Death of CA1 Neurons Following Transient Forebrain Ischemia

The neurotrophin family of growth factors, which includes Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT3) and Neurotrophin-4/5 (NT4/5) bind and activate specific tyrosine kinase (Trk) receptors to promote cell survival and growth of different cell populations. For these reasons, growing attention has been paid to the use of neurotrophins as therapeutic agents in neurodegeneration, and to the regulation of the expression of their specific receptors by the ligands. BDNF expression, as revealed by immunohistochemistry, is found in the pre-subiculum, CA1, CA3, and dentate gyrus of the hippocampus. Strong TrkB immunoreactivity is present in most CA3 neurons but only in scattered neurons of the CA1 area. Weak TrkB immunoreactivity is found in the granule cell layer of the dentate gyrus. Unilateral grafting of BDNF-transfected fibroblasts into the hippocampus resulted in a marked increase in the intensity of the immunoreaction and in the number of TrkB-immunoreactive neurons in the granule cell layer of the dentate gyrus, pre-subiculum and CA1 area in the vicinity of the graft. No similar effects were produced after the injection of control mock-transfected fibroblasts. Delayed cell death in the CA1 area was produced following 5 min of forebrain ischemia in the gerbil. The majority of living cells in the CA1 area at the fourth day were BDNF/TrkB immunoreactive. Unilateral grafting of control mock-transfected or BDNF fibroblasts two days before ischemia resulted in a moderate non-specific protection of TrkB-negative, but not TrkB-positive cells, in the CA1 area of the grafted side. This finding is in line with a vascular and glial reaction, as revealed, by immunohistochemistry using astroglial and microglial cell markers. This astroglial response was higher in the grafted side than in the contralateral side in ischemic gerbils, but no differences were seen between BDNF-producing and non-BDNF-producing grafts. However, grafting of BDNF-producing fibroblasts two days before ischemia significantly and specifically prevented nerve cells from dying in the CA1 area of the ipsilateral hippocampus. Cell survival was associated with increased TrkB immunoreactivity as the majority of living cells were TrkB immunoreactive. Thus, our results show that BDNF is able to up-regulate the expression of TrkB in control and pathological states, and that BDNF prevention of neuronal death following transient forebrain ischemia is associated with increased expression of its specific receptor.     

Changes in expression of BDNF and its receptors TrkB and p75NTR in the hippocampus of a dog model of chronic alcoholism and abstinence

Chronic ethanol consumption can produce learning and memory deficits. Brain-derived neurotrophic factor (BDNF) and its receptors affect the pathogenesis of alcoholism. In this study, we examined the expression of BDNF, tropomyosin receptor kinase B (TrkB) and p75 neurotrophin receptor (p75NTR) in the hippocampus of a dog model of chronic alcoholism and abstinence. Twenty domestic dogs (9-10 months old, 15-20 kg; 10 males and 10 females) were obtained from Harbin Medical University. A stable alcoholism model was established through ad libitum feeding, and anti-alcohol drug treatment (Zhong Yao Jie Jiu Ling, the main ingredient was the stems of watermelon; developed in our laboratory), at low- and high-doses, was carried out. The Zhong Yao Jie Jiu Ling was effective for the alcoholism in dogs. The morphology of hippocampal neurons was evaluated using hematoxylin-eosin staining. The number and morphological features of BDNF, TrkB and p75NTR-positive neurons in the dentate gyrus (DG), and the CA1, CA3 and CA4 regions of the hippocampus were observed using immunohistochemistry. One-way ANOVA was used to determine differences in BDNF, TrkB and p75NTR expression. BDNF, TrkB and p75NTR-positive cells were mainly localized in the granular cell layer of the DG and in the pyramidal cell layer of the CA1, CA3 and CA4 regions (DG>CA1>CA3>CA4). Expression levels of both BDNF and TrkB were decreased in chronic alcoholism, and increased after abstinence. The CA4 region appeared to show the greatest differences. Changes in p75NTR expression were the opposite of those of BDNF and TrkB, with the greatest differences observed in the DG and CA4 regions.     

Age-related changes in brain-derived neurotrophic factor and tyrosine kinase receptor isoforms in the hippocampus and hypothalamus in male rats

A large amount of aging individuals show diminished cognitive and endocrine capabilities. The main brain areas involved in these changes are the hippocampus and hypothalamus, two regions possessing high plasticity and implicated in cognitive and endocrine functions, respectively. Among neurotrophins (considered as genuine molecular mediators of synaptic plasticity), brain-derived neurotrophic factor (BDNF) exhibits in adult rats, the highest concentrations in the hippocampus and hypothalamus. Most of neuronal effects of BDNF are mediated through high-affinity cell surface BDNF tyrosine kinase receptors (TrkB). Different TrkB isoforms are issued by alternative splicing of mRNA encoding for TrkB (trkB mRNA) generating at least three different TrkB receptors with different signaling capabilities. The goal of this study was to examine simultaneously the expression (mRNAs and proteins) of BDNF and its three specific receptors, in the hippocampus and hypothalamus throughout lifespan in rats. We observed that BDNF essentially increased during the first 2 postnatal weeks in the hippocampus and hypothalamus, with no close correlation to its mRNA levels. In these regions, mRNA encoding for BDNF full-length catalytic receptor (trkB.FL mRNA) showed no important changes throughout life but of the mRNA truncated forms of TrkB receptors (trkB.T1 mRNA and trkB.T2 mRNA) trkB.T1 mRNA strongly increased after birth, then remaining stable during aging. trkB.T2 mRNA gradually decreased from 1 postnatal week becoming undetectable in the hippocampus in old-rats. Proteins issued from these mRNAs showed substantial quantitative modifications with aging. From 2 months old, the BDNF full-length catalytic receptor (TrkB.FL) gradually and significantly decreased in the hippocampus and the hypothalamus. Of the truncated forms of TrkB receptors (TrkB.T1 and TrkB.T2) TrkB.T1, which is essentially localized in glial cells, significantly increased from the first postnatal week in the hippocampus and in the hypothalamus, remaining stable during aging but reduced in old rats. TrkB.T2 which similarly to TrkB.FL has a neuronal localization also gradually decreased in the hippocampus and in the hypothalamus throughout lifespan. These reductions were significant at 21 and 30 days old, respectively. All the changes reported here could contribute to the reduced plasticity of these regions observed in old rats.     

Spatial memory training modifies the expression of brain-derived neurotrophic factor tyrosine kinase receptors in young and aged rats

Aging leads to alterations in the function of the hippocampus, a brain structure largely involved in learning processes. This study aimed at examining the basal levels and the impact of a learning-associated task on brain-derived neurotrophic factor (BDNF), on BDNF full-length catalytic receptor (TrkB.FL) and on the truncated forms (TrkB.T1 and TrkB.T2) receptor expression (mRNA and protein) in the hippocampus of young (2-month-old) and aged (24-month-old) Wistar rats. Spatial memory was evaluated using a water-maze procedure involving visible and invisible platform location learning. Aged rats showed higher latencies during the first two training days but rapidly exhibited learning performances similar to patterns observed with young rats. Real-time PCR measurements showed that aged rats had significantly higher levels of trkB.FL mRNAs than young rats under basal conditions. In situ hybridization analysis indicated that the highest level of trkB.FL mRNA (mRNA encoding for TrkB.FL receptor) was noted in the dentate gyrus, and in the CA2 and CA3 hippocampal layers. In contrast, there was no marked difference in trkB.T1 signal in any hippocampal region. Training induced a significant reduction in trkB.FL mRNA levels solely in aged rats. In contrast, in young and aged rats, trkB.T2 mRNA levels were significantly increased after training. Measurements of proteins revealed that learning significantly increased TrkB.FL content in aged rats. Untrained aged rats presented higher levels of BDNF and brain-derived neurotrophic factor precursor (proBDNF) proteins than young rats. Training strongly increased precursor BDNF metabolism in young and aged rats, resulting in increased levels of proBDNF in the two groups but in old rats the mature BDNF level did not change. This study shows that Wistar rats present age-related differences in the levels of BDNF and TrkB isoforms and that spatial learning differentially modifies some of these parameters in the hippocampus.     

Olanzapine counteracts reduction of brain-derived neurotrophic factor and TrkB receptors in rat hippocampus produced by haloperidol

Recently, we have reported studies in rats showing that the atypical antipsychotic olanzapine (OLZ), in contrast to haloperidol (HAL), was not associated with reduction of markers of central cholinergic neurons as well as decrements in cognitive performance after chronic exposure. We compared the effect of 45 day chronic exposure of HAL (2 mg/kg per day) to OLZ (10 mg/kg per day) on brain-derived neurotrophic factor (BDNF)) and its high affinity receptor TrkB in rat hippocampus. Since the use of OLZ is presently preferred over HAL in patients, effects of its post-treatment on HAL-induced changes in the expression of BDNF and its TrkB receptor were also investigated. OLZ was administered after 45 days of HAL exposure. HAL, but not OLZ, significantly reduced the levels of BDNF in hippocampus. These changes in BDNF paralleled the levels of TrkB receptors. Furthermore, post-treatment with OLZ markedly restored the HAL treatment associated reductions in both BDNF and TrkB receptors in hippocampus.