Cellular prion protein modulates age-related behavioral and neurochemical alterations in mice

The cellular prion protein (PrP^C) is a neuronal-anchored glycoprotein that has been associated with various functions in the CNS such as synaptic plasticity, cognitive processes and neuroprotection. Here we investigated age-related behavioral and neurochemical alterations in wild-type (Prnp^+/+), PrP^C knockout (Prnp^0/0) and the PrP^C overexpressing Tg-20 mice. Three- or 11 month-old animals were submitted to a battery of behavioral tasks including open field, activity cages, elevated plus-maze, social recognition and inhibitory avoidance tasks. The 11 month-old Prnp^+/+ and Prnp^0/0 mice exhibited significant impairments in their locomotor activity and social recognition memory and increased anxiety-related responses. Remarkably, Tg-20 mice did not present these age-related impairments. The i.c.v. infusion of STI1 peptide 230–245, which includes the PrP^C binding site, improved the age-related social recognition deficits in Prnp^+/+. In comparison with the two other age-matched genotypes, the 11 month-old Tg-20 mice also exhibited reduced activity of seric acetylcholinesterase, increased expression of the protein synaptophysin and decreased caspase-3 positive-cells in the hippocampus. The present findings obtained with genetic and pharmacological approaches provide convincing evidence that PrP^C exerts a critical role in the age-related behavioral deficits in mice probably through adaptive mechanisms including apoptotic pathways and synaptic plasticity.     

Symptomatic Intraspinal Oncocytic Adrenocortical Adenoma

Most intraspinal neoplasms of epithelial origin are metastases from primary carcinomas. Benign epithelial tumors are rarely found at this site. We here present the case of a 44-year-old woman with a lesion in the cauda equina that fulfilled the radiologic criteria of schwannoma and caused clinical symptoms for 3 years. The excised tumor was composed of nests of large polygonal cells with eosinophilic partial granular cytoplasm. Significant atypia, necrosis, and mitosis were absent from this lesion. The tumor showed diffuse positivity for melan-A, synaptophysin, and alpha-inhibin. Steroidogenic factor 1 and cytokeratins 8 and 18 were focally seen in the absence of S-100 and chromogranin. This immunoprofile indicated adrenocortical origin. Ultrastructural examination showed abundant mitochondria, suggesting an oncocytic tumor. The diagnosis of an oncocytic adrenal cortical adenoma was made. These extraadrenal tumors are thought to arise from heterotopic adrenocortical tissue in the spinal cavity. Oncocytic tumors are rare neoplasms and they comprise non-functioning variants of adrenal cortical adenomas. To date, only five such intraspinal tumors have been observed. Immunohistochemistry excluded oncocytic paraganglioma, oncocytic meningioma, renal cell carcinoma, alveolar soft part sarcoma, and granular cell tumor. A view of the literature of these rare but probably underdiagnosed intraspinal tumors is given.     

胸髓半横断引起腰髓前角钙网蛋白阳性中间神经元突触联系的变化

为检测大鼠胸髓半横断后后肢运动功能状况和腰髓前角中间神经元的突触联系的变化,并分析其相关关系,本实验通过BBB评分、钙网蛋白(CR)和突触囊泡素(SYN)免疫荧光双标记及相关分析方法进行了研究。结果显示:大鼠胸髓半横断后12 h时,后肢运动功能完全丧失,BBB分值下降,从第3 d开始后肢功能逐渐恢复,BBB分值逐渐增加,至第21 d基本恢复正常;同时观察到腰髓损伤侧12 h时CR免疫反应阳性(CR-IR)神经元周围的SYN-IR降低,第3 d时恢复至正常水平,至第21 d时升高;相关分析显示后肢运动功能BBB评分与CR-IR中间神经元周围的SYN表达水平呈正相关(r=0.45,P<0.05)。上述结果提示大鼠胸髓半横断后,与腰髓CR-IR中间神经元形成的突触联系出现可塑性改变,这种可塑性变化可能是后肢运动功能自发性恢复的形态学基础。     

脑室注射链脲佐菌素对大鼠空间学习记忆能力及海马CA1区神经元数量和海马突触素表达的影响

为了观察脑室内注射链脲佐菌素(streptozotocin,STZ)对大鼠空间学习记忆能力的影响,分析其可能的内在机制,本实验选用40只SD大鼠随机分成对照组和模型组,模型组于第1 d和第3 d脑室注射STZ(总量3 mg/kg)建立Alzheimer病(AD)模型,15 d后进行Morris水迷宫试验,利用RT-PCR方法检测突触素(synaptophysin,SYP)mRNA的表达变化;Nissl染色观察海马结构的改变。结果显示:与对照组相比,脑室注射STZ后大鼠平均上台潜伏期明显延长,穿越平台次数明显减少,靶象限游泳时间的百分比降低,SYP mRNA的表达明显减少,Nissl染色见海马CA1区神经元减少。以上结果提示脑室注射STZ可损伤大鼠的空间学习记忆能力,这可能与海马CA1区神经元和突触结构的损伤有关。     

Spatiotemporal alterations of presynaptic elements in the retina after high intraocular pressure

A rat model of acute high intraocular pressure was established by injecting saline into the anterior chamber of the left eye.Synaptophysin expression was increased in the inner plexiform layer at 2 hours following injury,and was widely distributed in the outer plexiform layer at 3-7 days,and then decreased to the normal level at 14 days.This suggests that expression of this presynaptic functional protein experienced spatiotemporal alterations after elevation of intraocular pressure.There was no significant change in the fluorescence intensity and distribution pattern for synapse-associated protein 102 following elevated intraocular pressure.Synapse-associated protein 102 immunoreactivity was confined to the outer plexiform layer,while synaptophysin immunoreactivity spread into the outer plexiform layer and the outer nuclear layer at 3 and 7 days following injury.These alterations in presynaptic elements were not accompanied by changes in postsynaptic components.     

Pleasurable behaviors reduce stress via brain reward pathways

Individuals often eat calorically dense, highly palatable "comfort" foods during stress for stress relief. This article demonstrates that palatable food intake (limited intake of sucrose drink) reduces neuroendocrine, cardiovascular, and behavioral responses to stress in rats. Artificially sweetened (saccharin) drink reproduces the stress dampening, whereas oral intragastric gavage of sucrose is without effect. Together, these results suggest that the palatable/rewarding properties of sucrose are necessary and sufficient for stress dampening. In support of this finding, another type of natural reward (sexual activity) similarly reduces stress responses. Ibotenate lesions of the basolateral amygdala (BLA) prevent stress dampening by sucrose, suggesting that neural activity in the BLA is necessary for the effect. Moreover, sucrose intake increases mRNA and protein expression in the BLA for numerous genes linked with functional and/or structural plasticity. Lastly, stress dampening by sucrose is persistent, which is consistent with long-term changes in neural activity after synaptic remodeling. Thus, natural rewards, such as palatable foods, provide a general means of stress reduction, likely via structural and/or functional plasticity in the BLA. These findings provide a clearer understanding of the motivation for consuming palatable foods during times of stress and influence therapeutic strategies for the prevention and/or treatment of obesity and other stress-related disorders.     

复合微量营养素对幼鼠学习记忆能力及脑海马CA3超微结构的影响

目的研究复合微量营养素对幼年大鼠学习记忆能力的影响及其机制。方法5周龄雄性SD大鼠40只,按体重随机分成3个实验组和1个对照组。实验组分别以低、中、高剂量复合微量营养素水悬液灌胃,对照组用安慰剂水悬液灌胃。30天后各组大鼠每隔1天在穿梭箱中进行双向回避实验训练,连续训练4次后,停止训练,并在14天内分2次测定其记忆消退情况;用电镜观察海马CA3区突触结构的变化;用免疫组织化学方法检测大鼠海马突触素(Syn)的免疫表达。结果高剂量组大鼠电击逃避时间长于对照组(P<0.05);高剂量组大鼠脑海马CA3区突触数量、突触后致密物质厚度、突触界面曲率、Syn免疫反应阳性产物吸光度均显著高于对照组(P<0.05);电击逃避时间和突触界面曲率呈剂量效应关系。结论复合微量营养素能通过提高大鼠脑海马的突触可塑性来改善幼年大鼠学习记忆能力。     

The synapsins: Key actors of synapse function and plasticity

The synapsins are a family of neuronal phosphoproteins evolutionarily conserved in invertebrate and vertebrate organisms. Their best-characterised function is to modulate neurotransmitter release at the pre-synaptic terminal, by reversibly tethering synaptic vesicles (SVs) to the actin cytoskeleton. However, many recent data have suggested novel functions for synapsins in other aspects of the pre-synaptic physiology, such as SV docking, fusion and recycling. Synapsin activity is tightly regulated by several protein kinases and phosphatases, which modulate the association of synapsins to SVs as well as their interaction with actin filaments and other synaptic proteins. In this context, synapsins act as a link between extracellular stimuli and the intracellular signalling events activated upon neuronal stimulation. Genetic manipulation of synapsins in various in vivo models has revealed that, although not essential for the basic development and functioning of neuronal networks, these proteins are extremely important in the fine-tuning of neuronal plasticity, as shown by the epileptic phenotype and behavioural abnormalities characterising mouse lines lacking one or more synapsin isoforms.     

Biomechanical properties and innervation of the female caveolin-1-deficient detrusor

BACKGROUND AND PURPOSE

Caveolin-1-deficiency is associated with substantial urogenital alterations. Here, a mechanical, histological and biochemical characterization of female detrusors from wild-type and caveolin-1-deficient (KO) mice was made to increase the understanding of detrusor changes caused by lack of caveolae.

EXPERIMENTAL APPROACH

Length–tension relationships were generated, and we recorded responses to electrical field stimulation, the muscarinic receptor agonist carbachol and the purinoceptor agonist ATP. Tyrosine nitration and the contents of caveolin-1, cavin-1, muscarinic M₃ receptors, phospholipase C_β1, muscle-specific kinase (MuSK) and L-type Ca²⁺ channels were determined by immunoblotting. Innervation was assessed by immunohistochemistry.

KEY RESULTS

Bladder to body weight ratio was not changed, nor was there any change in the optimum circumference for force development. Depolarization- and ATP-induced stress was reduced, as was carbachol-induced stress between 0.1 and 3 µM, but the supramaximal relative (% K⁺) response to carbachol was increased, as was M₃ expression. The scopolamine-sensitive component of the electrical field stimulation response was impaired, and yet bladder nerves contained little caveolin-1. The density of cholinergic nerves was unchanged, whereas CART- and CGRP-positive nerves were reduced. Immunoblotting revealed loss of MuSK.

CONCLUSIONS AND IMPLICATIONS

Ablation of caveolae in the female detrusor leads to generalized impairment of contractility, ruling out prostate hypertrophy as a contributing factor. Cholinergic neuroeffector transmission is impaired without conspicuous changes in the density of cholinergic nerves or morphology of their terminals, but correlating with reduced expression of MuSK.