Cadherins in the central nervous system

The central nervous system (CNS) is divided into diverse embryological and functional compartments. The early embryonic CNS consists of a series of transverse subdivisions (neuromeres) and longitudinal domains. These embryonic subdivisions represent histogenetic fields in which neurons are born and aggregate in distinct cell groups (brain nuclei and layers). Different subsets of these aggregates become selectively connected by nerve fiber tracts and, finally, by synapses, thus forming the neural circuits of the functional systems in the CNS. Recent work has shown that 30 or more members of the cadherin family of morphoregulatory molecules are differentially expressed in the developing and mature brain at almost all stages of development. In a regionally specific fashion, most cadherins studied to date are expressed by the embryonic subdivisions of the early embryonic brain, by developing brain nuclei, cortical layers and regions, and by fiber tracts, neural circuits and synapses. Each cadherin shows a unique expression pattern that is distinct from that of other cadherins. Experimental evidence suggests that cadherins contribute to CNS regionalization, morphogenesis and fiber tract formation, possibly by conferring preferentially homotypic adhesiveness (or other types of interactions) between the diverse structural elements of the CNS. Cadherin-mediated adhesive specificity may thus provide a molecular code for early embryonic CNS regionalization as well as for the development and maintenance of functional structures in the CNS, from embryonic subdivisions to brain nuclei, cortical layers and neural circuits, down to the level of individual synapses.     

中脑周围非动脉瘤性蛛网膜下腔出血患者的临床特点

目的　探讨中脑周围非动脉瘤性蛛网膜下腔出血(PNSH)患者的临床特点、放射学特点、诊断标准和预后。 方法 回顾性分析476例行数字减影全脑血管造影检查(DSA)的蛛网膜下腔出血(SAH)患者的临床和影像学资料,其中97例患者的DSA检查为阴性,患者在SAH后3 d内作头颅CT平扫,根据CT平扫检出了17例患者出血仅限于中脑周围脑池。 结果 17例患者SAH发作时均无意识丧失,无神经系统定位体征。所有患者的Hunt-Hess分级均为Ⅰ级或Ⅱ级。17例PNSH患者的随访期为10~70个月,平均随访44个月。无再出血、脑血管痉挛和脑积水。一般对症治疗,远期生活质量很高。 结论　PNSH临床表现平稳,影像学检查独特,恢复期短,预后良好,无再出血及脑缺血。正确认识、诊断PNSH,可以缩短住院时间,减少重复脑血管造影及开颅手术探查。     

Genetic determination of mesencephalic tyrosine hydroxylase activity in the mouse

The hereditary factors that affect mesencephalic tyrosine hydroxylase (TH) activity were investigated in highly inbred mouse strains (CXBI/ByJ, C57BL/6ByJ, and BALB/cJ). The progenitor strains and their F₁ hybrids, were compared for mesencephalic TH activity with each other and with replicated F₂ generations. Quantitative and non-parametric genetic analysis of the data raise the possibility that there is a major gene with robust additive effect that is primarily responsible for the difference between the progenitor strains with intermediate and high mesencephalic TH activity. Strain differences in mesencephalic TH activity have been linked to differences in number of dopamine (DA) neurons in that area. If genetic variation of mesencephalic TH activity is entirely attributable to variation in number of mesencephalic dopamine (DA) neurons, identification of the genetic sources of variation of mesencephalic TH activity may take us a step closer to animal models and preparations that are needed in the study of the physiological and constitutional mechanisms of human disorders in which DA neurotransmission is involved.     

Dorsolateral columns of the spinal cord are necessary for both suckling-induced neuroendocrine reflexes and the kyphotic nursing posture in lactating rats

Maternal behavior in rats consists of active behaviors, such as retrieval and licking of pups, and quiescent nursing, including the suckling-induced kyphotic (upright, dorsally-arched) posture. Because lesions of the dorsolateral, but not of the dorsal, columns are known to prevent the suckling-induced milk-ejection reflex, we asked whether the same is true for kyphosis as well. Bilateral lesions of the dorsolateral funiculus (DLF) or dorsal columns (DC) at spinal segments C(4-6) were made on day 5-8 postpartum; controls (CON) were subjected to a sham procedure. All aspects of maternal behavior and lactation were present in CON and DC dams soon after treatment. Among DLF dams, two had poor postural, ambulatory, and ingestive recovery that was associated with large lesions extending to the ventrolateral columns, while one with very small lesions continued to lactate. Of the remaining eight DLF dams, milk ejection was lost while recovery of retrieval and licking of pups occurred in all (between 1 and 4 days after surgery). All eight were quiescent for long periods in response to suckling but they did not display sustained kyphosis; rather, they nursed while prone or hunched over the pups, with little or no leg support, or while supine. Ventral trunk cutaneous sensitivity was present in all subjects. These data suggest that the dorsolateral funiculus relays both suckling-induced neuroendocrine and postural nursing reflexes that are mediated by separate supraspinal regions, hypothalamus and the ventrolateral sectors of the caudal periaqueductal gray, respectively.     

自发性蛛网膜下腔出血造影阴性148例临床分析

【目的】提高对自发性蛛网膜下腔出血(SAH)中特殊类型的中脑周围非动脉瘤性蛛网膜下腔出血(PNSH)的认识水平,指导临床诊治。【方法】回顾性分析148例首次造影阴性的自发性SAH病人的临床表现、影像学资料、治疗及预后情况。【结果】本组148例患者Ⅱ级以下133例,除5例患者行腰穿检查确诊为SAH外,其余患者均于发病1~2d内行头颅CT检查确诊。根据CT表现,出血仅位于中脑周围池者,和此部位延及一侧或两侧侧裂池者?延及纵裂池者?并有脑室出血者共122例。全部病人均在发病1~20d内首次行DSA检查,均为阴性。88例复查无阳性发现。139例病人愈后较好;3例有轻度的神经功能障碍;3例行脑室腹腔分流术恢复较好;3例因高龄合并其它脏器并发症家属放弃治疗。百余例患者随访6~36m,均无再出血发生。【结论】PNSH是一种特殊类型的SAH,无严重的脑血管痉挛、脑积水和再出血发生。提高对其的认识,对临床诊疗工作有重要的指导意义。对于非典型的PNSH患者,在除外脑血管痉挛的情况下,要有技术充分的6条血管的脑血管造影,多个角度投照。     

蛋白酶体抑制剂对中脑脑片的毒性作用及其机制研究

目的:观察蛋白酶体抑制剂对体外培养的大鼠中脑脑片黑质多巴胺(DA)能神经元的早期毒性作用,利用这种新型的组织模型探讨蛋白酶体功能异常在帕金森(PD)发病中的作用。方法:制备Wistar大鼠体外中脑黑质脑片的长期培养体系,加入蛋白酶体抑制剂lactacystin(0.1,0.5,1.0,5.0μmol/L)作用24 h后,测定培养基中乳酸脱氢酶(LDH)活力水平观察脑片活力。TH免疫组化观察黑质细胞变性缺失,α-synuclein免疫组化观察α-synuclein的表达,TUNEL法检测多巴胺能神经元凋亡。结果:经0.1,0.5,1.0和5.0μmol/L浓度的lactacystin作用24 h后,脑片黑质部位TH阳性神经元数量减少,α-synu-clein表达率增加,凋亡检测显示,5.0μmol/L的lactacystin组部分黑质细胞出现TUNEL染色阳性。结论:蛋白酶体抑制剂lactacystin对脑片中DA能神经元具有毒性作用,能诱导黑质细胞凋亡,其作用具有浓度依赖性。蛋白酶体功能缺陷在帕金森病发病机制中可能发挥重要作用。     

The projection to the mesencephalon from the sensory trigeminal nuclei. An anatomical study in the cat

The terminal areas and the cells of origin of the projection from the sensory trigeminal nuclei to the mesencephalon were investigated, using the method of anterograde and retrograde transport of horseradish peroxidase or wheat germ agglutinin-horseradish peroxidase conjugate. Injection of tracer into the nucleus interpolaris or nucleus oralis (in the latter cases with involvement of the nucleus principalis) resulted in dense anterograde labeling in the deep and intermediate gray layers of the contralateral superior colliculus, extending throughout the rostrocaudal extent of the colliculus with the exception of its caudalmost part, which was not labeled. Minor projections to the intercollicular nucleus, posterior pretectal nucleus and nucleus of Darkschewitsch were found. Injection of tracer into the nucleus caudalis yielded a completely different result; terminal labeling in the midbrain was now present only in the periaqueductal gray matter, in its rostral and middle parts. The retrograde labeling observed after injection of tracer into the midbrain terminal areas showed that the cells of origin were located mainly in the alaminar spinal trigeminal nucleus, and the highest density of labeled neurons was found in the rostral part (subnucleus y) of the nucleus oralis. The retrograde labeling in the nucleus principalis was very sparse and almost exclusively involved peripherally located neurons. In the nucleus caudalis the overwhelming majority of the retrogradely labeled neurons were situated in its marginal layer. The functional implications of the above observations are discussed in relation to the findings in previous studies of the projections from the dorsal column nuclei and spinal cord to the midbrain. The combined results suggest that the trigeminal projections to the superior colliculus may be involved in the mechanisms of orientational behavior. The observation that the projection to the periaqueductal gray matter originates in the marginal layer suggests that it transmits information related to noxious stimuli.     

Autoradiographic localization of delta opioid receptors within the mesocorticolimbic dopamine system using radioiodinated [2-D-penicillamine, 5-D-penicillamine]enkephalin (125I-DPDPE)

The enkephalin analog [2-D-penicillamine, 5-D-penicillamine]enkephalin was radioiodinated (125I-DPDPE) and shown to retain a pharmacological selectivity characteristic of the delta opioid receptor in in vitro binding studies. The distributions of 125I-DPDPE binding, using in vitro autoradiographic techniques, were similar to those previously reported for the delta opioid receptor. The nucleus accumbens, striatum, and medial prefrontal cortex contain dense gradients of 125I-DPDPE binding in regions known to receive dopaminergic afferents emanating from the mesencephalic tegmentum. Selective chemical lesions of the ventral tegmental area and substantia nigra were employed to deduce the location of the 125I-DPDPE binding within particular regions of the mesocorticolimbic dopamine system. Unilateral lesions of dopamine perikarya (A9 and A10) within the ventral tegmental area and substantia nigra produced by mesencephalic injection of 6-hydroxydopamine resulted in significant (20-30%) increases in 125I-DPDPE binding contralateral to the lesion within the striatum and nucleus accumbens. Lesions of the perikarya (dopaminergic and nondopaminergic) of the ventral tegmental area, induced by quinolinic acid injections, caused increases of less magnitude within these same nuclei. No significant alterations in 125I-DPDPE binding were observed within the mesencephalon as a result of either treatment. The specificity of the lesions was confirmed by immunocytochemistry for tyrosine hydroxylase. These results suggest that the enkephalins and opioid agonists acting through delta opioid receptors do not directly modulate dopaminergic afferents but do regulate postsynaptic targets of the mesocorticolimbic dopamine system.     

Neuroprotection by estrogen against MPP+-induced dopamine neuron death is mediated by ERalpha in primary cultures of mouse mesencephalon

Estrogen involvement in neuroprotection is now widely accepted, although the specific molecular and cellular mechanisms of estrogen action in neuroprotection remain unclear. This study examines estrogenic effects in a mixed population of cells in attempts to identify the contributing cells that result in estrogen-mediated neuroprotection. Utilizing primary mesencephalic neurons, we found expression of both estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) with a predominance of ERalpha on both dopamine neurons and astrocytes. We also found that 17beta-estradiol protects dopamine neurons from injury induced by the complex I inhibitor, 1-methyl-4-phenyl pyridinium (MPP(+)) in a time- and ER-dependent manner. At least 4 h of estrogen pre-treatment was required to elicit protection, an effect that was blocked by the ER antagonist, ICI 182,780. Moreover, ERalpha mediated the protection afforded by estrogen since only the ERalpha agonist, HPTE, but not the ERbeta agonist, DPN, protected against dopamine cell loss. Since glial cells were shown to express significant levels of ERalpha, we investigated a possible indirect mechanism of estrogen-mediated neuroprotection through glial cell interaction. Removal of glial cells from the cultures by application of the mitotic inhibitor, 5-fluoro-2'-deoxyuridine, significantly reduced the neuroprotective effects of estrogen. These data indicate that neuroprotection provided by estrogen against MPP(+) toxicity is mediated by ERalpha and involves an interplay among at least two cell types.     

Unit activity alterations induced in the mesencephalic periaqueductal gray by local electrical stimulation

In the framework of a series of investigations concerning the neural substrate of aversion, electrophysiological methods were used in order (1) to specify, within the rat's periaqueductal gray (PAG), functional properties, viz. conduction velocity and refractory period, of PAG neurons already assessed in previous studies by means of behavioral methods, and (2) to gather data on their local synaptic relationships. Unit activities were recorded from the periaqueductal gray with the aim of analyzing those alterations that would be induced by locally applying an electrical stimulation with parameters shown to elicit escape behavior. An implanted row of electrodes allowed the application of a stimulation to several sites aligned along a mediolateral or a rostrocaudal axis through the periaqueductal gray. The results indicate that an electrical stimulation applied to the periaqueductal gray may induce its effects through the activation of a number of dendrites and many slow conducting fibers running in a great variety of directions and branching within the periaqueductal gray. Their refractory period was surprisingly low (0.6 ms) for slow conducting fibers (below 1 m/s). The local circuitry appears to include many inhibitory connections. Their organization is assumed to be partly recurrent. Stimulation-induced inhibition becomes predominant when the stimulation is moved away from the recorded neuron along the mediolateral axis, but not along the rostrocaudal axis.