食蟹猴年龄相关的运动功能减退及其与纹状体多巴胺转运体的关系

目的研究食蟹猴老化过程中运动行为和脑内纹状体多巴胺系统功能变化及两者之间的相关关系。方法选取4岁、10岁和15岁3个年龄组的健康食蟹猴共29只,利用计算机化的网络摄像头视频检测系统和行为分析软件连续采集和分析每个动物8h随意运动活动总量,各年龄组分别选取4只动物用多巴胺转运体(DAT)配体99mTc-TRODAT-1结合单光子发射体层摄影术(SPECT)显像观察脑内纹状体多巴胺转运体放射性摄取率的变化。结果在4岁、10岁和15岁年龄组,8h随意运动活动总量(×106)分别为5·00±1·93,3·28±1·02,2·79±0·67,在10岁和15岁较之4随年龄组分别降低了34·50%和55·71%(P<0·05,P<0·01),但此两个年龄组运动活动总量无显著差异(P>0·05);纹状体99mTc-TRODAT-1放射性摄取率分别为2·98±0·08,2·56±0·12和2·27±0·35,10岁和15岁较之4随年龄组分别降低了14·00%和25·60%,但仅4岁与15岁年龄组存在显著相关关系(P<0·01)。二者均随着年龄的增长呈逐渐减低的趋势,直线回归分析显示两者分别与年龄呈负相关关系(r=-0·57,P=0·001;r=-0·86,P<0·01)。8h随意运动活动总量与纹状体99mTc-TRODAT-1放射性摄取率呈显著的正相关关系(r=0·70,P<0·05)。结论正常食蟹猴老化过程中,脑内多巴胺神经系统功能的减退伴随着运动行为的减少,两者之间的相关关系进一步佐证了运动功能的减退可能是由于纹状体内多巴胺神经元功能减退所致。     

Synaptic Plasticity in an In Vitro Slice Preparation of the Rat Nucleus Accumbens

Extra- and intracellular recordings in slices were used to examine what types of synaptic plasticity can be found in the core of the nucleus accumbens, and how these forms of plasticity may be modulated by dopamine. Stimulus electrodes were placed at the rostral border of the nucleus accumbens in order to excite primarily infralimbic and prelimbic afferents, as was confirmed by injections of the retrograde tracer fluoro-gold. In extracellular recordings, tetanization induced long-term potentiation (LTP) of the population spike in 20 out of 53 slices. The presynaptic compound action potential did not change following LTP induction. For the intracellularly recorded excitatory postsynaptic potential, three types of synaptic plasticity were noted: long-term potentiation (16 out of 54 cells), decremental potentiation (eight cells) and long-term depression (LTD; six cells). No correlation was found between the occurrence of potentiation or depression and various parameters of the tetanic depolarization (e.g. peak voltage, integral under the curve). The N -methyl- d -aspartate receptor antagonist d (–)-2-amino-5-phosphonopentanoic acid (50 μM; d -AP5) reduced, but did not completely prevent, the induction of LTP. The incidence of LTD was not markedly affected by d -AP5. No difference in LTP was found when comparing slices bathed in dopamine (10 μM) and controls. Likewise, slices treated with a mixture of the D1 receptor antagonist Sch 23390 (1 μM) and the D2 antagonist S (–)-sulpiride (1 μM) generated a similar amount of LTP as controls. In conclusion, both LTP and LTD can be induced in a key structure of the limbic-innervated basal ganglia. LTP in the nucleus accumbens strongly depends on N -methyl- d -aspartate receptor activity, but is not significantly affected by dopamine.     

Tolerance-like attenuation to contingent and noncontingent cocaine-induced elevation of extracellular dopamine in the ventral striatum following 7 days of withdrawal from chronic treatment

Time-dependent changes in mesolimbic dopamine (DA) function are believed to play a role in behavioral sensitization and drug craving experienced during withdrawal from chronic cocaine administration. The present study utilized intravenous (IV) cocaine self-administration coupled with intracranial microdialysis in rats to investigate time dependent changes during withdrawal from chronic cocaine exposure. Following 2 weeks of IV cocaine self-administration, rats were allowed contingent access to cocaine at 1 and 7 days of withdrawal while extracellular levels of DA were measured from the ventral striatum. A second group of animals received yoked, noncontingent cocaine for 2 weeks and were then administered noncontingent cocaine on days 1 and 7 of withdrawal. In addition, a third group of animals received 2 weeks of yoked saline followed by noncontingent cocaine 1 day after withdrawal. There were no significant differences between groups for the overall cocaine dosage or temporal pattern of infusions on days 1 and 7 of withdrawal. Basal extracellular DA concentrations did not differ between any treatment groups at either withdrawal time. Extracellular DA levels were increased throughout the session on both days; however, the increases at day 7 were significantly less than day 1 for both contingent and noncontingent conditions. DA overflow on day 1 did not differ between animals receiving chronic yoked cocaine or saline. These results suggest that tolerance-like attenuation to the DA-elevating effects of cocaine is not apparent early in withdrawal, but does develop by later time points. DA release in the ventral striatum may not be directly related to cocaine self-administration following withdrawal, since DA levels were attenuated after 7 days of withdrawal while responding for cocaine was unaltered.     

Release of newly synthesized h-dopamine in the striatum: An adaptation of the push-pull cannula method to awake restrained and anesthetized rats

The release of newly synthesized ³H-dopamine (³H-DA) was measured in the rat striatum superfused, through a push-pull cannula, with a physiological medium enriched in ³H-tyrosine. The level of spontaneous ³H-DA release was dependent on the topographical localisation of the cannula in the striatum (anterior parts displayed higher levels than posterior ones) and on the anesthetic state (halothane anesthetized rats demonstrated higher levels than awake ones). Inhibition of DA inactivation processes by local application of benztropine (a DA reuptake inhibitor, 10⁻⁶ M) or by IV administration of pargyline (a MAO inhibitor, 100 mg/kg) enhanced the detectable outflow of ³H-DA from the striatum in both halothane anesthetized and awake rats. Local application of D-amphetamine (10⁻⁵ M) or acetylcholine (5 × 10⁻⁵ M) in the presence of eserine (5 × 10⁻⁵ M) evoked respectively a fivefold and a 30% increase in spontaneous ³H-DA release in halothane anesthetized rats. Inhibition of the firing of dopaminergic neurons by IV injection of gamma-hydroxybutyrate (400 mg/kg) produced a 30% decrease in striatal ³H-DA release. The present results demonstrate that the push-pull cannula method is suitable for the study of DA release in both the anesthetized and the awake rat.     

黑质内注射FeCl3对大鼠纹状体多巴胺释放量及含量的影响

①目的探讨黑质(SN)内注射不同剂量的FeCl3对大鼠纹状体(CPu)多巴胺(DA)释放量和含量的影响.②方法实验用SD大鼠32只,分成4组6只大鼠为正常对照组;9只大鼠左侧SN内注射 FeCl3溶液10 μg(Ⅰ组);8只大鼠左侧SN内注射FeCl3溶液20 μg(Ⅱ组);9只大鼠左侧SN内注射FeCl3溶液40 μg(Ⅲ组),3周后采用快速周期伏安法(FCV)监测纹状体D A的释放量,高效液相色谱法(HPLC)检测纹状体DA含量.③结果在FeCl3单侧损毁大鼠中,损毁侧CPu DA释放量的减少和DA含量的降低与注射FeCl3剂量之间有明显剂量依赖关系(F=93.78,164.51,q=3.50～29.79,P<0.05).Ⅲ组损毁侧CP u DA的更新率[以(DOPAC+HVA)/DA表示]明显加快,与其他组比较差异有显著性(F=13 6.22,q=22.32～22.72,P<0.05);而Ⅰ,Ⅱ组变化较小,与正常大鼠相比差别无统计学意义 (q=0.25,2.04,P>0.05).④结论黑质内Fe3+含量升高可使CPu内DA释放量和含量均降低,铁含量高可能参与帕金森病的病理改变.     

Effect of CNTF on low-affinity NGF receptor expression by cultured neurons from different rat brain regions.

Our previous work indicated that in E14 embryonic rat spinal cord cultures ciliary neuronotrophic factor (CNTF) exerted (1) a survival-promoting effect on motor neurons and on a large population of unidentified neurons, and (2) a regulatory role on the expression of ChAT and low affinity NGF receptor (LNGFR) in a population of small/medium-sized neurons. In the present study, we examined the effect of CNTF on the expression of LNGFR in cultures of different regions from the E18 embryonic rat brain, namely cortex, septum, striatum, mesencephalon, hippocampus, brainstem, and cerebellum. The number of LNGFR-positive neurons (stained with the 192-IgG monoclonal antibody) was determined in untreated cultures and in cultures treated for 6 days (0-6) with human recombinant CNTF. To distinguish between effects on survival and on LNGFR expression, experiments were performed in which CNTF was administered only for the last 48 h of the culture (from days 4-6). LNGFR positive neurons were found in the cultures of all the regions examined. In each one of them, CNTF increased the number of LNGFR-positive neurons by three- to fourfold after 6 days of treatment. In the striatum, septum, mesencephalon, and cerebellum, the effect of CNTF was shown to be on the regulation of LNGFR expression and not on survival. In cultures from the cortex, hippocampus and brainstem, a survival-promoting role of CNTF could be demonstrated. The effect of CNTF was dose dependent, with half-maximal effects (ED50) achieved at 2-4.5 TU/ml for all the brain regions. Maximal effects were reached at 100-250 TU/ml. From these results, we conclude that (1) there exists a wide spectrum of CNTF-responsive neurons in the central nervous system, and (2) CNTF plays an important and widespread role in regulating the expression of the LNGFR in neurons.     

Transmitter Release Associated with Long-term Synaptic Depression in Rat Corticostriatal Slices

Using a corticostriatal slice preparation, we have recently shown that tetanic stimulation of the corticostriatal pathway produces long-term depression (LTD) of striatal excitatory synaptic transmission. In the present study we have analysed the relationship between LTD and the striatal release of different endogenous transmitters. Samples of perfusate were collected via a small cannula placed just above the surface of the striatal slice close to the recording electrode, and were analysed by HPLC. The high-frequency stimulation (100 Hz, three trains, 3 s duration, 20 s intervals) used to induce LTD caused a significant but transient increase in the release of both excitatory (aspartate and glutamate) and inhibitory (glycine and GABA) amino acid transmitters. Tetanic stimulation also produced a significant, but transient increase in the release of endogenous dopamine. We conclude that the tetanic stimulation of the corticostriatal pathway is able to induce a large but transient release of excitatory amino acids and of dopamine, whose participation in the induction of striatal LTD has been demonstrated previously. Moreover, the maintenance of this form of synaptic plasticity does not seem to require a sustained change in transmitter release.     

Functional Anatomy of Visuomotor Skill Learning in Human Subjects Examined with Positron Emission Tomography

The present study was designed to examine patterns of regional cerebral blood flow (CBF) associated with the learning of a repeated visuomotor sequence both in the early and late phases of the acquisition process. In addition, changes in blood flow related to the implicit versus explicit aspects of learning such a skill were investigated. Fourteen normal control subjects were scanned while performing the task (i) in both early and advanced learning stages of the visuomotor sequence; (ii) after having acquired explicit knowledge of the sequences; and (iii) in two control conditions (perceptual and random sequence). Subtraction of the random condition from the highly learned condition revealed specific areas of activity in the right ventral striatum and dentate nucleus of the cerebellum. Blood flow changes in the right hemisphere were also seen in the medial posterior parietal and prestriate regions, as well as in the anterior cingulate cortex. Finally, once the subjects had acquired explicit knowledge of the embedded sequence that was presented in the highly learned condition, increased CBF activity was observed only in the mid-ventrolateral frontal area in the right hemisphere. These findings confirm that both the striatum and the cerebellum are involved in the implicit acquisition of a visuomotor skill, especially in the advanced stages of the learning process, and furthermore that the ventrolateral prefrontal cortex contributes preferentially to the declarative aspect of this task.     

Organization of visual corticostriatal projections in the cat,with observations on visual projections to claustrum and amygdala

Electrophysiological mapping criteria were employed to identify visual areas 20a, 20b, 21a, 21b, PMLS, AMLS, ALLS, PLLS, DLS, VLS, and PS in the cat, and to guide placement of tracer deposits. Anterograde tracer methods were used to study the corticostriatal projections of these extrastriate visual areas. The experiments demonstrate that all 11 extrastriate areas send projections to two distinct regions within the striatum, an extensive longitudinal zone within the caudate nucleus, and a more compact region within the posterolateral putamen. Cortical visual projections to the putamen terminate in relatively compact sheets or slabs, and appear to overlap extensively, while those to the caudate nucleus are irregularly patchy and more widely dispersed. Retrograde tracer deposits into the visual recipient zone of the caudate nucleus reveal substantial convergence of other cortical inputs to this same domain. Aspects of visuotopic organization are preserved in the visual projections to both the putamen and the caudate nucleus, but unequivocal retinotopic organization could not be inferred from the available material. Ten of the eleven extrastriate visual area also project topographically onto the visual zone of the claustrum. Area PS does not appear to contribute to the corticoclaustral projections. Five of the extrastriate visual areas (ALLS, PLLS, DLS, VLS, PS) also send sparse projections to the amygdaloid complex. c 1993 Wiley-Liss, Inc.     

Efferent connections of the centromedian and parafascicular thalamic nuclei in the squirrel monkey: a light and electron microscopic study of the thalamostriatal projection in relation to striatal heterogeneity.

The organization of the thalamostriatal projections arising from the centromedian (CM) and parafascicular (Pf) thalamic nuclei in the squirrel monkey (Saimiri sciureus) was studied at both light and electron microscopic levels. Following selective injections of the anterograde axonal tracer Phaseolus vulgaris-leucoagglutinin (PHA-L) into the CM or Pf, patterns of terminal arborization within the striatum were compared to the biochemical heterogeneity of the striatum as revealed by immunohistochemical staining for the calcium-binding protein calbindin D-28k (CaBP), and histochemical staining for the enzymes acetylcholinesterase (AChE) and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-diaphorase). The PHA-L-labeled axon terminals within the striatum were further analyzed at the ultrastructural level to characterize their pattern of synaptic organization. Dense and heterogeneous terminal fields occur in the "sensorimotor" territory of the striatum after CM injections, or in the "associative" striatal territory following Pf injections. In the associative territory labeled axons arborize in a diffuse manner predominantly within areas enriched with CaBP, AChE, or NADPH-diaphorase, representing the matrix compartment, and tend to avoid areas poor in these substances, corresponding to the patch/striosome compartment. In the sensorimotor territory labeled axons form bands that occupy a subregion of the NADPH-diaphorase-rich zone in the putamen. The terminal pattern of the CM-striatal projection suggests the existence of a more complex mosaic organization within the sensorimotor territory. Ultrastructural analysis of PHA-L-labeled elements within the striatum reveals that both CM and Pf projections form asymmetric synapses upon dendrites and spines of striatal cells. A total of 339 PHA-L-labeled boutons were examined after CM injections and compared to 293 boutons following Pf injections. After CM injections, 29% of PHA-L-labeled terminals form synapses on dendritic spines and 66% on dendritic shafts, whereas after Pf injections only 12% of synapses occur on dendritic spines compared to 81% on dendritic shafts. Labeled terminals forming axosomatic or axoaxonic synapses were not seen within the striatum following either CM or Pf injections. It is concluded that in the squirrel monkey: 1) Pf-striatal fibers profusely arborize within the matrix compartment of the associative territory, 2) CM-striatal fibers form bands that occupy a subregion of the NADPH-diaphorase-rich zone within the sensorimotor territory, and 3) that both Pf- and CM-striatal projections establish asymmetric synapses with dendrites and spines of medium-sized spiny cells.(ABSTRACT TRUNCATED AT 400 WORDS)