Pharmacological and autoradiographic studies on the pathophysiological role of GABAB receptors in the dystonic hamster: pronounced antidystonic effects of baclofen after striatal injections

The GABA_B receptor (GABA_BR) agonist baclofen is known to have a beneficial potency in patients who suffer from dystonia, a neurological syndrome characterized by involuntary co-contractions of opposing muscles. The underlying mechanisms of this movement disorder are still unclear. Previous studies in the dt^sz hamster, an animal model of primary paroxysmal dystonia, revealed alterations of the GABAergic system, including a reduction of striatal GABAergic interneurons and an altered GABA_A receptor (GABA_AR) binding in several brain regions. In order to clarify the pathophysiological role of central GABA_BRs in the hamster mutant, we performed pharmacological and receptor autoradiographic studies. Systemic administration of the GABA_BR agonist (R)-baclofen (1.5, 2.5 and 3.5 mg/kg i.p.) produced pronounced antidystonic effects in the dt^sz hamster. Striatal microinjections of baclofen (0.125, 0.25 and 0.5 μg/0.5 μl) also strongly reduced the severity of dystonia. Single striatal administration of the selective GABA_BR antagonist CGP 35348 [(3-Aminopropyl)(diethoxymethyl)phosphinic acid, 5 and 10 μg/0.5 μl] did not influence the severity of dystonia, but antagonized the antidystonic effect of baclofen. For receptor autoradiographic studies, [H3]-CGP 54626 ([S-(R*,R*)]-[3-[[1-(3,4-Dichlorophenyl)ethyl]amino]-2-hydroxypropyl](cyclohexylmethyl)phosphinic acid) binding was determined in dt^sz hamsters in comparison to non-dystonic control hamsters. [H3]-CGP 54626 binding was not altered in motor areas but in some limbic structures of dt^sz hamsters. In view of the absence of striatal changes in GABA_B binding, the strong antidystonic effect of baclofen after its striatal microinjection is probably related to a suppression of a pathophysiologically increased synaptic activity.     

Effects of Parkinson's disease on proprioceptive control of posture and reaching while standing

Although previous studies have shown pointing errors and abnormal multijoint coordination in seated subjects with Parkinson's disease (PD) who cannot view their arm, the extent to which subjects with PD have problems using proprioception to coordinate equilibrium maintenance and goal-oriented task execution has not been adequately investigated. If a common motor program controls voluntary arm pointing movements and the accompanying postural adjustments, then impairments of proprioceptive integration in subjects with PD should have similar effects on pointing and body center of mass (CoM) control with eyes closed. Ten standing subjects with PD (OFF-medication) and 10 age-matched control (CTR) subjects pointed to a target with their eyes closed and open. Although pointing accuracy was not significantly different between groups, body CoM displacements were reduced in subjects with PD, but not in CTR, when eyes were closed. In addition, with eyes closed, PD subjects showed reduced temporal coupling between pointing and CoM velocity profiles and reduced spatial coupling between pointing and CoM endpoints. This poor coupling with eyes closed could be related to the PD subjects' increased jerkiness of CoM displacements. The different effects of eye closure between CTR and PD subjects on the CoM displacements, but not pointing accuracy, are consistent with separate motor programs for the pointing and postural components of this task. Furthermore, the decoupling between the two movement components in subjects with PD when they could not use vision, suggests that the basal ganglia are involved in the integration of proprioceptive information for posture–movement coordination.     

Extracellular amino acid levels in the striatum of the dt(sz) mutant, a model of paroxysmal dystonia

The pathophysiology of idiopathic dystonia is still unknown, but it is regarded as a basal ganglia disorder. Previous studies indicated an involvement of a striatal GABAergic disinhibition and a cortico-striatal glutamatergic overactivity in the manifestation of stress-inducible dystonic episodes in the dt(sz) hamster, a model of idiopathic paroxysmal dystonia. These investigations were carried out postmortem or in anesthetized animals. In the present study, in vivo microdialysis in conscious, freely-moving dt(sz) and non-dystonic control hamsters was used to examine the levels of GABA, aspartate, glutamate, glutamine, glycine and taurine in each animal during following conditions: (1) at baseline in the absence of dystonia, (2) during an episode of paroxysmal dystonia precipitated by stressful stimuli, (3) during a recovery period and (4) at baseline after complete recovery. In comparison to non-dystonic controls, which were treated in the same manner as the dystonic animals, no differences could be detected under basal conditions. The induction of a dystonic episode in mutant hamsters led to higher contents of glycine in these animals in comparison to stressed but non-dystonic controls. Significant changes of glycine levels within the animal groups were not detected. The levels of the excitatory amino acids glutamate, glutamine and aspartate as well as the levels of the inhibitory amino acids GABA and taurine did not differ between the animal groups or between the periods of measurement. The higher levels of glycine might contribute to the manifestation of paroxysmal dystonia in dt(sz) hamsters, although unaltered glutamate, glutamine and aspartate levels do not support the hypothesis of a critical involvement of a cortico-striatal overactivity. It seems that a deficiency of GABAergic interneurons, found by previous immunohistochemical examinations, does not lead to reduced extracellular GABA levels in the striatum.     

基底节假性钙化

观察分析16例基底节假性钙化,结果表明,全部发生于苍白球。除1例伴有少量钙盐外,其余全部为铁,临床和化验检查未见异常,发生率随年龄增长而增加。因此,认为基底节假性钙化系生理性的。铁沉积继发于血管外膜增厚,铁可能来自血管周围脑组织。故推测血管外膜增厚可能是在渗出物基础上,继而发生机化,最后胶原化所致。     

基底节梗塞与出血对记忆影响的研究

采用《临床记忆量表》研究了９１例基底节梗塞与出血患者的记忆损害状况。研究表明：（１）基底节梗塞与出血病人的记忆商数（ＭＱ）约６４％在中等水平以下，与对照组比较差异显著；（２）基底节出血组的记忆障碍比基底节梗塞组更为严重；（３）四项与词有关的分测验及ＭＱ均以基底节左侧损害组下降明显，联想学习尤为明显，呈现大脑功能一侧化现象；（４）基底节梗塞或出血其损害体积的大小与记忆障碍的程度无明显正相关。     

Functional details of the basal ganglia as related to the spatial organization of their fibers in cortex and thalamus

This study compared the results of experimental-morphological and physiological studies in which facts were obtained regarding the functional and morphological heterogeneity of the basal ganglia. Experiments were done on dogs in order to study delayed responses and Hunterian delayed choice responses. Electrical and chemical stimulation of striopallidal structures and recording of spike activity in neurons were done in cats during the formation of conditioned reflexes. Morphological studies were done on cats and dogs by the technique of axon-terminal degeneration. On the basis of an analysis of our own data and data in the literature we have advanced the hypothesis that: 1)There is a correlation between the general features of the disturbance in higher nervous activity and the overlap of striopallidal projections onto cortical and thalamic structures; 2) in a series of cases the behavioral disturbance after shut-off or stimulation of the basal ganglia can be correlated with the topical details of their projection onto cortical fields and thalamic nuclei.Translated from Fiziologicheskii Zhurnal SSSR im. I. M. Sechenova, Vol. 65, No. 4, pp. 527–534, April, 1979.     

The role of the superior colliculus in predatory hunting

Combining the results of behavioral, neuronal immediate early gene activation, lesion and neuroanatomical experiments, we have presently investigated the role of the superior colliculus (SC) in predatory hunting. First, we have shown that insect hunting is associated with a characteristic large increase in Fos expression in the lateral part of the intermediate gray layer of the SC (SCig). Next, we have shown that animals with bilateral NMDA lesions of the lateral parts of the SC presented a significant delay in starting to chase the prey and longer periods engaged in other activities than predatory hunting. They also showed a clear deficit to orient themselves toward the moving prey and lost the stereotyped sequence of actions seen for capturing, holding and killing the prey. Our Phaseolus vulgaris-leucoagglutinin analysis revealed that the lateral SCig, besides providing the well-documented descending crossed pathway to premotor sites in brainstem and spinal cord, projects to a number of midbrain and diencephalic sites likely to influence key functions in the context of the predatory behavior, such as general levels of arousal, motivational level to hunt or forage, behavioral planning, appropriate selection of the basal ganglia motor plan to hunt, and motor output of the primary motor cortex. In contrast to the lateral SC lesions, medial SC lesions produced a small deficit in predatory hunting, and compared to what we have seen for the lateral SCig, the medial SCig has a very limited set of projections to thalamic sites related to the control of motor planning or motor output, and provides conspicuous inputs to brainstem sites involved in organizing a wide range of anti-predatory defensive responses. Overall, the present results served to clarify how the different functional domains in the SC may mediate the decision to pursue and hunt a prey or escape from a predator.     

Comparative effect of amphetamine and caffeine on spontaneous activity of sensomotor cortical units and their responses to stimulation of the caudate nucleus

In acute experiments on anesthetized cats activity of sensomotor cortical units was recorded during low-frequency stimulation of the head of the caudate nucleus. Amphetamine (1 mg/kg), although not significantly affecting the spontaneous firing rate, increased the number of spontaneously active cortical units. Meanwhile inhibition of these units during stimulation of the caudate nucleus was weakened. Amphetamine had a stronger suppressive action on the inhibition arising from the ventro-lateral portion than from the dorso-medial portion of the head. In the case of caffeine the location of the stimulating electrodes was unimportant.Department of Pharmacology, Medical Institute, Chita. (Presented by Academician of the Academy of Medical Sciences of the USSR V. V. Zakusov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 78, No. 7, pp. 59–62, July, 1974.     

The relationship between physiological tremor and the performance of rapid alternating movements in healthy elderly subjects

The power distribution in the frequency spectrum of tremor is known to vary among individuals and its median power frequency declines with ageing. The purpose of the present study was to determine whether a reduction of the central component of physiological tremor would correlate with a reduction of motor performance. Then, the power distribution in the frequency spectrum of tremor from limb extremities might serve as an index of neural drive in healthy elderly subjects. Rest tremor, postural tremor from the finger, and pronation-supination at the wrist were recorded in 102 healthy nuns living in a convent (mean of 72±12 years). Results reveal that several elderly subjects possessed a power distribution of tremor very similar to that of much younger subjects (mean 27 years±3 SD), showing a preponderance of power within the 7.6- to 12.5-Hz band. Duration of pronation-supination cycles of these elderly subjects was, however, similar to that of other elderly subjects who had a preponderance of power within the 3.6- to 7.5-Hz band. Consequently, healthy elderly subjects who possessed a predominance of power within higher frequencies were not at an advantage over other healthy elderly subjects when performing a pronation-supination task. The age of subjects was, however, a better predictor or motor performance. In conclusion, the present findings suggest that, under normal physiological conditions, a reduction of the central component of physiological tremor does not induce a reduction of motor performance. Consequently, tremor recorded at limb extremities cannot be used as an index of neural drive. Electronic Publication     

Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat

Midbrain dopamine neurons in the ventral tegmental area, substantia nigra and retrorubral field play key roles in reward processing, learning and memory, and movement. Within these midbrain regions and admixed with the dopamine neurons, are also substantial populations of GABAergic neurons that regulate dopamine neuron activity and have projection targets similar to those of dopamine neurons. Additionally, there is a small group of putative glutamatergic neurons within the ventral tegmental area whose function remains unclear. Although dopamine neurons have been intensively studied and quantified, there is little quantitative information regarding the GABAergic and glutamatergic neurons. We therefore used unbiased stereological methods to estimate the number of dopaminergic, GABAergic and glutamatergic cells in these regions in the rat. Neurons were identified using a combination of immunohistochemistry (tyrosine hydroxylase) and in situ hybridization (glutamic acid decarboxylase mRNA and vesicular glutamate transporter 2 mRNA). In substantia nigra pars compacta 29% of cells were glutamic acid decarboxylase mRNA-positive, 58% in the retrorubral field and 35% in the ventral tegmental area. There were further differences in the relative sizes of the GABAergic populations in subnuclei of the ventral tegmental area. Thus, glutamic acid decarboxylase mRNA-positive neurons represented 12% of cells in the interfascicular nucleus, 30% in the parabrachial nucleus, and 45% in the parainterfascicular nucleus. Vesicular glutamate transporter 2 mRNA-positive neurons were present in the ventral tegmental area, but not substantia nigra or retrorubral field. They were mainly confined to the rostro-medial region of the ventral tegmental area, and represented approximately 2-3% of the total neurons counted ( approximately 1600 cells). These results demonstrate that GABAergic and glutamatergic neurons represent large proportions of the neurons in what are traditionally considered as dopamine nuclei and that there are considerable heterogeneities in the proportions of cell types in the different dopaminergic midbrain regions.     

Tremor,ataxia and dementia in older men may indicate a carrier of the fragile X syndrome

Recently it has been reported that late-onset tremor, gait unsteadiness and dementia can be associated with brain atrophy in males of normal intelligence and the pre-mutation carrier state of the fragile X syndrome. We have shown, by means of a telephone survey, that this association is probably causal rather than coincidental. These findings have uncovered another testable cause of late-onset neurological symptoms in males, which also has serious genetic implications for their daughters who are at risk of having sons with full mutations causing mental handicap - the fragile X syndrome.     

Projections of the basal ganglia to the zona incerta of the dog diencephalon

Retrograde axonal transport of horseradish peroxidase was used to show that the projections of the globus pallidus, entopeduncular nucleus, substantia nigra, and pedunculopontine tegmental nucleus in dogs are directed to all segments of the zone incerta. The experiments reported here identified no topical features in the organization of these projections in dogs, as application of marker to different areas of the zona incerta yielded similar distributions of labeled neurons in the basal ganglia. No striatal projections to the zone incerta were found.     

正常人心动周期信号的混沌特征随年龄的变化

心动周期信号（ＨＰＳ）具有混沌特征，含有重要的生理、病理信息。我们利用自行研制的计算机化心动周期信号混沌分析系统，研究了２７１例正常人心动周期信号的混沌特征参数如相对分散度（ＨＲＤ）、李雅普诺夫数（ＨＬＥ）和分维数（ＨＦＤ），发现随着年龄的增加，ＨＲＤ、ＨＬＥ、ＨＦＤ逐步降低，即心血管动力学的复杂性逐步降低     

Sequential Rearrangements of the Ensemble Activity of Putamen Neurons in the Monkey Brain as a Correlate of Continuous Behavior

Simultaneous recordings were made of the spike activity of groups of 6-7 neurons in the putamen in two monkeys (Macaca nemestrina and Macaca mulatta) during performance of alternative spatial selection. Discriminant analysis was used to evaluate the magnitude of rearrangements in spike activity in groups of neurons during transitions from each step of the behavioral program to the next, along with the degree of differences in reactivity mosaics formed at each step in different versions of task execution. Rearrangements in spike activity were noted at all steps of the program. The dynamics of rearrangements on selection of the right and left feeders were different, leading to the appearance of significant differences in the reactivity mosaics at the decision-taking and reinforcement-receiving steps. The rearrangements preceding voluntary movement of one hand were more marked in the contralateral hemisphere. During performance of movements, the volume of rearrangements could increase, though differences in rearrangements accompanying movements of the right and left hands decreased. On receipt of reinforcement, rearrangements were greater when the animals selected a specified feeder (the left feeder) independently of which hemisphere was recorded.     

Organization of the Thalamic Projections of the Striopallidum of the Dog Brain

Experiments based on double luminescent labeling were performed to study the distribution of labeled neurons in the thalamic nuclei depending on the injection sites of luminescent markers into functionally similar or functionally different areas of the striopallidum of 16 dogs. The organizational characteristics of the thalamo-striopallidal projection system in dogs provide evidence for its high level of specificity, as not only the motor and limbic areas of the striopallidum, but also its functionally related areas, receive separate inputs mainly from diverse cellular groups. The centromedian nucleus contained groups of diffusely mixed cells, labeled with different markers and innervating functionally diverse segments of the caudate nucleus. In the centromedian, parafascicular, central medial, and medial dorsal nuclei of the thalamus, projection neurons form analogous cell populations innervating different segments of the striopallidal structures belonging to the same functional system. These striopallidal areas receive projections from small numbers of neurons via axon collaterals.     

神经生长因子对体外培养大脑基底神经节神经元的保护作用

目的:研究神经生长因子(NGF)对谷氨酸造成的体外培养大脑基底神经节神经元损伤后的再生及防止神经元坏死的保护作用。方法:原代培养的胎鼠前脑基底神经节神经元,分为对照组、谷氨酸损伤组和谷氨酸损伤后NGF保护组。用倒置相差显微镜进行活细胞观察、采用RT-PCR技术检测前脑基底神经节神经元GAP-43和NF-L基因表达。结果:谷氨酸损伤神经元胞体回缩,突起消失或断裂。加入NGF后神经元绝大多数细胞胞体饱满,突起明显,细胞问的网络联系清晰可见,接近于对照组;NGF保护组大脑基底神经节GAP-43 mRNA和NF-L mRNA表达与损伤组比较具有显著性差异。结论:NGF可保护谷氨酸造成体外培养的大脑基底神经节损伤后的再生,并防止神经元坏死。     

Possible Mechanisms of the Involvement of Dopaminergic Cells and Cholinergic Interneurons in the Striatum in the Conditioned-Reflex Selection of Motor Activity

A possible mechanism for the involvement of cholinergic interneurons in the striatum and dopaminergic cells in the substantia nigra in the selection from among several types of motor activity during learning is proposed. Selection is triggered by simultaneous increases in the activity of dopaminergic neurons and a pause in the activity of cholinergic interneurons in response to the conditioned signal. The appearance of the pause may facilitate activation of GABAergic interneurons in the striatum and the action of dopamine on D2 receptors on cholinergic interneurons. Differently directed changes in dopamine and acetylcholine levels synergistically modulate the efficiency of corticostriatal inputs, such that the rules for modulation of the “strong” and “weak” inputs are opposite in sign. The subsequent reorganization of neuron activity in the cortex-basal ganglia-thalamus-cortex circuit leads to increased activity in those cortical neurons providing “strong” innervation to the striatum with simultaneous decreases in the activity of neurons providing “weak” innervation to the striatum, which may underlie the selection of the movement reaction, in which the neocortex is involved. It follows from this model that if the delay between the conditioned and unconditioned stimuli is not longer than the latent period of the reactions of dopaminergic and cholinergic cells (about 100 msec), selection of movement activity in response to the conditioned signal and learning is hindered. __________ Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 54, No. 6, pp. 734–749, November–December, 2004.     

Organization of the efferent projections of the pedunculopontine tegmental nucleus of the midbrain of the dog pallidum

Studies of the pedunculopontinopallidal projections of the dog brain based on the retrograde axonal transport of horseradish peroxidase demonstrated that the compact zone (PPNc) and the lateral area of the diffuse zone (PPNd) of the pedunculopontine tegmental nucleus (PPN) of the midbrain project to the globus pallidus, entopeduncular nucleus, and ventral pallidum. The medial area of the PPNd, adjacent to the chiasm of the upper cerebellar peduncles and seen in other animals as the mesencephalic extrapyramidal area (MEA), projects only to the globus pallidus. In dogs, this area of the tegmentum is not a major source of projections to the striopallidum, such that it is inappropriate to regard it as a separate structure, comment being restricted to the topical organization of PPNd projections to the pallidum. Projection fibers to pallidal structures arise from both cholinergic and non-cholinergic PPN neurons. __________ Translated from Morfologiya, Vol. 127, No. 2, pp. 19–23, March–April, 2005.     

Functional mapping of the prosencephalic systems involved in organizing predatory behavior in rats

The study of the neural basis of predatory behavior has been largely neglected over the recent years. Using an ethologically based approach, we presently delineate the prosencephalic systems mobilized during predation by examining Fos immunoreactivity in rats performing insect hunting. These results were further compared with those obtained from animals killed after the early nocturnal surge of food ingestion. First, predatory behavior was associated with a distinct Fos up-regulation in the ventrolateral caudoputamen at intermediate rostro-caudal levels, suggesting a possible candidate to organize the stereotyped sequence of actions seen during insect hunting. Insect predation also presented conspicuous mobilization of a neural network formed by a distinct amygdalar circuit (i.e. the postpiriform-transition area, the anterior part of cortical nucleus, anterior part of basomedial nucleus, posterior part of basolateral nucleus, and medial part of central nucleus) and affiliated sites in the bed nuclei of the stria terminalis (i.e. the rhomboid nucleus) and in the hypothalamus (i.e. the parasubthalamic nucleus). Accordingly, this network is likely to encode prey-related motivational values, such as prey’s odor and taste, and to influence autonomic and motor control accompanying predatory eating. Notably, regular food intake was also associated with a relatively weak Fos up-regulation in this network. However, during regular surge of food intake, we observed a much larger mobilization in hypothalamic sites related to the homeostatic control of eating, namely, the arcuate nucleus and autonomic parts of the paraventricular nucleus. Overall, the present findings suggest potential neural systems involved in integrating prey-related motivational values and in organizing the stereotyped sequences of action seen during predation. Moreover, the comparison with regular food intake contrasts putative neural mechanisms controlling predatory related eating vs. regular food intake.