Effects of the Activity of the Internal Globus Pallidus-Pedunculopontine Loop on the Transmission of the Subthalamic Nucleus-External Globus Pallidus-Pacemaker Oscillatory Activities to the Cortex

Resting tremor is the most specific sign for idiopathic Parkinson' disease. It has been proposed that parkinsonian tremor results from the activity of the central oscillators. One of the hypotheses, which have been proposed about the possible principles underlying such central oscillations, is the subthalamic nucleus (STN)-external globus pallidus (GPe)-pacemaker hypothesis. Activity from the central oscillator is proposed to be transmitted via trans-cortical pathways to the periphery. A computational model of the basal ganglia (BG) is proposed for simulating the effects of the internal globus pallidus (GPi)-pedunculopontine (PPN) loop activity on the transmission of the STN-GPe-pacemaker oscillatory activities to the cortex, based on known anatomy and physiology of the BG. According to the result of the simulation, the GPi-PPN loop activity can suppress the transmission of the STN-GPe-pacemaker oscillatory activities to the cortex. This suppressive effect is controlled by various factors such as the strength of the synaptic connection from the PPN to the GPi, the strength of the synaptic connection from the GPi to the PPN, the spontaneous tonic activities of the GPi and PPN, the direct excitatory projections from the STN to the PPN, the frequency of the STN oscillatory burst activity, the duration of the STN burst, and the maximum T-type calcium channel conductance in the type-I PPN neurons.     

High Frequency Stimulation of the Subthalamic Nucleus Eliminates Pathological Thalamic Rhythmicity in a Computational Model

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) has recently been recognized as an important form of intervention for alleviating motor symptoms associated with Parkinson's disease, but the mechanism underlying its effectiveness remains unknown. Using a computational model, this paper considers the hypothesis that DBS works by replacing pathologically rhythmic basal ganglia output with tonic, high frequency firing. In our simulations of parkinsonian conditions, rhythmic inhibition from GPi to the thalamus compromises the ability of thalamocortical relay (TC) cells to respond to depolarizing inputs, such as sensorimotor signals. High frequency stimulation of STN regularizes GPi firing, and this restores TC responsiveness, despite the increased frequency and amplitude of GPi inhibition to thalamus that result. We provide a mathematical phase plane analysis of the mechanisms that determine TC relay capabilities in normal, parkinsonian, and DBS states in a reduced model. This analysis highlights the differences in deinactivation of the low-threshold calcium T -current that we observe in TC cells in these different conditions. Alternative scenarios involving convergence of thalamic signals in the cortex are also discussed, and predictions associated with these results, including the occurrence of rhythmic rebound bursts in certain TC cells in parkinsonian states and their drastic reduction by DBS, are stated. These results demonstrate how DBS could work by increasing firing rates of target cells, rather than shutting them down.     

Effect of subthalamic nucleus or entopeduncular nucleus lesion on levodopa-induced neurochemical changes within the basal ganglia and on levodopa-induced motor alterations in 6-hydroxydopamine-lesioned rats

Inactivation of the subthalamic nucleus (STN) or the internal segment of the pallidum (GPi)/entopeduncular nucleus (EP) by deep brain stimulation or lesioning alleviates clinical manifestations of Parkinson's disease (PD) as well as reducing the side-effects of levodopa treatment. However, the effects of STN or entopeduncular nucleus (EP) lesion on levodopa-related motor fluctuations and on neurochemical changes induced by levodopa remain largely unknown. The effects of such lesions on levodopa-induced motor alterations were studied in 6-hydroxydopamine (6-OHDA)-lesioned rats and were assessed neurochemically by analyzing the functional activity of the basal ganglia nuclei, using the expression levels of the mRNAs coding for glutamic acid decarboxylase and cytochrome oxidase as molecular markers of neuronal activity. At the striatal level, preproenkephalin (PPE) mRNA levels were analyzed. We found in 6-OHDA-lesioned rats that a unilateral STN or EP lesion ipsilateral to the 6-OHDA lesion had no effect on either the shortening in the duration of the levodopa-induced rotational response or the levodopa-induced biochemical changes in the basal ganglia nuclei. In contrast, overexpression of PPE mRNA due to levodopa treatment was reversed by the STN or EP lesion. Our study thus shows that lesion of the EP or STN may counteract some of the neurochemical changes induced by levodopa treatment within the striatum.     

Understanding decision-making deficits in neurological conditions: insights from models of natural action selection

Models of natural action selection implicate fronto-striatal circuits in both motor and cognitive 'actions'. Dysfunction of these circuits leads to decision-making deficits in various populations. We review how computational models provide insights into the mechanistic basis for these deficits in Parkinson's patients and those with ventromedial frontal damage. We then consider implications of the models for understanding behaviour and cognition in attention-deficit/hyperactivity disorder (ADHD). Incorporation of cortical noradrenaline function into the model improves action selection in noisy environments and accounts for response variability in ADHD. We close with more general clinical implications.     

Role of Neostriatal Dopamine D1 and D2 Receptors in the Organization of Neuronal Activity in the Entopeduncular Nucleus

In chronic experiments on cats, we studied the effects of selective blockade of the dopamine D1 and D2 receptors in the nucleus caudatus (NC) against the background neuronal activity (BA) in the entopeduncular nucleus (ENT) and on the responses of these neurons evoked by stimulation of the subthalamic nucleus (STN). A blocker of D1 receptors, SCH 23390, and sulpiride, a blocker of D2 receptors, when injected into the NC head, led to changes in the BA frequency. The direction of these effects was different: blockade of the D2 receptors evoked a significant decrease in the BA frequency of ENT neurons, but when the D2 receptors were blocked, a trend toward an increase in this frequency was observed. Some of the ENT cells demonstrated similar changes in the temporal organization of their impulse activity with blockade of the D1 and D2 receptors. Namely, besides single action potentials (AP), high-frequency burst discharges began to be generated. Blockade of both D1 and D2 receptors prolonged the responses of ENT neurons to STN stimulation due to the appearance of similar AP bursts, while control animals demonstrated reactions consisting of solely single AP. The question on a dual (synergic and antagonistic) involvement of the neostriatal D1 and D2 receptors in the dopaminergic regulation of the basal ganglia is under discussion.     

A Possible Mechanism of Blocking of Limbic Motor Seizure Reactions Induced by Activation of the Thalamic Reticular Nucleus

Experiments were directed toward elucidation of the role of the thalamic reticular nucleus (R) in the modulation of generalized seizure reactions under kindling conditions and of the mechanisms mediating the effects of stimulation of the above nucleus on seizure activity. It was shown that activation of the thalamic R in rats limits generalization of the seizure reactions both in the course of development of seizures of limbic genesis (evoked by stimulation of the hippocampus) and under conditions of the existence of a pre-formed epileptic nidus. Tetanic stimulation of the R in cats under conditions of acute experiments induced significant facilitation of IPSPs in thalamo-cortical neurons of the ventrolateral thalamic nucleus. This effect is rather long-lasting and may be considered a mechanism providing blocking of generalized seizures under kindling conditions. Neirofiziologiya/Neurophysiology, Vol. 37, No. 4, pp. 352–361, July–August, 2005.     

Comparison of the Connectional Properties of the Two Forelimb Areas of the Rat Sensorimotor Cortex: Support for the Presence of a Premotor or Supplementary Motor Cortical Area

The existence of multiple motor cortical areas that differ in some of their properties is well known in primates, but is less clear in the rat. The present study addressed this question from the point of view of connectional properties by comparing the afferent and efferent projections of the caudal forelimb area (CFA), considered to be the equivalent of the forelimb area of the primary motor cortex (MI), and a second forelimb motor representation, the rostral forelimb area (RFA). As a result of various tracing experiments (including double labeling), it was observed that CFA and RFA had reciprocal corticocortical connections characterized by preferential, asymmetrical, laminar distribution, indicating that RFA may occupy a different hierarchical level than CFA, according to criteria previously discussed in the visual cortex of primates. Furthermore, it was found that RFA, but not CFA, exhibited dense reciprocal connections with the insular cortex. With respect to their efferent projection to the basal ganglia, it was observed that CFA projected very densely to the lateral portion of the ipsilateral caudate putamen, whereas the contralateral projection was sparse and more restricted. The ipsilateral projection originating from RFA was slightly less dense than that from CFA, but it covered a larger portion of the caudate putamen (in the medial direction); the contralateral projection from RFA to the caudate putamen was of the same density and extent as the ipsilateral projection. The reciprocal thalamocortical and corticothalamic connections of RFA and CFA differed from each other in the sense that CFA was mainly interconnected with the ventrolateral thalamic nucleus, while RFA was mainly connected with the ventromedial thalamic nucleus. Altogether, these connectional differences, compared with the pattern of organization of the motor cortical areas in primates, suggest that RFA in the rat may well be an equivalent of the premotor or supplementary motor area. In contrast to the corticocortical, corticostriatal, and thalamocortical connections, RFA and CFA showed similar efferent projections to the subthalamic nucleus, substantia nigra, red nucleus, tectum, pontine nuclei, inferior olive, and spinal cord.     

Responses of Neurons in the Rat Nucleus Submedius to Noxious and Innocuous Mechanical Cutaneous Stimulation

Extracellular recordings were used to characterize responses to cutaneous mechanical stimulation of 78 neurons in the rat nucleus submedius (SM). Thirty-nine of these units were activated by some type of cutaneous mechanical stimulation. Eighteen cells were activated exclusively by noxious stimuli. In 13 of these cells, responses were of swift onset and relatively rapid termination following stimulus application. In contrast, in three neurons responses were delayed both in onset and termination, and in two the response was immediate, but the markedly increased evoked activity outlasted stimulus application by 13 min. Receptive fields (RFs) of these nociceptive neurons were generally large, although none were bilateral. Four SM neurons were activated by innocuous stimuli, but their maximal response was obtained only after noxious stimulation. Responses of all of these neurons were of immediate onset and recovery, and their RFs were large (two were bilateral). Twelve SM neurons were activated maximally by innocuous stimuli. Responses of seven of these cells were immediate in onset and termination, while that of three were delayed in both onset and termination. Two of the 12 innocuous-only neurons quickly became unresponsive to repeated stimulus applications, and could be reactivated only after a rest period during which no stimuli were applied. RFs of these units were also generally large, and in three cases were bilateral. Five SM neurons responded by decreasing, or completely ceasing, their firing subsequent to noxious-only (n = 2), or innocuous-only (n = 3) stimulation. Four of these units had large RFs (two were bilateral). The remaining 39 SM neurons could not be activated by any type of mechanical cutaneous stimulation we tried.

Electrical stimulation of the ventrolateral orbital cortex (VLO) was employed to examine frontal cortical projections of 21 SM neurons. Ten of these units were activated, although all of them synaptically rather than antidromically, and two were inhibited. There was no clear-cut relationship between neuronal location, physiological type, RF site, or VLO stimulation effects among the 39 SM neurons.

These results provide further support for the involvement of SM neurons in nociceptive information signaling, and suggest additionally that the role of the nucleus is not limited to nociception but encompasses a wider range of cutaneous sensations.     

Computational studies of sialyllactones: methods and uses

N-Acetylneuraminic acid (1) is a common sugar in many biological recognition processes. Neuraminidase enzymes recognize and cleave terminal sialic acids from cell surfaces. Viral entry into host cells requires neuraminidase activity, thus inhibition of neuraminidase is a useful strategy for development of drugs for viral infections. A recent crystal structure for influenza viral neuraminidase with sialic acid bound shows that the sialic acid is in a boat conformation [Prot Struct Funct Genet 14: 327 (1992)]. Our studies seek to determine if structural pre-organization can be achieved through the use of sialyllactones. Determination of whether siallylactones are pre-organized in a binding conformation requires conformational analysis. Our inability to find a systematic study comparing the results obtained by various computational methods for carbohydrate modeling led us to compare two different conformational analysis techniques, four different force fields, and three different solvent models. The computational models were compared based on their ability to reproduce experimental coupling constants for sialic acid, sialyl-1,4-lactone, and sialyl-1,7-lactone derivatives. This study has shown that the MM3 forcefield using the implicit solvent model for water implemented in Macromodel best reproduces the experimental coupling constants. The low-energy conformations generated by this combination of computational methods are pre-organized toward conformations which fit well into the active site of neuraminidase. This revised version was published online in November 2006 with corrections to the Cover Date.     

Towards an executive without a homunculus: computational models of the prefrontal cortex/basal ganglia system

The prefrontal cortex (PFC) has long been thought to serve as an 'executive' that controls the selection of actions and cognitive functions more generally. However, the mechanistic basis of this executive function has not been clearly specified often amounting to a homunculus. This paper reviews recent attempts to deconstruct this homunculus by elucidating the precise computational and neural mechanisms underlying the executive functions of the PFC. The overall approach builds upon existing mechanistic models of the basal ganglia (BG) and frontal systems known to play a critical role in motor control and action selection, where the BG provide a 'Go' versus 'NoGo' modulation of frontal action representations. In our model, the BG modulate working memory representations in prefrontal areas to support more abstract executive functions. We have developed a computational model of this system that is capable of developing human-like performance on working memory and executive control tasks through trial-and-error learning. This learning is based on reinforcement learning mechanisms associated with the midbrain dopaminergic system and its activation via the BG and amygdala. Finally, we briefly describe various empirical tests of this framework.     

Modifications of Neuronal Activity in the Medial Vestibular Nucleus during Long-Term Vibration

The impulse background activity (BA) of neurons of the rat medial vestibular nucleus (MVN) was subjected to computer analysis, and its modifications related to long-term vibration were studied. It was shown that following 5 days of 2-h-long vibration sessions, statistically significant changes in some basic characteristics of BA generated by MVN neurons were observed. More than a twofold increase in the mean BA frequency and substantial shifts practically of all statistical BA parameters were found after 10 days of vibration. Following a 15-day-long vibration, MVN neurons showed a clear-cut tendency to restore control values of the BA indices, which probably was related to adaptation processes.     

Effect of Long-Lasting Vibration on the Impulse Activity of Neurons of the Inferior Vestibular Nucleus

We analyzed the impulse background activity (BA) of neurons of the inferior vestibular nucleus (IVN) of rats during exposure to long-lasting vibration (daily 2-h-long sessions). It was demonstrated that 5 days after the beginning of vibration stimulation, practically all main characteristics of the BA of IVN neurons changed significantly. In the studied neuronal group, 10 days after the vibration onset we observed an increase in the mean frequency of the BA and shifts in many statistical parameters of the BA, while after 15 days of vibration only significant modifications of dynamic characteristics of the BA of IVN neurons were manifested.Neirofiziologiya/Neurophysiology, Vol. 37, No. 1, pp. 32–38, January–February, 2005.     

An Integrated Computational Approach to Rationalize the Activity of Non-Zinc-Binding MMP-2 Inhibitors

Matrix metalloproteinases are a family of Zn-proteases involved in tissue remodeling and in many pathological conditions. Among them MMP-2 is one of the most relevant target in anticancer therapy. Commonly, MMP inhibitors contain a functional group able to bind the zinc ion and responsible for undesired side effects. The discovery of potent and selective MMP inhibitors not bearing a zinc-binding group is arising for some MMP family members and represents a new opportunity to find selective and non toxic inhibitors.In this work we attempted to get more insight on the inhibition process of MMP-2 by two non-zinc-binding inhibitors, applying a general protocol that combines several computational tools (docking, Molecular Dynamics and Quantum Chemical calculations), that all together contribute to rationalize experimental inhibition data. Molecular Dynamics studies showed both structural and mechanical-dynamical effects produced by the ligands not disclosed by docking analysis. Thermodynamic Integration provided relative binding free energies consistent with experimentally observed activity data. Quantum Chemical calculations of the tautomeric equilibrium involving the most active ligand completed the picture of the binding process. Our study highlights the crucial role of the specificity loop and suggests that enthalpic effect predominates over the entropic one.     

A Bioluminescence Method for the Measurement of l-Glutamate: Applications to the Study of Changes in the Release of l-Glutamate from Lateral Geniculate Nucleus and Superior Colliculus After Visual Cortex Ablation in Rats

We have developed a rapid, simple, specific, and very sensitive bioluminescence method for the measurement of L-glutamate (L-Glu). Oxidation of L-Glu by glutamate dehydrogenase has been coupled with bacterial FMN reductase and luciferase. Light production (i.e., peak height or integral) was linear from less than 0.5 to 500 pmol of L-Glu. Potential interfering substances that may be encountered in brain tissue have been identified. The most potent inhibitors were ascorbate and the biogenic amines. Procedures that conferred long-term stability of the reagent mixture (greater than 8 h) were established. Bioluminescence analysis of L-Glu content in brain tissue extracts, fractions from release experiments, and human CSF corroborated respective results obtained by HPLC analysis. In this study, we have applied the method to monitor changes in the KCl-evoked release of endogenous L-Glu from milligram amounts of brain tissue, i.e., from lateral geniculate nucleus and superior colliculus after visual cortex ablation.     

A Comparison of Biochemical Indices of 5-Hydroxytryptaminergic Neuronal Activity Following Electrical Stimulation of the Dorsal Raphe Nucleus

The activity of 5-hydroxytryptaminergic neurons has been estimated from measurements of: concentrations of 5-hydroxyindoleacetic acid; the ratio of the concentrations of 5-hydroxyindoleacetic acid to 5-hydroxytryptamine; the rate of accumulation of 5-hydroxytryptophan following the administration of an aromatic L-amino acid decarboxylase inhibitor (e.g., NSD 1015); the rate of accumulation of 5-hydroxytryptamine, and the rate of decline of 5-hydroxyindoleacetic acid following the administration of a monoamine oxidase inhibitor (e.g., pargyline). The purpose of the present study was to compare these different methods under conditions of changing neuronal impulse traffic produced by electrical stimulation of 5-hydroxytryptaminergic neurons. Male rats anesthetized with chloral hydrate were killed following 0, 15, or 30 min of electrical stimulation of the dorsal raphe nucleus at a frequency of 0, 5, or 10 Hz. The concentrations of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, and 5-hydroxytryptophan in nucleus accumbens, amygdala, suprachiasmatic nucleus, and dorsomedial nucleus were measured using HPLC coupled to an electrochemical detector. In each brain region, stimulation elicited an increase in the concentration of 5-hydroxyindoleacetic acid and the 5-hydroxyindoleacetic acid/5-hydroxytryptamine concentration ratio in saline-treated animals and an increase in 5-hydroxytryptophan accumulation in NSD 1015-treated animals, but did not alter the concentration of 5-hydroxytryptamine or 5-hydroxyindoleacetic acid in pargyline-treated rats. The results o f this study indicate that although the first three methods serve as valid indices of 5-hydroxytryptaminergic neuronal activity, the pargyline-dependent techniques are not responsive to changes in the rate of 5-hydroxytryptamine nerve firing.     

Evidence for Glutamatergic Projections from the Cochlear Nucleus to the Superior Olive and the Ventral Nucleus of the Lateral Lemniscus

Abstract: This study attempts to determine if projections ascending from the guinea pig cochlear nucleus (CN) could be glutamatergic and/or aspartatergic. Multiple radio frequency lesions were made to ablate the right CN. The ablation was verified histologically. To identify the principal targets of CN efferents, silver impregnation methods were used to localize the preterminal degeneration of fibers in transverse sections of the brainstem 5 and 7 days after CN ablation. CN efferents projected heavily to the lateral superior olive (LSO) ipsilaterally, the medial superior olive (MSO) bilaterally, and contralaterally to the medial (MNTB) and ventral (VNTB) nuclei of the trapezoid body, the ventral (VNLL) and intermediate nuclei of the lateral lemniscus and the central nucleus of the inferior colliculus (ICc). There were smaller projections to the lateral nucleus of the trapezoid body ipsilaterally, the dorsal and dorsomedial periolivary nuclei bilaterally, and the dorsal nucleus of the lateral lemniscus contralaterally. There were sparse projections to the VNLL and ICc ipsilaterally and the CN contralaterally, and a very sparse projection to the contralateral LSO. To determine if CN efferents were glutamatergic and/or aspartatergic, the fresh brainstem was sectioned transversely and samples of the LSO, MSO, MNTB, VNLL, and ICc were taken to measure the electrically evoked release and the uptake of d -[³H]Asp and [¹⁴C]Gly or [¹⁴C]GABA 3–5 days after the CN ablation. The release studies suggest that only certain of the histologically identified projections ascending from the CN may be glutamatergic and/or aspartatergic. CN ablation depressed d -[³H]Asp release in the MSO bilaterally and in the contralateral MNTB and VNLL, suggesting that the CN efferents to these nuclei may use glutamate or aspartate as a transmitter. It was unclear whether a marginal depression of d -[³H]Asp release in the ipsilateral LSO reflected the presence of glutamatergic CN projections to this nucleus. d -[³H]Asp release in the ICc was unaffected, suggesting that CN efferents to this nucleus may not be glutamatergic. There were no deficits in d -[³H]Asp uptake. [¹⁴C]Gly release from the LSO and MSO was unchanged. [¹⁴C]Gly uptake was unchanged in the MSO and depressed only in the contralateral LSO, possibly reflecting subnormal uptake activity in endings contributed by contralateral MNTB cells that had lost their CN efferents. [¹⁴C]GABA uptake in the MNTB, VNLL, and ICc was unchanged. [¹⁴C]GABA release was unchanged in the VNLL and ICc. [¹⁴C]GABA release was depressed only in the contralateral MNTB, possibly reflecting the loss of a small complement of GABAergic CN efferents and the reaction of GABAergic projections from the contralateral VNTB to their loss of CN efferents.     

Neuronal Types in the Human Anterior Ventral Thalamic Nucleus: A Golgi Study

Neurons in the anterior ventral (AV) thalamic nucleus of human adults were impregnated by Golgi-Kopsch impregnation method. Results showed that at least three morphological types of neurons could be recognized in the human AV thalamic nucleus. Type I neurons were medium to large with rich dendritic arborization. Both tufted and radiating dendritic branching patterns were seen in almost every neuron of this type. Only the initial axonal segments of these cells were impregnated suggesting that these axons were heavily myelinated. Type II neurons were medium in size with poor to moderate dendritic arborization. Many of these cells possess a few dendritic grape-like appendages. Long segments (up to 300 μm) of their axons were impregnated suggesting that these axons were either unmyelinated or thinly myelinated. These axons change their direction and form loops very often. No local branches were seen for these axons suggesting that they could be projection axons. Type III neurons were small with only one or two dendrites with poor arborization. No axons for these cells were seen in this study. The three neuronal types in the human AV thalamic nucleus were compared with neuronal types already described in other thalamic nuclei of human and non-human species. The results of this study might provide a morphological basis for further electrophysiological and / or pathological studies.     

鱼类三叉神经运动核的形态学研究

目的:应用生物胞素法观察罗非鱼三叉神经运动核的形态及细胞分布特征.方法:本实验用罗非鱼,15只(性别不限),体长12～16 cm,动物浸入140 mg/L三卡因间氨苯酸乙脂甲磺酸盐{tricaine methanesulfonate (MS222)}溶液中麻醉,在手术显微镜下暴露神经,通过生物胞素(Biocytin)结晶追踪技术研究定位硬骨鱼类三叉神经运动核的形态及细胞分布.结果:①硬骨鱼类罗非鱼的三叉神经运动核分为腹侧和背侧两组细胞群.②三叉神经根注入列中两组细胞群都能观察到被标记的细胞.下颌神经注入列中被标记的细胞以背侧群为主.上颌神经及眼神经注入列中两群细胞都没有发现被标记细胞,但上颌神经组中能观察到神经终末及突触联系.结论:硬骨鱼类罗非鱼的三叉神经运动核分为两组细胞群.三叉神经运动核发出的纤维走行于下颌神经内.     

Effect of Unilateral Decortication on Choline Acetyltransferase Activity in the Nucleus Basalis and Other Areas of the Rat Brain

Acetyl-coenzyme A: choline O-acetyltransferase (EC 2.3.1.6) (ChAT) enzyme activity was measured in the nucleus basalis and other microscopically identified brain areas at various times after unilateral cortical lesions were made in the rat. Initially, a significant decrease in ChAT activity was detected in the nucleus basalis ipsilateral to the lesion. However, after 120 days ChAT activity had apparently recovered, as levels of the enzyme at that time were not significantly different from control values. No changes in ChAT activity could be detected in any of the other brain areas similarly studied. The significance of these findings and their relationship to the morphological changes seen in neurones of the nucleus basalis after cortical lesions are discussed.