Thalamus & related systems最新文献

Advances in the neurosciences and functional neurosurgery have led to a renaissance in the use of brain stimulation technology. A number of intractable neurological disorders can now be safely and successfully treated with brain stimulation. Although this technique was first performed over 50 years ago, it has only now begun to reach its vast clinical potential. This article will provide a historical overview of brain stimulation, describe state-of-the-art clinical applications, and discuss future prospects in this rapidly advancing field.

Thalamic and cortical neurons are richly and reciprocally interconnected and support recurrent functional loops in the intact brain, but the role of this circuitry is still poorly understood. Here, we present evidence—from cellular and from functional neuroimaging in control and clinical domains—that thalamocortical resonance is not only a prerequisite for normal cognition, but that its perturbation, in a dynamic sense (e.g. a dysrhythmia) can underlie a variety of neurological and psychiatric disorders.

High-frequency electrical stimulation (deep brain stimulation (DBS)) of the thalamus and basal ganglia (subthalamic nucleus, internal segment of the globus pallidus) is used to treat motor disorders arising in Parkinson’s disease, multiple sclerosis, and essential tremor. Although clinically effective, the mechanisms of action of DBS are unknown. A number of plausible hypotheses have been offered, however, until the effects of the applied current on the surrounding neurons are understood, it will prove difficult to determine the underlying mechanisms. Computational models of central neurons were used to determine what neural elements are activated by extracellular stimulation. Thresholds for activation of local cells and axons of passage were similar with conventional stimuli. With electrodes positioned over the cell body, action potential initiation invariably occurred in the axon. As a result, activity generated by extracellular stimulation could vary between the soma and axon of the same neuron. Additionally, extracellular chronaxie times were insensitive to the neural element (cell versus axon) that was stimulated. The non-specific activation that occurs with conventional stimuli complicates the determination of the mechanisms of action and may contribute to side effects. Novel asymmetrical stimuli were developed that enable selective stimulation of different populations of neural elements. Understanding the effects of extracellular stimulation on central neurons will limit the plausible hypotheses to explain the effects of DBS, and lead to new stimulation technologies that will improve clinical efficacy.

The suprachiasmatic nucleus (SCN) projections to the midline and intralaminar thalamic nuclei were examined in the rat. Stereotaxic injections of the retrograde tracer cholera toxin-β subunit (CTb) were made in 12 different thalamic sites. These included individual midline thalamic nuclei (anterior, middle, and posterior portions of the paraventricular thalamic nucleus (PVT), intermediodorsal, paratenial, rhomboid, or reuniens nuclei) and intralaminar thalamic nuclei (lateral parafascicular, central lateral, or central medial nuclei) as well as the mediodorsal and anteroventral thalamic nuclei. After 10–14 days survival, the brains from these animals were processed histochemically and the distribution of retrogradely-labeled neurons was mapped throughout the rostralcaudal extent of the SCN. Within this collective group of midline and intralaminar thalamic nuclei, the only region innervated by the SCN was the PVT. Approximately 80% of this projection arose from the dorsomedial SCN, and the remaining projection originated from the ventrolateral SCN which targeted mainly the anterior division of the PVT. Virtually no SCN neurons were labeled after CTb injections centered in any of the other midline thalamic nuclei, which includes the intermediodorsal, mediodorsal, paratenial, rhomboid, or reuniens thalamic nuclei. Similarly, no evidence for a SCN projection to the intralaminar thalamic nuclei was found. The discussion focuses on the role of SCN→PVT pathway in modulating cerebral cortical functions.

The thalamus of the spiny rat Proechimys guyannensis (casiragua), a common rodent of the Amazon basin, was investigated with immunohistochemistry, using as markers GABA and glutamic acid decarboxylase, and calcium binding proteins. As in all mammals, GABAergic neurons containing also parvalbumin filled the reticular nucleus, and GABAergic cells were seen in the dorsal lateral geniculate nucleus. At variance with the laboratory rat, GABAergic and parvalbumin-containing neurons were also seen in the laterodorsal and anterodorsal nuclei, in which the two markers were co-distributed. Calbindin-immunopositive cells were widely distributed in dorsal thalamic domains, except for the intralaminar nuclei, and prevailed in the laterodorsal nucleus. The distribution of calretinin-immunopositive neurons was more restricted, and they were especially concentrated in the laterodorsal and midline nuclei.

At variance with the laboratory rat, in which systemic pilocarpine administration induces status epilepticus and results in chronic limbic epilepsy, pilocarpine elicited in casiragua an acute seizure that was not followed by spontaneous seizures up to 1 month, when changes were evaluated in the thalamus using also image analysis. Parvalbumin immunostaining in reticular nucleus neurons and in the dorsal thalamus neuropil, and the number of parvalbumin-positive and GABAergic cells in the laterodorsal and anterodorsal nuclei, exhibited an increase with respect to controls. Calbindin immunostaining was also enhanced, whereas calretinin immunostaining was mostly reduced, but was preserved in midline neurons. The findings show, after an acute seizure induced in an animal model of anti-convulsant mechanisms, regional long-term neurochemical alterations that could reflect functional changes in inhibitory and excitatory thalamic neurons.

The effects of different dendritic geometries and distal dendritic Na⁺ current distributions on the propagation of action potentials (APs) and sensory EPSPs were investigated using a multi-compartment model of thalamocortical (TC) neurones where the somatic and proximal dendritic distribution of voltage-gated channels matched the ones measured experimentally, i.e. a uniform distribution of K⁺ currents and a non-uniform distribution of Na⁺ and T-type Ca²⁺ currents.

Our simulations indicated that the distal dendritic Na⁺ channel density has not to be larger than 50% of the somatic density in order to reproduce the electrical activities recorded experimentally from the soma and proximal dendrites of TC neurones. Moreover, we could highlight the existence of a distinct threshold density of distal dendritic Na⁺ channels necessary to support the regeneration of APs in this part of the dendritic tree: this threshold density was smaller for non-branching than for heavily branching dendrites.

The amplitude of the somatic EPSP mainly depended on the number of simultaneously activated synapses on any dendritic branch, despite large differences in the size of the dendritic EPSPs. The amplitude of the EPSP on a proximal dendrite was also dependent on the number and relative location of simultaneously activated synapses on all other proximal dendritic branches. The dendritic geometry did not affect these features of the simulated sensory EPSPs. In addition, the duration of somatic and proximal dendritic EPSPs was markedly increased (100%) in the presence of somatic and proximal dendritic T-type Ca²⁺ current.

The backpropagation of EPSPs to distal dendrites was affected by the dendritic Na⁺ channel distributions, but even in the absence of distal dendritic Na⁺ channels the EPSP reached the dendritic ends with less than 40% decrease in amplitude. Overall, the amplitude of the backpropagating EPSP was not greatly affected by the dendritic geometry, though a smaller amplitude reduction in unbranched than in heavily branching dendrites was observed.

We studied the synchronous cortical and thalamic activities induced by low (0.5–1 mM) and high (50–100 mM) concentrations of the K⁺ channel blocker 4-aminopyridine (4AP) in a rat thalamocortical preparation. The presence of reciprocal thalamocortical connectivity was documented by diffusion of the fluorescent tracer Di-IC₁₈ between the somatosensory cortex and the ventrobasal complex (VB) of the thalamus in vitro. Functional reciprocal connectivity was also demonstrated by stimulating the cortical middle-deep layers (which elicited orthodromic responses in VB) or the VB (which induced orthodromic and antidromic responses in the cortex). Spontaneous field potentials were not recorded in either the thalamus or cortex in control medium. Low concentrations of 4AP produced local spindle-like rhythmic oscillations in cortex and VB (duration=0.4–3.5 s; frequency=9–16 Hz). In contrast, high concentrations of 4AP induced widespread ictal-like epileptiform discharges (duration=8–45 s) characterised by a ‘tonic’ component followed by a period of ‘clonic’ discharges in both cortex and VB. Spindle-like activity was abolished in cortex and thalamus by applying the excitatory amino acid receptor antagonist kynurenic acid in VB. In contrast, the same procedure exacerbated ictal-like discharges, while depressing VB activity. Our results indicate that thalamus and cortex can produce synchronous activities in this in vitro thalamocortical network: spindle-like rhythmic oscillations are generated at the thalamic level and imposed upon the cortical network whereas ictal-like discharges have a cortical origin and are modulated by the thalamic network activity. In addition, we have shown that it is possible to preserve reciprocal projections between cortex and thalamus in an in vitro rat slice preparation that could be a valuable tool to study epileptic-prone rat strains.

Intrathalamic oscillations related to sleep and epilepsy depend on interactions between synaptic mechanisms and intrinsic membrane excitability. One intrinsic conductance implicated in the genesis of thalamic oscillations is the H-current — a cationic current activated by membrane hyperpolarization. Activation of H-current promotes rebound excitation of thalamic relay neurons and can thus enhance recurrent network activity.

We examined the effects of H-current modulation on bicuculline-enhanced network oscillations (2–4 Hz) in rat thalamic slices. The adrenergic agonist norepinephrine, a known regulator of H-current, caused an alteration of the internal structure of the oscillations — they were enhanced and accelerated as the interval between bursts was shortened. The acceleration was blocked by the β-adrenergic antagonist propranolol. The β-agonist isoproterenol mimicked the effect of norepinephrine on oscillation frequency and truncated the responses suggesting that a β-adrenergic up-regulation of H-current modifies the internal structure (frequency) of thalamic oscillations. Consistent with this, we found that H-channel blockade by Cs⁺ or ZD7288 could decelerate the oscillations and produce more robust (longer lasting) responses. High concentrations of either Cs⁺ or ZD7288 blocked the oscillations.

These results indicate that a critical amount of H-current is necessary for optimal intrathalamic oscillations in the delta frequency range. Up- or down-regulation of H-current alter not only the oscillation frequency but also retard or promote the development of thalamic synchronous oscillations. This conclusion has important implications regarding the development of epilepsy in thalamocortical circuits.

Voltage-activated calcium channels in thalamic neurons are considered important elements in the generation of thalamocortical burst firing during periods of electroencephalographic synchronization. A potent counterpart of calcium-mediated depolarization may reside in the activation of calcium-dependent potassium conductances. In the present study, thalamocortical relay cells that were acutely dissociated from the rat ventrobasal thalamic complex (VB) were studied using whole-cell patch-clamp techniques. The calcium-dependent potassium-current (I_K(Ca)) was evident as a slowly activating component of outward current sensitive to the calcium ions (Ca²⁺)-channel blocker methoxyverapamil (10 μM) and to substitution of external calcium by manganese. The I_K(Ca) was blocked by tetraethylammonium chloride (1 mM) and iberiotoxin (100 nM), but not apamin (1 μM). In addition, isolated VB neurons were immunopositive to anti-α_(913–926) antibody, a sequence-directed antibody to the α-subunit of “big” Ca²⁺-dependent K⁺-channel (BK_Ca) channels. Activators of the adenylyl cyclase cyclic adenosine monophosphate (cAMP) system, such as forskolin (20 μM), dibutyryl-cAMP (10 mM) and 3-isobutyl-1-methylxanthine (500 μM), selectively and reversibly suppressed I_K(Ca). These results suggest that a rise in intracellular cAMP level leads to a decrease in a calcium-dependent potassium conductance presumably mediated via BK_Ca type channels, thereby providing an additional mechanism by which neurotransmitter systems are able to control electrogenic activity in thalamocortical neurons and circuits during various states of electroencephalographic synchronization and de-synchronization.