Anesthetics are used extensively clinically and in research. However, the mechanisms by which anesthetics act to produce the desired end-points of unconsciousness, amnesia and immobility are only beginning to be understood. Recent evidence indicates that the immobilizing effect of anesthetics occurs largely in the spinal cord, whereas it is assumed that the sedative and amnesic actions occur in the brain. Our recent studies, however, indicate that anesthetics exert an indirect, spinal effect on reticulo-thalamo-cortical mechanisms of arousal and, thus, might affect consciousness and memory. These data are consistent with reports of reduced anesthetic requirements for sedation during neuroaxial blockade by spinal anesthesia. The presumed mechanism is decreased afferent impulses to the brain, which reduces arousal and, thereby, reduces sedative requirements. We have used the complementary approaches of single-unit recording and intracranial electrical stimulation to investigate the effects of a common inhaled anesthetic, isoflurane, on reticulo-thalamo-cortical arousal in a goat preparation. The excitatory responses of single neurons in the midbrain reticular formation (MRF) to noxious somatic stimulation are significantly attenuated when the concentration of systemically delivered isoflurane was increased above 1 MAC (the minimum alveolar concentration required to prevent coordinated movement in response to a noxious stimulus), in parallel with a loss of stimulus-evoked desynchronization of the cortical electroencephalogram (EEG). Part of this depressant effect is mediated indirectly in the spinal cord because selectively reducing the concentration of isoflurane delivered differentially to the spinal cord enhances MRF neuronal responses and cortical arousal. In goats anesthetized with isoflurane at ∼1 MAC, electrical stimulation at distinct sites, including the MRF, peduncolopontine tegmentum (PTT), and medial/intralaminar thalamus, elicits desynchronization of the cortical EEG. Increasing the concentration of isoflurane above 1 MAC abolished this effect. In goats prepared for differential delivery of anesthetic to the cranial and torso (spinal) circulations, electrical stimulation in the medial thalamus elicits greater cortical desynchronization at lower currents when the concentration of isoflurane delivered to the spinal cord is reduced while maintaining the cranial isoflurane concentration ≥1 MAC. These results indicate that the depressant effect of isoflurane anesthesia on spinal somatosensory transmission indirectly influences the threshold for reticulo-thalamo-cortical arousal.

In thalamocortical neurons relaying sensory information, we recently described a phosphorylation mechanism that induces a marked increase in the amplitude of the low-voltage activated Ca2+ current (T-type). Surprisingly, potentiation of the T-current closely depends on the state of the channel and is, therefore, both voltage- and ATP-dependent. Further analysis of the modification of channel activity induced by this regulation, and underlying the increase in the macroscopic current amplitude, requires a detailed study of the T-current biophysical properties that, unfortunately, might be constrained by the technical limitations of whole-cell recordings. Therefore, in the present study we have developed an alternative approach that is based on computational models of T-channel activity using Markov gating schemes. We show that both modifications in the activation kinetics of the channels and/or the existence of a second channel population with a conducting state conditioned by a phosphorylation step can explain the specific properties of T-currents that have been observed in thalamocortical neurons as a result of their ATP/voltage-dependent regulation. The flexibility in the T-type current behavior that is incorporated in these models might also help to unravel new roles for T-channels in shaping the different firing properties of thalamocortical neurons.

Both the thalamocortical and limbic systems generate a variety of brain state-dependent rhythms but the relationship between the oscillatory families is not well understood. Transfer of information across structures can be controlled by oscillations. We suggest that slow oscillation of the neocortex, which was discovered by Mircea Steriade, temporally coordinates the self-organized oscillations in the neocortex, entorhinal cortex, subiculum and hippocampus. Transient coupling between rhythms can guide bidirectional information transfer among these structures and might serve to consolidate memory traces.

Previous studies have demonstrated that peripheral inflammation leads to long-term increases in spinal dorsal horn neuronal excitability (i.e. central sensitization) and behavioral hyperalgesia that is mediated by glutamate receptor activation. The present study has examined spinal cord changes in serine phosphorylation of the NMDA receptor NR1 and AMPA receptor GluR1 subunits after peripheral inflammation. Using site-specific antibodies, Western blots showed a significant increase in phosphorylation at serine residues 896 and 897 of the NR1 and at serine residues 831 and 845 of the GluR1 subunits in the rat spinal cord after injection of complete Freund's adjuvant into the hindpaw. For all four serine sites, the increased phosphoserine NR1 and GluR1 levels occurred as early as 10 minutes, lasted for at least 3 days, and returned to control level 7–14 days following inflammation. There was also an increase in total NR1 and GluR1 proteins after inflammation, but with a different time course. The phosphorylation of different serine residues of NR1 and GluR1 depended on input from the injured site. Local anesthesia of the inflamed paw with lidocaine (2%), blocked the increase in phosphoserine 896 (NR1) and phosphoserine 831 (GluR1) with a time course corresponding to the duration of anesthesia. However, the increased phosphoserine 845 (GluR1) was blocked only transiently and the concentration of phosphoserine 897 (NR1) was not affected by local anesthesia. Consistent with previous biochemical analysis, phosphorylation of serine 896 NR1 and serine 831 of GluR1 was blocked by intrathecal chelerythrine (0.01–1 nmol), a PKC inhibitor, and phosphorylation of serine 897 NR1 was blocked by H-89 (0.01–1 nmol), a PKA inhibitor. In addition, there appeared to be an interaction between the PKC and PKA cellular pathways because phosphorylation of serine 897 of NR1, a substrate of PKA, was also blocked by chelerythrine. These findings correlate serine phosphorylation of the NR1 and GluR1 subunits to spinal hyperexcitability and hyperalgesia, and indicate a role of serine phosphorylation of NMDA and AMPA receptors in initiating central sensitization.

We have studied circuit activities in layer IV of rat somatosensory barrel cortex that contains microgyri induced by neonatal freeze lesions. Structural abnormalities in GABA-containing interneurons are present in the epileptogenic paramicrogyral area (PMG). We therefore tested the hypothesis that decreased postsynaptic inhibition within barrel microcircuits occurs in the PMG and contributes to epileptogenesis when thalamocortical afferents are activated. In thalamocortical (TC) slices from naïve animals, single electrical stimuli within the thalamic ventrobasal (VB) nucleus evoked transient cortical multi-unit activity lasting 65 ± 42 msec. Similar stimuli in TC slices from lesioned barrel cortex elicited prolonged (850 ± 100 msec) paroxysmal discharges that originated in the PMG and propagated laterally over several mm. The duration of paroxysmal discharges were shortened by ∼70% when APV was applied and were abolished by CNQX. The cortical paroxysmal discharges did not evoke thalamic oscillations. Whole-cell patch-clamp recordings show that there is a shift in the balance of TC-evoked responses in the PMG that favors excitation over inhibition. Dual, whole-cell recordings in layer IV of the PMG indicated that selective loss of inhibition from fast-spiking interneurons to spiny neurons in the barrel circuits is likely to contribute to unconstrained cortical recurrent excitation with generation and spread of paroxysmal discharges.

Recent findings in two rat models of absence epilepsy, the Wistar Albino Glaxo Rats from Rijswik (WAG/Rij) and the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), support the idea that defects in the function of hyperpolarization-activated, cyclic nucleotide-gated cation channels (HCN1-4) and the resulting membrane current, Ih, in thalamocortical relay neurons are crucially involved in epilepsy. After a developmental evolution the expression of HCN1, which is relatively insensitive to cAMP, is elevated significantly in epileptic rats with no changes in expression of the other isoforms. This is accompanied by a hyperpolarizing shift in Ih activation and reduced sensitivity to cAMP. Thus, modification of thalamic Ih occurs at pre-epileptic stages and seems to be crucial to the development of spike-and-wave-discharges that characterize absence seizures.

Thalamic relay neurons have homogeneous, adult-like firing properties and similar morphology by 12 days postnatally (PN 12). Parafascicular (Pf) neurons have a different morphology compared with typical thalamic relay neurons, but the development of their electrophysiological properties is not well studied. Intracellular recordings in PN 12–50 Pf neurons revealed several heterogeneous firing patterns different from those in thalamic relay neurons. Two types of cells were identified: Type I cells displayed a fast afterhyperpolarization (AHP) followed by a large-amplitude, slow AHP; whereas Type II cells had only a fast AHP. These cell types had overlapping membrane properties but differences in excitability. Some properties of Pf neurons were adult-like by PN 12, but, unlike thalamic relay neurons, there were significant maturational changes thereafter, including decreased action potential (AP) duration, increased fast AHP amplitude and increased excitability. Pf neurons did not exhibit rhythmic bursting and generally lacked low-threshold spike (LTS) responses that characterize thalamic relay neurons. Pf neurons exhibited non-linear I-V relationships, and only a third of the cells expressed the time and voltage-dependent hyperpolarization activated (Ih) current, which declined with age. These results indicate that the morphological differences between Pf neurons and typical thalamic relay neurons are paralleled by electrophysiological differences, and that Pf membrane properties change during postnatal development.

Layer 4 of the mouse somatosensory (barrel) cortex has a diversity of interneuron cell types. Tonic inhibition in other regions is cell type-specific and mediated, in part, by δ-subunit containing, extrasynaptic, GABAA receptors. We have investigated tonic inhibition in LTS cells, a major type of inhibitory neuron, and excitatory cells in layer 4 of the mouse barrel cortex using 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridine-3-ol (THIP), a superagonist of these receptors. Bath application of 20 µM THIP produced baseline shifts, which indicates activation of tonic inhibition of both excitatory and LTS cells. The baseline shift was significantly larger in LTS cells. This finding of greater induced current in LTS cells was paralleled by a significantly greater increase in conductance with THIP application in LTS cells. The increase in conductance resulted in LTS cells requiring more current to reach threshold. Because of the differential effects of tonic inhibition on LTS cells and excitatory cells, bath application of THIP increased the network excitability, measured by multi-unit recordings. Thus, the network effect of tonic inhibition in horizontal layer 4 circuits is a paradoxical increase in excitation.

The absence epilepsies are characterized by recurrent episodes of loss of consciousness associated with generalized spike-and-wave discharges, with an abrupt onset and offset, in the thalamocortical system. In the absence of detailed neurophysiological studies in humans, many of the concepts regarding the pathophysiological basis of absence seizures are based on studies in animal models. Each of these models has its particular strengths and limitations, and the validity of findings from these models for the human condition cannot be assumed. Consequently, studies in different models have produced some conflicting findings and conclusions. A long-standing concept, based primarily from studies in vivo in cats and in vitro brain slices, is that these paroxysmal electrical events develop suddenly from sleep-related spindle oscillations. More specifically, it is proposed that the initial mechanisms that underlie absence-related spike-and-wave discharges are located in the thalamus, involving especially the thalamic reticular nucleus. By contrast, more recent studies in well-established, genetic models of absence epilepsy in rats demonstrate that spike-and-wave discharges originate in a cortical focus and develop from a wake-related natural corticothalamic sensorimotor rhythm. In this review we integrate recent findings showing that, in both the thalamus and the neocortex, genetically-determined, absence-related spike-and-wave discharges are the manifestation of hypersynchronized, cellular, rhythmic excitations and inhibitions that result from a combination of complex, intrinsic, synaptic mechanisms. Arguments are put forward supporting the hypothesis that layer VI corticothalamic neurons act as ‘drivers’ in the generation of spike-and-wave discharges in the somatosensory thalamocortical system that result in corticothalamic resonances particularly initially involving the thalamic reticular nucleus. However an important unresolved question is: what are the cellular and network mechanisms responsible for the switch from physiological, wake-related, natural oscillations into pathological spike-and-wave discharges? We speculate on possible answers to this, building particularly on recent findings from genetic models in rats.

Activation of cyclic AMP response element-binding protein (CREB) in the spinal dorsal horn may be a crucial contributor to the activity-dependent synaptic plasticity that is thought to underlie the development of persistent pain following peripheral nerve injury. In this study, we examined the early period of CREB activation following chronic constriction injury (loose ligation) of the sciatic nerve in rats. The estimated levels of Ser133-phosphorylated (activated) CREB significantly increased at 2 hours (424 ± 85%) and remained elevated at 4 hours (349 ± 97%) and 8 hours (258 ± 69%) after sciatic ligation compared with control animals. By contrast, activated CREB levels in sham-operated animals were not significantly greater than in control animals except at 1 hour (176 ± 6%) and 8 hours (288 ± 16%). The maximal ligation-associated activation of CREB at 2 hours occurred bilaterally and was dependent, at least partly, on NMDA-receptor activation because pretreatment with 20 µg MK-801 significantly attenuated the ligation-associated activation of CREB. The levels of non-phosphorylated CREB in ligated and sham-operated animals did not differ significantly from controls at the time-points examined.

These data establish a significant, persistent increase in CREB phosphorylation within hours of loose ligation of the sciatic nerve and indicate an early but consequential injury-related shift in the manner in which spinal dorsal horn neurons processed sensory information. The data lend further support to the notion that ligation-associated CREB-dependent synaptic plasticity in the spinal dorsal horn might underlie the development of persistent pain following peripheral nerve injury.

As established in early studies, the basalo-cortical system serves as an extra-thalamic relay from the brainstem reticular activating system to the cerebral cortex. As Mircea Steriade documented, activating impulses are transmitted through either the nonspecific thalamo-cortical projection system or the basalo-cortical projection system to stimulate widespread, fast, cortical activity that is characteristic of the activation that occurs naturally during waking (W) and paradoxical sleep (PS) states. However, basal forebrain (BF) neurons are different from thalamic neurons in several ways. First, many cortically projecting BF neurons utilize acetylcholine (ACh), which has a crucial role in stimulating fast cortical activity. Second, ACh-releasing neurons discharge selectively during W and PS and cease firing during slow-wave sleep (SWS). Third, ACh-releasing neurons discharge rhythmically in bursts during cortical activation and can, thus, modulate the cortex in a slow rhythmic manner to facilitate coherent activity across broad cortical networks. Fourth, the rhythmic discharge by BF neurons that release ACh, GABA or glutamate and project to the cortex occurs at respiratory or theta frequencies of the olfactory and limbic cortices, which reveals the particular importance of these inputs as well as outputs within basalo-cortico-basalo circuits. Fifth, other noncholinergic BF neurons, including GABA-releasing neurons, are active selectively during sleep: some of these potentially promote slow-wave activity during SWS through cortical projections; and others might promote behavioral quiescence during SWS and PS through descending projections. Finally, BF neurons also project to the thalamus and might, thus, either recruit or join thalamic neurons in modulating cortical activity across the sleep–waking cycle.

Mircea Steriade exerted a powerful, driving influence on systems neuroscience for nearly five decades. Here, we review the case of a influential individual of another sort: a single thalamocortical (TC) neuron that exerts an extraordinary influence on fast-spike interneurons of somatosensory ‘barrel’ cortex. This cell was studied over a period of several days in an awake rabbit using methods of extracellular cross-correlation. In many ways, the influence of this TC neuron on topographically aligned fast-spike interneurons is typical of TC inputs to these cells, manifested as a fast-rising, very brief increase in postsynaptic spike probability. However, this TC neuron was distinct from other TC neurons studied because of the potency of that influence and the number of interneurons influenced. In one of these recipient interneurons, the probability of spike generation within a narrow window (0.7 msec) following a TC spike was 21%, and this value reached 53% for TC spikes with long preceding interspike intervals (conditions that allow recovery from chronic, activity-dependent depression at the TC synapse). Based on these data, we maintain that, in the awake state, spontaneous spikes of single TC neurons drive some classes of cortical neurons powerfully. Moreover, we suggest that neighboring TC neurons (like neuroscientists) vary greatly in their global ‘driving influence’ on recipient neocortical circuits, and that a few of these cells exert a disproportionate impact on cortical networks.

Visceral nociceptive responses to distention of the ureter, and responses to innocuous and noxious mechanical stimulation of the skin were recorded from neurons in the ventral posterior lateral nucleus of the thalamus in anesthetized rats. The ventral posterior lateral (VPL) neurons were classified by their responses to cutaneous stimuli as either low-threshold or wide-dynamic-range neurons. No high-threshold neurons were found in the population of VPL neurons sampled. Some VPL neurons that responded to distention of the ureter appeared to lack a cutaneous receptive field. The majority of VPL neurons that responded to noxious visceral stimulation of the ureter were classified as low-threshold neurons, based on their responses to cutaneous stimuli. Transection of the DC at an upper cervical level dramatically reduced the responses of VPL neurons to ureter distention and to innocuous mechanical stimulation of the skin, but the responses to noxious mechanical stimulation of the skin remained intact. Ureter distention and mechanical stimulation of the skin might activate dorsal horn neurons, including postsynaptic dorsal-column pathway (PSDC) neurons and spinothalamic tract (STT) cells. We conclude that both the DC pathway and the STT are likely to contribute to the visceral and somatic responses of some VPL neurons.

The over-inhibition of thalamic relay cells by hyperactivity of the internal part of the globus pallidus is a cornerstone of the parkinsonian pathophysiology that leads to a distortion of the thalamocortical dynamics called thalamocortical dysrhythmia (TCD). Here, we present the results of the stereotactic pallidothalamic tractotomy (PTT), which interrupts selectively the enhanced pallidal output to the thalamus in a restricted location in the fields of Forel. This operation represents a reactualization of Spiegel's campotomy. PTT was offered to 41 patients (66.1±8.5 years) suffering from chronic, therapy-resistant Parkinson's disease. It was performed bilaterally in 21 patients. Forty patients displayed mixed, i.e. tremulent and akinetic parkinsonian signs, and seven had drug-induced dyskinesias. One patient had only rest tremor. The evaluation was based on the Unified Parkinson's Disease Rating Scale (UPDRS) scores, comparing the patients' preoperative medicated state with the state at the last postoperative follow-up. We, thus, tested surgical success in terms of superiority to drug treatment. Mean follow-up was 22.4 months with 15 patients followed for >2 years. Mean improvement was 60% (P<0.001) for UPDRS III and 51% (P<0.001) for UPDRS II. Significant improvement (P<0.001) appeared in subscores for tremor (87%), limb akinesia (58%) and axial akinesia (33%). Improvement of postural stability and gait was at the limit of significance (P<0.05). Improvement of hypomimia and hypophonia did not reach statistical significance. Increase of dysarthria was significant (P<0.01). Intake of L-DOPA was reduced significantly and 21 patients were able to stop intake. Median improvement of the Quality of Life score was 67%. Improvement remained, independent of follow-up length. In conclusion, PTT provides a high, stable level of relief to parkinsonian patients whose condition cannot be controlled with pharmacotherapy. The rationale of the surgical therapy is based on a selective extrathalamic regulation of the parkinsonian TCD.

Recent work on the visual thalamic relays provides two key properties reviewed here. First, ∼95% of input to lateral geniculate relay cells is non-retinal and dynamically modulates the relay based on behavioral state, including attention. Part of this relates to control of a voltage-gated, low-threshold Ca2+ conductance that controls the relay cell response mode (tonic or burst). Second, the lateral geniculate nucleus and pulvinar are examples of two relay types: the former is a first order relay, transmitting subcortical (retinal) information, while the latter is mostly a higher order relay, transmitting information from layer 5 of one cortical area to another. Higher order relays seem to be important to corticocortical communication, which challenges the dogma that such communication is based on direct cortico–cortical connections. Other examples of first order and higher order relays also exist. Interesting differences in functional circuitry between first and higher order thalamic relays are beginning to accumulate, which indicate extramodulatory functions for higher order relays. Thus, the thalamus provides a behaviorally relevant, dynamic control over the nature of information relayed, and also plays a key role in basic cortico–cortical communication.

Although a tremendous honour, it is with great sadness that this review is dedicated to Mircea's memory. Mircea has been, not only an inspiration throughout my career, but a generous and supportive friend whose kindly, incisive criticism has been a constant reminder that what we study in vitro must eventually be understood in the context of the whole system. Quoting from the Preface to his elegant monograph ‘The evolution of work on extremely simplified preparations has reached the point where some investigators are not shy to jump from single-cell properties to global brain functions, such as arousal and sleep, paroxysmal events of the epileptic type, and even conscious thinking.’ (Steriade, 2001). Bearing in mind that the properties both of single neurons and the connections between them might vary in different brain states and in different phases of cortical rhythms, in this review I summarize studies of the local circuitry of the thalamo-recipient layers 4 and 6 focussing on results obtained with dual intracellular recordings and biocytin-labelling in adult neocortical slices.

This study examines the temporal properties of geniculocortical and corticogeniculate (CG) pathways that link the lateral geniculate nucleus (LGN) and primary visual cortex in the ferret. Using electrical stimulation in the LGN to evoke action potentials in geniculocortical and CG axons, results show that conduction latencies are significantly faster in geniculocortical neurons than in CG neurons. Within each pathway, axonal latency and visual physiology support the view of sub-classes of neurons. By examining the timing of visual responses and the latency of CG feedback, estimates indicate that visual information can reach the cortex and return to the LGN as early as 60 msec following the onset of a visual stimulus. These findings place constraints on the functional role of corticogeniculate feedback for visual processing.

The paraventricular thalamic nucleus (PVT) receives dense noradrenergic input, but little is known about α2 adrenoceptors (ARs) in this nucleus. We have investigated effects of the agonist α-methyl-norepinephrine (m-NE) on PVT neurons in vitro. Based on their physiological and morphological characteristics, three distinct classes of PVT neurons have been identified. The first class exhibits membrane hyperpolarization on stimulation with m-NE (0.05–25 µM). This hyperpolarizing effect is observed in the presence of tetrodotoxin (TTX; 0.5–1 µM), blocked by yohimbine (1 µM) and mimicked by clonidine (10 µM), which indicates that it is mediated by postsynaptic α2 ARs. Further experiments indicate that it is mediated through an increase in G protein-coupled K+ conductance. In a second class of neurons, m-NE (0.05–25 µM) induces a slow membrane depolarization that is mimicked by phenylephrine (5 µM) and blocked by prazosin (75 nM), which indicates the involvement of α1 ARs. The third class of neurons is insensitive to m-NE (5–25 µM), and has a lower input resistance and a larger dendritic tree compared to the two other classes. The three types of neurons differ in their resting properties, and their firing patterns are changed by m-NE. These findings indicate anatomical and functional specialization of PVT neurons.

Abnormal thalamocortical dynamics have been proposed as the underlying mechanism for a subset of neurological and psychiatric disorders that include centrally generated pain. Spectral analysis and independent component-based localization of neuromagnetic signals reveal ongoing theta-range activity localized to physiologically significant cortical regions in a group of subjects with well-characterized central and peripheral lesions. In addition, recordings from subjects who failed to obtain relief from spinal cord stimulation (SCS) and from those in whom SCS was successful further delineate thalamocortical dysrhythmias as a mechanism that underlies chronic pain.