Cerebro–cerebellar interactions are becoming progressively more focused in their anatomical substrate but their functional meaning is still elusive. Here, we review current data on the cerebellar influence on cortical function, with special emphasis on the importance of the cerebellar input for cortical processing in primary motor and sensorimotor areas. Differences in the intracortical processing of cerebellar information are described and the possible role of the thalamus in controlling cerebro–cerebellar loops discussed.

The responses of relay cells in the human thalamic ventral caudal nucleus (Vc) was explored in a set of experiments designed to study neuronal firing patterns evoked in humans by pain and thermal cutaneous stimuli. Cells responsive to cold or painful stimuli have been found to produce low threshold spike (LTS) bursting preferentially in response to these stimuli. This appears to be an intrinsic thalamic phenomenon and not a firing pattern produced by input from the periphery. Microstimulation within the Vc during awake surgical procedures demonstrates that cold and pain sensations can be evoked by short bursts of electrical stimuli in a pattern similar to that observed during neuronal LTS bursts. These results strongly suggest that that cold and pain sensations may be mediated in part by human thalamic LTS burst firing patterns.

The transcriptional mechanisms that govern the development and plasticity of somatopic sensory maps in the cerebral cortex have not been studied extensively. In particular, no studies have addressed the role of epigenetic mechanisms in the development of sensory maps. DNA methylation is one of the main epigenetic mechanisms by which mammalian cells regulate gene transcription. Demethylation results in embryonic lethality, so it has been very difficult to study the role of DNA methylation in brain development. We have used cre-loxP technology to generate forebrain-specific deletion of DNA methyltransferase 1 (Dnmt1), the enzyme required for the maintenance of DNA methylation. We find that DNA hypomethylation of neurons in the cerebral cortex results in the failure of development of somatosensory barrel cortex. We also find that, despite functional thalamocortical neurotransmission, thalamocortical long-term potentiation cannot be induced in slices from Emx1-cre;Dnmt1 mutant mice. These studies emphasize the importance of DNA methylation for the development of sensory maps and indicate that epigenetic mechanisms might play a role in the development of synaptic plasticity.

The somatotopic organization, mechanoreceptive field (RF) and response properties of nociceptive neurons in the ventral posteromedial thalamic nucleus (VPM) were studied in urethane/α-chloralose anesthetized rats. Microelectrode recordings were made of the activity of single neurons within VPM, and neurons were identified as either nociceptive [wide-dynamic-range (WDR), nociceptive-specific (NS)] or non-nociceptive [low-threshold mechanoreceptive (LTM)]. Of the 350 neurons tested, 317 responded to orofacial mechanical stimulation; all the RFs were contralateral. The incidence of NS neurons was significantly higher than that of WDR neurons (21.2% versus 4.2%) but LTM neurons were most common (62.9%). WDR and NS neurons were scattered among the LTM neurons in the VPM. NS neurons were significantly denser in rostral and caudal portions of VPM; most of the WDR neurons (87%) were located in the core of VPM. Neurons with an ophthalmic division RF were located most dorsally and those with a mandibular division RF most ventrally. The RF of most neurons (77%) was located in the maxillary region, with the RF of nociceptive neurons mainly in the intraoral region and that of most LTM neurons in the perioral region. The majority of LTM, WDR and NS neurons tested had a low spontaneous activity and there was a significant difference in spontaneous firing between WDR and NS neurons, and between WDR and LTM neurons. The mean mechanical activation threshold of NS neurons (195 ± 11.2 g) was significantly higher than that of WDR neurons (4.7 ± 1.3 g). Response magnitude and peak firing frequency to graded mechanical stimuli were significantly higher in the WDR neurons. These findings indicate significant differences in the spontaneous activity, RF and response properties between WDR and NS neurons in VPM. However, they also indicate that both types of nociceptive neurons can encode the spatial properties and intensity of a noxious orofacial stimulus and, thus, might contribute to the sensory-discriminative component of pain.

The Eph family of receptor tyrosine kinases and their partner ligands, the ephrins, mediate cell–cell interactions in the developing nervous system. Signaling events between Eph receptors and ephrin ligands on interacting cells affect the growth, maturation, migration and connectivity of individual neurons and neural networks. Here we review the known roles of Eph–ephrin signaling in the development of the thalamus and its connections, and pose new questions for experimental study.

Spindle oscillation is generated in intrathalamic circuits and thalamic reticular (RE) neurons act as pacemakers. To assess the consequences of this oscillation on membrane properties of RE neurons, we performed in vivo intracellular recordings in anesthetized cats during periods of intense synaptic activity, represented by spindle waves, compared to silent periods (interspindle lulls) that corresponded to a hyperpolarization of about −75 mV. During spindles, the massive activation of T-currents generated powerful low-threshold spikes (LTSs) that changed the membrane potential of RE cells by 10–20 mV and increased their membrane fluctuations by one order of magnitude (from 1–3 mV to 10 mV). Besides, the generation of LTSs decreased the apparent input resistance by ∼80% for ∼20–30 mseconds, in a cyclic way. The changes in basic membrane properties proved to be functionally significant for RE neurons, because both synaptic and intrinsic responsiveness were enhanced during active network states. Thus, synaptic responses tested by stimulating afferent (corticothalamic and thalamo-RE) pathways displayed increased spiking. The same result was found for intrinsic responses using positive and negative current pulses, and sinusoidal wave currents. Bursting discharges, responsible for the generation of the above changes, proved to be a very robust and reliable firing pattern in RE neurons. Our data demonstrate that ongoing network activity of RE neurons during spindle oscillations influence the expression of intrinsic properties of these pacemaking neurons, similarly to the previously shown effect exerted by spontaneously occurring synaptic activity on the intrinsic properties of thalamocortical and neocortical neurons.

Mechanisms underlying seizure cessation remain elusive. The Lennox-Gastaut syndrome, a severe childhood epileptic disorder, is characterized by episodes of seizure with alternating epochs of spike-wave and fast run discharges. In a detailed computational model that incorporates extracellular potassium dynamics, we studied the dynamics of these state transitions between slow and fast oscillations. We show that dynamic modulation of synaptic transmission can cause termination of paroxysmal activity. An activity-dependent shift in the balance between synaptic excitation and inhibition towards more excitation caused seizure termination by favoring the slow oscillatory state, which permits recovery of baseline extracellular potassium concentration. We found that slow synaptic depression and change in chloride reversal potential can have similar effects on the seizure dynamics. Our results indicate a novel role for synaptic dynamics during epileptic neural activity patterns.

Neurophysiological studies at the cellular level (microelectrode unit activity recordings and local field potentials) as well as electro- and magnetoencephalographic recordings provide converging evidence for a thalamocortical dysregulation at the source of chronic neurogenic pain of both peripheral and central origin. These indicate an increase of low frequency thalamocortical rhythmicity originating in disfacilitation of thalamic relay neurons, followed by cortical activation due to asymmetries of corticocortical inhibition. This process, called thalamocortical dysrhythmia, might become self-sustained and, thus, chronic due to recurrent thalamoreticulothalamic and corticoreticulothalamic feedback inhibition. Our surgical approach is centered on re-establishment of normal thalamocortical oscillatory activity using small, strategically placed medial thalamic and prethalamic lesions. These reduce the increased low frequency thalamocortical recurrent network activity via low frequency desamplification and thalamic disinhibition, providing long term therapeutic efficiency coupled with sparing of the specific thalamocortical loops.

This physiopathological framework should be helpful when considering differential mechanisms and treatment modalities for different types of chronic pain. It underscores the risks of any surgical procedure aiming at reducing further the activation of specific thalamic relay cells and, thus, increasing thalamic disfacilitation and dysrhythmic pain mechanisms. In addition, the normal low frequency generation by activation of the paralimbic and high order association networks provides, in the context of a well established thalamocorticothalamic divergent and, thus, interactive organization, a basis for understanding the relevance of the conceptual-affective internal environment in the maintenance and amplification of many chronic neurogenic pain situations.

We compared the developmental periods in the mouse when projections from the two eyes become segregated in the dorsal lateral geniculate nucleus with the time when this nucleus becomes innervated by cholinergic fibers from the brainstem. Changes in labeling patterns of different tracers injected into each eye revealed that segregation of retinogeniculate inputs commences at postnatal day five (P5) and is largely complete by P8. Immunocytochemical staining showed that cholinergic neurons are present in the parabrachial region of the brain stem on the day of birth. However, cholinergic fibers are not evident in the geniculate until P5, and these are sparse at this age, increasing in density to form well-defined clusters by P12. These results indicate that segregation of eye-specific projections during normal development is unlikely to be regulated by cholinergic inputs from the brainstem.

Chronic pain is an immense, unsolved, clinical problem. Current approaches to this condition are limited by uncertainty about mechanisms of acute and chronic pain in humans. Although much progress has been made toward understanding peripheral neural mechanisms of human nociception, we have a poor understanding of CNS pain mechanisms. Here, we review the anatomy and physiology of the ascending spinal pathways and supraspinal centers with pain-related activity. This review focuses on the primate nervous systems because there are significant differences between pain transmission in primates and other species such as cats and rats.