Upregulated and Hyperactivated Thalamic Connexin 43 Plays Important Roles in Pathomechanisms of Cognitive Impairment and Seizure of Autosomal Dominant Sleep-Related Hypermotor Epilepsy with S284L-Mutant α4 Subunit of Nicotinic ACh Receptor

To understand the pathomechanism and pathophysiology of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), we studied functional abnormalities of glutamatergic transmission in thalamocortical pathway from reticular thalamic nucleus (RTN), mediodorsal thalamic nucleus (MDTN) to orbitofrontal cortex (OFC) associated with S286L-mutant α4β2-nicotinic acetylcholine receptor (nAChR), and connexin43 (Cx43) hemichannel of transgenic rats bearing rat S286L-mutant Chrna4 gene (S286L-TG), corresponding to the human S284L-mutant CHRNA4 gene using simple Western analysis and multiprobe microdialysis. Cx43 expression in the thalamic plasma membrane fraction of S286L-TG was upregulated compared with that of wild-type. Subchronic administrations of therapeutic-relevant doses of zonisamide (ZNS) and carbamazepine (CBZ) decreased and did not affect Cx43 expression of S286L-TG, respectively. Upregulated Cx43 enhanced glutamatergic transmission during both resting and hyperexcitable stages in S286L-TG. Furthermore, activation of GABAergic transmission RTN–MDTN pathway conversely enhanced, but not inhibited, l-glutamate release in the MDTN via upregulated/activated Cx43. Local administration of therapeutic-relevant concentration of ZNS and CBZ acutely supressed and did not affect glutamatergic transmission in the thalamocortical pathway, respectively. These results suggest that pathomechanisms of ADSHE seizure and its cognitive deficit comorbidity, as well as pathophysiology of CBZ-resistant/ZNS-sensitive ADSHE seizures of patients with S284L-mutation.

Brain metabolites in chronic migraine patients with medication overuse headache

Background Medication overuse headache may be associated with widespread alterations along the thalamocortical pathway, a pathway involved in pain perception and disease progression. This study addressed whether brain metabolites in key regions of the thalamocortical pathway differed between chronic migraine patients with medication overuse headache and without medication overuse headache. Methods Magnetic resonance spectroscopic imaging was used to map metabolites in the bilateral anterior cingulate cortices, mid cingulate cortices, posterior cingulate cortices, and the thalami. Sixteen patients with medication overuse headache were compared with 16 matched patients without medication overuse headache and 16 matched healthy controls. Results Glutamate and glutamine in the right mid cingulate cortex and myo-inositol in the left anterior cingulate cortex were significantly higher in patients with medication overuse headache than patients without medication overuse headache, but similar to healthy controls. Both patient groups exhibited reduced N-acetyl-aspartate and creatine in the thalamus, reduced myo-inositol in the right anterior cingulate cortex, and elevated choline in the right mid cingulate cortex. Finally, a negative association between myo-inositol laterality index in the anterior cingulate cortices and number of days per month with acute medication use was found across all patients. Conclusions Patients with medication overuse headache were characterized by a distinct concentration profile of myo-inositol, a glial marker, in the anterior cingulate cortices that may have arisen from medication overuse and could contribute to the development of medication overuse headache.

Intact tactile detection yet biased tactile localization in a hand-centered frame of reference: A case study

We examined the performance of an individual with subcortical damage, but an intact somatosensory thalamocortical pathway, to examine the functional architecture of tactile detection and tactile localization processes. Consistent with the intact somatosensory thalamocortical pathway, tactile detection on the contralesional hand was well within the normal range. Despite intact detection, the individual demonstrated substantial localization biases. Across all experiments, he consistently localized tactile stimuli to the left side in space relative to the long axis of his hand. This was observed when the contralesional hand was palm up, palm down, rotated 90° relative to the long axis of the trunk, and when making verbal responses. Furthermore, control experiments demonstrated that this response pattern was unlikely a motor response error. Overall these findings provide strong evidence that tactile detection and localization are completely dissociable processes, and tactile localization on the body is influenced by proprioceptive information specifically in a hand-centered frame of reference. We discuss implications of these findings on models of tactile processing.

Cerebellar-recipient motor thalamus drives behavioral context-specific movement initiation

SummaryTo initiate goal-directed behavior, animals must transform sensory cues into motor commands that generate appropriately timed actions. Sensorimotor transformations along the cerebellar-thalamocortical pathway are thought to shape motor cortical output and movement timing, but whether this pathway initiates goal-directed movement remains poorly understood. Here, we recorded and perturbed activity in cerebellar-recipient regions of motor thalamus (dentate / interpositus nucleus-recipient regions, MThDN/IPN) and primary motor cortex (M1) in mice trained to execute a cued forelimb lever push task for reward. MThDN/IPN population responses were dominated by a time-locked increase in activity immediately prior to movement that was temporally uncoupled from cue presentation, providing a fixed latency feedforward motor timing signal to M1FL. Blocking MThDN/IPN output suppressed cued movement initiation. Stimulating the MThDN/IPN thalamocortical pathway in the absence of the cue recapitulated cue-evoked M1 membrane potential dynamics and forelimb behavior in the learned behavioral context, but generated semi-random movements in an altered behavioral context. Thus, cerebellar-recipient motor thalamocortical input to M1 is indispensable for the generation of motor commands that initiate goal-directed movement, refining our understanding of how the cerebellar-thalamocortical pathway contributes to movement timing.

The effect of NMDA-R antagonist, MK-801, on neuronal mismatch along the auditory thalamocortical pathway

ABSTRACTEfficient sensory processing requires that the brain is able to maximize its response to unexpected stimuli, while suppressing responsivity to expected events. Mismatch negativity (MMN) is an auditory event-related potential that occurs when a regular pattern is interrupted by an event that violates the expected properties of the pattern. MMN has been found to be reduced in individuals with schizophrenia in over 100 separate studies, an effect believed to be underpinned by glutamate N-methyl-D-aspartate receptor (NMDA-R) dysfunction, as it is observed that NMDA-R antagonists also reduce MMN in healthy volunteers. The aim of the current study is to examine this effect in rodents. Using single unit recording in specific auditory areas using methods not readily utilized in humans, we have previously demonstrated that neuronal indices of rodent mismatch responses recorded from thalamic and cortical areas of the brain can be decomposed into a relatively simple repetition suppression and a more sophisticated prediction error process. In the current study, we aimed to test how the NMDA-R antagonist, MK-801, affected both of these processes along the rat auditory thalamocortical pathway. We found that MK-801 had the opposite effect than expected, and enhanced thalamic repetition suppression and cortical prediction error. These single unit data correlate with the recordings of local field responses. Together with previous data, this study suggests that our understanding of the contribution of NMDA-R system to MMN generation is far from complete, and also has potential implications for future research in schizophrenia.Significance StatementIn this study, we demonstrate that an NMDA-R antagonist, MK-801, differentially affects single neuron responses to auditory stimuli along the thalamocortical axis by increasing the response magnitude of unexpected events in the auditory cortex and intensifying the adaptation of responses to expected events in the thalamus. Thus, we provide evidence that NMDA-R antagonists alter the balance between prediction-error and repetition suppression processes that underlie the generation of mismatch responses in the brain, and these effects are differentially expressed at different levels of auditory processing. As effects of MK-801 were in the opposite direction to our expectations, it demonstrates that our understanding of role of NMDA-R in synaptic plasticity and the neural processes underpinning MMN generation are far from complete.

Thalamocortical Interactions for Sensory Processing

The thalamocortical pathway is the main route of sensory information to the cerebral cortex. Vision, touch, hearing, taste, and balance all depend on the integrity of this pathway that connects the thalamic structures receiving sensory input with the cortical areas specialized in each sensory modality. Only the ancient sense of smell is independent of the thalamus, gaining access to cortex through more anterior routes. While the thalamocortical pathway targets different layers of the cerebral cortex, its main stream projects to the middle layers and has axon terminals that are dense, spatially restricted, and highly specific in their connections. The remarkable specificity of these thalamocortical connections allows for a precise reconstruction of the sensory dimensions that need to be most finely sampled, such as spatial acuity in vision and sound frequency in hearing. The thalamic axon terminals also segregate topographically according to their stimulus preferences, providing a simple principle to build cortical sensory maps: neighboring values in sensory space are represented by neighboring points within the cortex. Thalamocortical processing is not static. It is continuously modulated by the brain stem and corticothalamic feedback based on the level of attention and alertness, and during sleep or general anesthesia. When alert, visual thalamic responses become stronger, more reliable, more sustained, more effective at sampling fast changes in the scene, and more linearly related to the stimulus. The high firing rates of the alert state make thalamocortical synapses chronically depressed and excitatory synaptic potentials less dependent on temporal history, improving even further the linear relation between stimulus and response. In turn, when alertness wanes, the thalamus reduces its firing rate, and starts generating spike bursts that drive large postsynaptic responses and keep the cortex responsive to sudden stimulus changes.