Thalamic Relay Nuclei Research Articles

Functional circuit mapping of striatal output nuclei using simultaneous deep brain stimulation and fMRI

The substantia nigra pars reticulata (SNr) and external globus pallidus (GPe) constitute the two major output targets of the rodent striatum. Both the SNr and GPe converge upon thalamic relay nuclei (directly or indirectly, respectively), and are traditionally modeled as functionally antagonistic relay inputs. However, recent anatomical and functional studies have identified unanticipated circuit connectivity in both the SNr and GPe, demonstrating their potential as far more than relay nuclei. In the present study, we employed simultaneous deep brain stimulation and functional magnetic resonance imaging (DBS-fMRI) with cerebral blood volume (CBV) measurements to functionally and unbiasedly map the circuit- and network level connectivity of the SNr and GPe. Sprague-Dawley rats were implanted with a custom-made MR-compatible stimulating electrode in the right SNr (n=6) or GPe (n=7). SNr- and GPe-DBS, conducted across a wide range of stimulation frequencies, revealed a number of surprising evoked responses, including unexpected CBV decreases within the striatum during DBS at either target, as well as GPe-DBS-evoked positive modulation of frontal cortex. Functional connectivity MRI revealed global modulation of neural networks during DBS at either target, sensitive to stimulation frequency and readily reversed following cessation of stimulation. This work thus contributes to a growing literature demonstrating extensive and unanticipated functional connectivity among basal ganglia nuclei.

Visuomotor signals for reaching movements in the rostro-dorsal sector of the monkey thalamic reticular nucleus.

The thalamic reticular nucleus (TRN) collects inputs from the cerebral cortex and thalamus and, in turn, sends inhibitory outputs to the thalamic relay nuclei. This unique connectivity suggests that the TRN plays a pivotal role in regulating information flow through the thalamus. Here, we analyzed the roles of TRN neurons in visually guided reaching movements. We first used retrograde transneuronal labeling with rabies virus, and showed that the rostro-dorsal sector of the TRN (TRNrd) projected disynaptically to the ventral premotor cortex (PMv). In other experiments, we recorded neurons from the TRNrd or PMv while monkeys performed a visuomotor task. We found that neurons in the TRNrd and PMv showed visual-, set-, and movement-related activity modulation. These results indicate that the TRNrd, as well as the PMv, is involved in the reception of visual signals and in the preparation and execution of reaching movements. The fraction of neurons that were non-selective for the location of visual signals or the direction of reaching movements was greater in the TRNrd than in the PMv. Furthermore, the fraction of neurons whose activity increased from the baseline was greater in the TRNrd than in the PMv. The timing of activity modulation of visual-related and movement-related neurons was similar in TRNrd and PMv neurons. Overall, our data suggest that TRNrd neurons provide motor thalamic nuclei with inhibitory inputs that are predominantly devoid of spatial selectivity, and that these signals modulate how these nuclei engage in both sensory processing and motor output during visually guided reaching behavior.

ID 83 – Burst activity features of relay thalamic nuclei in patients with spasmodic torticollis

Objective Research of burst activity at rest and during execution of functional tests and its possible connection with pathology of spasmodic torticollis. Methods Extracellular activity was obtained by microelectrode technique during stereotactic neurosurgical operations. Simultaneously, electromyographic data from neck and arm muscles were registered. Neuronal reactions to functional tests (verbally-ordered movement tasks) were also recorded. Results There was burst activity in Voi and Voa thalamic nuclei both at rest and during functional tests. In Voi tonic reactions generally were observed during movement execution and in after-effect and were connected with neck muscles movements. It could be caused by Voi’s cerebellar connections and posture functions. In Voa tonic and phasic reactions were observed during initiation, preparation, execution of movement and in after-effect, sometimes even on verbal command. These reactions weren’t connected only with neck muscles movements. It could be caused by Voa’s pallidal connections and execution of motor program. Significant prevalence of burst activity in surgical target (Voi) wasn’t observed. Conclusion Burst activity was common phenomenon in studied thalamic nuclei at rest and was reactive to functional tests. In general, burst activity wasn’t connected with pathology of spasmodic torticollis directly. Key message Thalamus, microelectrode, single unit activity, burst, spasmodic torticollis.

A Subcortical Pathway for Rapid, Goal-Driven, Attentional Filtering

Prefrontal cortex can exercise goal-driven attentional control over sensory information via cortical pathways. However, recent work demonstrates that prefrontal cortex can also influence thalamic relay nuclei via the thalamic reticular nucleus. This suggests the prefrontal-thalamic pathway mediates rapid and goal-driven attentional filtering at the earliest stages of sensory processing.

Congenital blindness affects diencephalic but not mesencephalic structures in the human brain.

While there is ample evidence that the structure and function of visual cortical areas are affected by early visual deprivation, little is known of how early blindness modifies subcortical relay and association thalamic nuclei, as well as mesencephalic structures. Therefore, in the present multicenter study, we used MRI to measure volume of the superior and inferior colliculi, as well as of the thalamic nuclei relaying sensory and motor information to the neocortex, parcellated according to atlas-based thalamo-cortical connections, in 29 individuals with congenital blindness of peripheral origin (17 M, age 35.7 ± 14.3 years) and 29 sighted subjects (17 M, age 31.9 ± 9.0). Blind participants showed an overall volume reduction in the left (p = 0.008) and right (p = 0.007) thalami, as compared to the sighted individuals. Specifically, the lateral geniculate (i.e., primary visual thalamic relay nucleus) was 40% reduced (left: p = 4 × 10(-6), right: p < 1 × 10(-6)), consistent with findings from animal studies. In addition, associated thalamic nuclei that project to temporal (left: p = 0.005, right: p = 0.005), prefrontal (left: p = 0.010, right: p = 0.014), occipital (left: p = 0.005, right: p = 0.023), and right premotor (p = 0.024) cortical regions were also significantly reduced in the congenitally blind group. Conversely, volumes of the relay nuclei directly involved in auditory, motor, and somatosensory processing were not affected by visual deprivation. In contrast, no difference in volume was observed in either the superior or the inferior colliculus between the two groups. Our findings indicate that visual loss since birth leads to selective volumetric changes within diencephalic, but not mesencephalic, structures. Both changes in reciprocal cortico-thalamic connections or modifications in the intrinsic connectivity between relay and association nuclei of the thalamus may contribute to explain these alterations in thalamic volumes. Sparing of the superior colliculi is in line with their composite, multisensory projections, and with their not exclusive visual nature.

Systematic expression analysis of Hox genes at adulthood reveals novel patterns in the central nervous system.

Hox proteins are key regulators of animal development, providing positional identity and patterning information to cells along the rostrocaudal axis of the embryo. Although their embryonic expression and function are well characterized, their presence and biological importance in adulthood remains poorly investigated. We provide here the first detailed quantitative and neuroanatomical characterization of the expression of the 39 Hox genes in the adult mouse brain. Using RT-qPCR we determined the expression of 24 Hox genes mainly in the brainstem of the adult brain, with low expression of a few genes in the cerebellum and the forebrain. Using in situ hybridization (ISH) we have demonstrated that expression of Hox genes is maintained in territories derived from the early segmental Hox expression domains in the hindbrain. Indeed, we show that expression of genes belonging to paralogy groups PG2-8 is maintained in the hindbrain derivatives at adulthood. The spatial colinearity, which characterizes the early embryonic expression of Hox genes, is still observed in sequential antero-posterior boundaries of expression. Moreover, the main mossy and climbing fibres precerebellar nuclei express PG2-8 Hox genes according to their migration origins. Second, ISH confirms the presence of Hox gene transcripts in territories where they are not detected during development, suggesting neo-expression in these territories in adulthood. Within the forebrain, we have mapped Hoxb1, Hoxb3, Hoxb4, Hoxd3 and Hoxa5 expression in restricted areas of the sensory cerebral cortices as well as in specific thalamic relay nuclei. Our data thus suggest a requirement of Hox genes beyond their role of patterning genes, providing a new dimension to their functional relevance in the central nervous system.

Morphology and connectivity of parabrachial and cortical inputs to gustatory thalamus in rats.

The ventroposterior medialis parvocellularis (VPMpc) nucleus of the thalamus, the thalamic relay nucleus for gustatory sensation, receives primary input from the parabrachial nucleus, and projects to the insular cortex. To reveal the unique properties of the gustatory thalamus in comparison with archetypical sensory relay nuclei, this study examines the morphology of synaptic circuitry in the VPMpc, focusing on parabrachiothalamic driver input and corticothalamic feedback. Anterogradely visualized parabrachiothalamic fibers in the VPMpc bear large swellings. At electron microscope resolution, parabrachiothalamic axons are myelinated and make large boutons, forming multiple asymmetric, adherent, and perforated synapses onto large-caliber dendrites and dendrite initial segments. Labeled boutons contain dense-core vesicles, and they resemble a population of terminals within the VPMpc containing calcitonin gene-related peptide. As is typical of primary inputs to other thalamic nuclei, parabrachiothalamic terminals are over five times larger than other inputs, while constituting only 2% of all synapses. Glomeruli and triadic arrangements, characteristic features of other sensory thalamic nuclei, are not encountered. As revealed by anterograde tracer injections into the insular cortex, corticothalamic projections in the VPMpc form a dense network of fine fibers bearing small boutons. Corticothalamic terminals within the VPMpc were also observed to synapse on cells that were retrogradely filled from the same injections. The results constitute an initial survey describing unique anatomical properties of the rodent gustatory thalamus.

Retinal Input Directs the Recruitment of Inhibitory Interneurons into Thalamic Visual Circuits

Inhibitory interneurons (INs) critically control the excitability and plasticity of neuronal networks, but whether activity can direct INs into specific circuits during development is unknown. Here, we report that in the dorsal lateral geniculate nucleus (dLGN), which relays retinal input to the cortex, circuit activity is required for the migration, molecular differentiation, and functional integration of INs. We first characterize the prenatal origin and molecular identity of dLGN INs, revealing their recruitment from an Otx2(+) neuronal pool located in the adjacent ventral LGN. Using time-lapse and electrophysiological recordings, together with genetic and pharmacological perturbation of retinal waves, we show that retinal activity directs the navigation and circuit incorporation of dLGN INs during the first postnatal week, thereby regulating the inhibition of thalamocortical circuits. These findings identify an input-dependent mechanism regulating IN migration and circuit inhibition, which may account for the progressive recruitment of INs into expanding excitatory circuits during evolution.

Effect of prenatal sound stimulation on the morphology of auditory thalamic relay nuclei of domestic chick

Effect of prenatal sound stimulation on the morphology of auditory thalamic relay nuclei of domestic chick

Effect of prenatal sound stimulation on the morphology of visual thalamic relay nuclei of domestic chick

Background: The knowledge of the effects of prenatal sensory environment on the development of sensory systems and other behavioral traits has important implications with regard to the optimum management of preterm infants. There is a controversy regarding the potential benefits and hazards of providing supplemental sensory stimulation to preterm infants. The views range from the perceived importance of minimal handling and reduced stimulation of preterm infants on one end, to the value of providing supplemental tactile, vestibular, auditory or visual stimulation (either alone or in combination) in promoting normal development at the other end. It is therefore important to know whether early prenatal stimulation of one sensory modality can affect behavioral responsiveness to stimulation of another different sensory system. Aims & Objective: The present study is aimed to see the effects of prenatal sound stimulation on the auditory thalamic nuclei in the domestic chick by examining quantitatively some morphological parameters. Materials and Methods: The auditory stimulus of frequency ranging between 100-6300 Hz at 65 dB was given to the chick embryos from E10 to E20. One group was given species-specific sounds of maternal calls (100-1600 Hz) from E10-E15 followed by chick hatchling calls (1600-6300 Hz) from E15-E20. The other experimental group received sitar music sounds given as slow music (1001600 Hz) from E10-E15 followed by fast music (100-4000 HZ) from E15-E20. The volume, neuronal number and neuronal nuclear area of nucleus ovoidalis, and nucleus ruber- a motor nucleus were quantitatively evaluated on serial Nissl stained sections by stereological methods. Results: Following the auditory stimulation, the nucleus ovoidalis, which is an important auditory nucleus, shows a considerable increase in volume and neuronal number. In concurrence with the effects on other brainstem auditory nuclei studied earlier, the prenatal auditory stimulation also has a positive influence on the developing auditory thalamic nucleus ovoidalis. The nucleus ruber showed no change in volume and neuronal nuclear area but only some increase in the neuronal number. Conclusion: The study demonstrates the positive effect of stimulation of one sensory modality (sound) on development of auditory system.

Prediction and verification of nonlinear sleep spindle harmonic oscillations

This paper examines nonlinear effects in a neural field model of the corticothalamic system to predict the EEG power spectrum of sleep spindles. Nonlinearity in the thalamic relay nuclei gives rise to a spindle harmonic visible in the cortical EEG. By deriving an analytic expression for nonlinear spectrum, the power in the spindle harmonic is predicted to scale quadratically with the power in the spindle oscillation. By isolating sleep spindles from background sleep in experimental EEG data, the spindle harmonic is directly observed.

Novel song-stimulated dendritic spine formation and Arc/Arg3.1 expression in zebra finch auditory telencephalon are disrupted by cannabinoid agonism

Cannabinoids are well-established to alter processes of sensory perception; however neurophysiological mechanisms responsible remain unclear. Arc, an immediate-early gene (IEG) product involved in dendritic spine dynamics and necessary for plasticity changes such as long-term potentiation, is rapidly induced within zebra finch caudal medial nidopallium (NCM) following novel song exposure, a response that habituates after repeated stimuli. Arc appears unique in its rapid postsynaptic dendritic expression following excitatory input. Previously, we found that vocal development-altering cannabinoid treatments are associated with elevated dendritic spine densities in motor-(HVC) and learning-related (Area X) song regions of zebra finch telencephalon. Given Arc's dendritic morphological role, we hypothesized that cannabinoid-altered spine densities may involve Arc-related signaling. To test this, we examined the ability of the cannabinoid agonist WIN55212-2 (WIN) to (1) acutely disrupt song-induced Arc expression, (2) interfere with habituation to auditory stimuli, and (3) alter dendritic spine densities in auditory regions. We found that WIN (3mg/kg) acutely reduced Arc expression within both NCM and Field L2 in an antagonist-reversible manner. WIN did not alter Arc expression in thalamic auditory relay nucleus ovoidalis (Ov), suggesting that cannabinoid signaling selectively alters responses to auditory stimulation. Novel song stimulation rapidly increased dendritic spine densities within auditory telencephalon, an effect blocked by WIN pretreatments. Taken together, cannabinoid inhibition of both Arc induction and its habituation to repeated stimuli, combined with prevention of rapid increases in dendritic spine densities, implicates cannabinoid signaling in modulation of physiological processes important to auditory responsiveness and memory.

A defined heteromeric KV1 channel stabilizes the intrinsic pacemaking and regulates the output of deep cerebellar nuclear neurons to thalamic targets

The output of the cerebellum to the motor axis of the central nervous system is orchestrated mainly by synaptic inputs and intrinsic pacemaker activity of deep cerebellar nuclear (DCN) projection neurons. Herein, we demonstrate that the soma of these cells is enriched with K(V)1 channels produced by mandatory multi-merization of K(V)1.1, 1.2 α and KV β2 subunits. Being constitutively active, the K(+) current (IK(V)1) mediated by these channels stabilizes the rate and regulates the temporal precision of self-sustained firing of these neurons. Placed strategically, IK(V)1 provides a powerful counter-balance to prolonged depolarizing inputs, attenuates the rebound excitation, and dampens the membrane potential bi-stability. Somatic location with low activation threshold render IK(V)1 instrumental in voltage-dependent de-coupling of the axon initial segment from the cell body of projection neurons, impeding invasion of back-propagating action potentials into the somato-dendritic compartment. The latter is also demonstrated to secure the dominance of clock-like somatic pacemaking in driving the regenerative firing activity of these neurons, to encode time variant inputs with high fidelity. Through the use of multi-compartmental modelling and retro-axonal labelling, the physiological significance of the described functions for processing and communication of information from the lateral DCN to thalamic relay nuclei is established.

Systematic mapping of fragile X granules in the mouse brain reveals a potential role for presynaptic FMRP in sensorimotor functions

Loss of Fragile X mental retardation protein (FMRP) leads to Fragile X syndrome (FXS), the most common form of inherited intellectual disability and autism. Although the functions of FMRP and its homologs FXR1P and FXR2P are well studied in the somatodendritic domain, recent evidence suggests that this family of RNA binding proteins also plays a role in the axonal and presynaptic compartments. Fragile X granules (FXGs) are morphologically and genetically defined structures containing Fragile X proteins that are expressed axonally and presynaptically in a subset of circuits. To further understand the role of presynaptic Fragile X proteins in the brain, we systematically mapped the FXG distribution in the mouse central nervous system. This analysis revealed both the circuits and the neuronal types that express FXGs. FXGs are enriched in circuits that mediate sensory processing and motor planning-functions that are particularly perturbed in FXS patients. Analysis of FXG expression in the hippocampus suggests that CA3 pyramidal neurons use presynaptic Fragile X proteins to modulate recurrent but not feedforward processing. Neuron-specific FMRP mutants revealed a requirement for neuronal FMRP in the regulation of FXGs. Finally, conditional FMRP ablation demonstrated that FXGs are expressed in axons of thalamic relay nuclei that innervate cortex, but not in axons of thalamic reticular nuclei, striatal nuclei, or cortical neurons that innervate thalamus. Together, these findings support the proposal that dysregulation of axonal and presynaptic Fragile X proteins contribute to the neurological symptoms of FXS.

Differentiated Participation of Thalamocortical Subnetworks in Slow/Spindle Waves and Desynchronization

During sleep, the electroencephalogram exhibits synchronized slow waves that desynchronize when animals awaken [desynchronized states (DSs)]. During slow-wave states, the membrane potentials of cortical neurons oscillate between discrete depolarized states ("Up states") and periods of hyperpolarization ("Down states"). To determine the role of corticothalamic loops in generating Up/Down oscillations in rats, we recorded unit activities of layer 5 (L5) corticothalamic (CTh) cells in the frontal cortex, neurons in the thalamic reticular nucleus, and basal ganglia- and cerebellum-linked thalamic relay nuclei, while simultaneously monitoring the local cortical field potential to identify slow-wave/spindle oscillations and desynchronization. We found that (1) some basal ganglia-linked and reticular thalamic cells fire preferentially near the beginning of Up states; (2) thalamic cells fire more selectively at a given Up-state phase than do CTh cells; (3) CTh and thalamic cells exhibit different action potential timings within spindle cycles; and (4) neurons exhibit different firing characteristics when comparing their activity during Up states and DSs. These data demonstrate that cortico-thalamo-cortical subnetworks are temporally differentiated during slow and spindle oscillations, that the basal ganglia-linked thalamic nuclei are closely related with Up-state initiation, and that Up states and DSs are distinguished as different depolarization states of neurons within the network.

Early Microglial Activation Precedes Neuronal Loss in the Brain of theCstb−/−Mouse Model of Progressive Myoclonus Epilepsy, EPM1

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is a hereditary neurodegenerative disorder caused by mutations in the cystatin B (CSTB) gene encoding an inhibitor of cysteine proteases. Here, we provide the first detailed description of the onset and progression of pathologic changes in the CNS of Cstb-deficient (Cstb) mice. Our data reveal early and localized glial activation in brain regions where neuron loss subsequently occurs. These changes are most pronounced in the thalamocortical system, with neuron loss occurring first within the cortex and only subsequently in the corresponding thalamic relay nucleus. Microglial activation precedes the emergence of myoclonia and is followed by successive astrocytosis and selective neuron loss. Neuron loss was not detected in thalamic relay nuclei that displayed no glial activation. Microglia showed morphologic changes during disease progression from that of phagocytic brain macrophages in young animals to having thickened branched processes in older animals. These novel data on the timing of pathologic events in the CSTB-deficient brain highlight the potential role of glial activation at the initial stages of the disease. Determining the precise sequence of the neurodegenerative events in Cstb mouse brains will lay the basis for understanding the pathophysiology of EPM1.

Potentiation of sensory responses in ventrobasal thalamus in vivo via selective modulation of mGlu1 receptors with a positive allosteric modulator

Metabotropic glutamate subtype 1 (mGlu1) receptor is thought to play a role in synaptic responses in thalamic relay nuclei. The aim of this study was to evaluate the positive allosteric modulator (PAM) Ro67-4853 as a tool to modulate thalamic mGlu1 receptors on single thalamic neurones in vivo. Ro67-4853, applied by iontophoresis onto ventrobasal thalamus neurones of urethane-anaesthetised rats, selectively enhanced responses to the agonist (S)-3,5-dihydroxy-phenylglycine (DHPG), an effect consistent with mGlu1 potentiation. The PAM was also able to enhance maintained responses to 10 Hz trains of sensory stimulation of the vibrissae, but had little effect on responses to single sensory stimuli. Thus Ro67-4853 appears to be a highly selective tool that can be useful in investigating how mGlu1 receptor potentiation can alter neural processing in vivo. Our results show the importance of mGlu1 in sensory processing and attention mechanisms at the thalamic level and suggest that positive modulation of mGlu1 receptors might be a useful mechanism for enhancing cognitive and attentional processes.

Goodbye to Edward G. (Ted) Jones, MD, DPhil, 1939‐2011

Goodbye to Edward G. (Ted) Jones, MD, DPhil, 1939‐2011

Involvement of the anterior thalamic radiation in boys with high functioning autism spectrum disorders: A Diffusion Tensor Imaging study

Background: Autism has been hypothesized to reflect neuronal disconnection. Several recent reports implicate the key thalamic relay nuclei and cortico-thalamic connectivity in the pathophysiology of autism. Accordingly, we aimed to focus on evaluating the integrity of the thalamic radiation and sought to replicate prior white matter findings in Korean boys with high-functioning autism spectrum disorders (ASD) using Diffusion Tensor Imaging (DTI). Methods: We compared fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in 17 boys with ASD and 17 typically developing controls in the anterior thalamic radiation (ATR), superior thalamic radiation (STR), posterior thalamic radiation (PTR), corpus callosum (CC), uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF). Results: The two groups were group-matched on age, IQ, handedness and head circumference. In whole-brain voxel-wise analyses, FA was significantly reduced and MD was significantly increased in the right ATR, CC, and left UF in subjects with ASD (p < 0.05, corrected). We found significantly lower FA in right and left ATR, CC, left UF and right and left ILF and significantly higher MD values of the CC in the ASD group in region of interest-based analyses. We also observed significantly higher RD values of right and left ATR, CC, left UF, left ILF in subjects with ASD compared to typically developing boys and significantly lower AD values of both ILF. Right ATR and right UF FA was significantly negatively correlated with total SRS score within the ASD group (r = −.56, p = .02). Conclusions: Our preliminary findings support evidence implicating disturbances in the thalamo-frontal connections in autism. These findings highlight the role of hypoconnectivity between the frontal cortex and thalamus in ASD.

Attenuation of inhibitory synaptic transmission by glial dysfunction in rat thalamus

The thalamus serves as the obligatory gateway to the neocortex for sensory processing, and also serves as a pathway for corticocortical communication. In addition, the reciprocal synaptic connectivity between the thalamic reticular nucleus (TRN) and adjacent thalamic relay nuclei generates rhythmic activities similar to that observed during different arousal states and certain neurological conditions such as absence epilepsy. Epileptiform activity can arise from a variety of neural mechanisms, but in addition glia are thought to have an important role in such activities as well. Glia serve a central role in glutamine synthesis, a precursor for glutamate or GABA in nerve terminals. While alterations in glutamine shuttling from glia to neurons can influence GABA and glutamate neurotransmission; the consequences of such action on synaptic transmission and subsequent network activities within thalamic circuits is less understood. We investigated the consequences of altering glutamine transport on inhibitory transmission and intrathalamic activities using the in vitro thalamic slice preparation. Disruption of the glutamine shuttling by the neuronal glutamine transporter (system A transporter) antagonist, α-(methylamino)isobutyric acid (MeAIB), or the selective gliotoxic drug, fluorocitric acid (Fc) dramatically decreased intrathalamic rhythmic activities. At the single cell level, MeAIB and Fc significantly attenuated electrically evoked inhibitory postsynaptic currents (eIPSCs) in thalamic relay neurons; however, miniature IPSCs were unaffected. These data indicate that glutamate-glutamine shuttle is critical for sustaining thalamic synaptic transmission, and thereby alterations in this shuttle can influence intrathalamic rhythmic activities associated with absence epilepsy.