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Nature Neuroscience Feb 2022The thalamus engages in various functions including sensory processing, attention, decision making and memory. Classically, this diversity of function has been... (Review)
Review
The thalamus engages in various functions including sensory processing, attention, decision making and memory. Classically, this diversity of function has been attributed to the nuclear organization of the thalamus, with each nucleus performing a well-defined function. Here, we highlight recent studies that used state-of-the-art expression profiling, which have revealed gene expression gradients at the single-cell level within and across thalamic nuclei. These gradients, combined with anatomical tracing and physiological analyses, point to previously unappreciated heterogeneity and redefine thalamic units of function on the basis of unique input-output connectivity patterns and gene expression. We propose that thalamic subnetworks, defined by the intersection of genetics, connectivity and computation, provide a more appropriate level of functional description; this notion is supported by behavioral phenotypes resulting from appropriately tailored perturbations. We provide several examples of thalamic subnetworks and suggest how this new perspective may both propel progress in basic neuroscience and reveal unique targets with therapeutic potential.
Topics: Attention; Neural Pathways; Thalamic Nuclei; Thalamus
PubMed: 35102334
DOI: 10.1038/s41593-021-00996-1 -
NeuroImage Dec 2018The human thalamus is a brain structure that comprises numerous, highly specific nuclei. Since these nuclei are known to have different functions and to be connected to...
The human thalamus is a brain structure that comprises numerous, highly specific nuclei. Since these nuclei are known to have different functions and to be connected to different areas of the cerebral cortex, it is of great interest for the neuroimaging community to study their volume, shape and connectivity in vivo with MRI. In this study, we present a probabilistic atlas of the thalamic nuclei built using ex vivo brain MRI scans and histological data, as well as the application of the atlas to in vivo MRI segmentation. The atlas was built using manual delineation of 26 thalamic nuclei on the serial histology of 12 whole thalami from six autopsy samples, combined with manual segmentations of the whole thalamus and surrounding structures (caudate, putamen, hippocampus, etc.) made on in vivo brain MR data from 39 subjects. The 3D structure of the histological data and corresponding manual segmentations was recovered using the ex vivo MRI as reference frame, and stacks of blockface photographs acquired during the sectioning as intermediate target. The atlas, which was encoded as an adaptive tetrahedral mesh, shows a good agreement with previous histological studies of the thalamus in terms of volumes of representative nuclei. When applied to segmentation of in vivo scans using Bayesian inference, the atlas shows excellent test-retest reliability, robustness to changes in input MRI contrast, and ability to detect differential thalamic effects in subjects with Alzheimer's disease. The probabilistic atlas and companion segmentation tool are publicly available as part of the neuroimaging package FreeSurfer.
Topics: Aged; Aged, 80 and over; Atlases as Topic; Bayes Theorem; Female; Histological Techniques; Humans; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Middle Aged; Thalamic Nuclei; Tissue Banks
PubMed: 30121337
DOI: 10.1016/j.neuroimage.2018.08.012 -
Nature Jul 2020The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, regulates thalamocortical interactions that are critical for sensory processing, attention...
The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, regulates thalamocortical interactions that are critical for sensory processing, attention and cognition. TRN dysfunction has been linked to sensory abnormality, attention deficit and sleep disturbance across multiple neurodevelopmental disorders. However, little is known about the organizational principles that underlie its divergent functions. Here we performed an integrative study linking single-cell molecular and electrophysiological features of the mouse TRN to connectivity and systems-level function. We found that cellular heterogeneity in the TRN is characterized by a transcriptomic gradient of two negatively correlated gene-expression profiles, each containing hundreds of genes. Neurons in the extremes of this transcriptomic gradient express mutually exclusive markers, exhibit core or shell-like anatomical structure and have distinct electrophysiological properties. The two TRN subpopulations make differential connections with the functionally distinct first-order and higher-order thalamic nuclei to form molecularly defined TRN-thalamus subnetworks. Selective perturbation of the two subnetworks in vivo revealed their differential role in regulating sleep. In sum, our study provides a comprehensive atlas of TRN neurons at single-cell resolution and links molecularly defined subnetworks to the functional organization of thalamocortical circuits.
Topics: Animals; Cluster Analysis; Female; Gene Expression Profiling; Gene Regulatory Networks; In Situ Hybridization, Fluorescence; Metalloendopeptidases; Mice; Neural Pathways; Neurons; Osteopontin; Patch-Clamp Techniques; RNA-Seq; Single-Cell Analysis; Sleep; Thalamic Nuclei; Transcriptome
PubMed: 32699411
DOI: 10.1038/s41586-020-2504-5 -
Cell Stem Cell May 2023Human brain organoids provide unique platforms for modeling several aspects of human brain development and pathology. However, current brain organoid systems mostly lack...
Human brain organoids provide unique platforms for modeling several aspects of human brain development and pathology. However, current brain organoid systems mostly lack the resolution to recapitulate the development of finer brain structures with subregional identity, including functionally distinct nuclei in the thalamus. Here, we report a method for converting human embryonic stem cells (hESCs) into ventral thalamic organoids (vThOs) with transcriptionally diverse nuclei identities. Notably, single-cell RNA sequencing revealed previously unachieved thalamic patterning with a thalamic reticular nucleus (TRN) signature, a GABAergic nucleus located in the ventral thalamus. Using vThOs, we explored the functions of TRN-specific, disease-associated genes patched domain containing 1 (PTCHD1) and receptor tyrosine-protein kinase (ERBB4) during human thalamic development. Perturbations in PTCHD1 or ERBB4 impaired neuronal functions in vThOs, albeit not affecting the overall thalamic lineage development. Together, vThOs present an experimental model for understanding nuclei-specific development and pathology in the thalamus of the human brain.
Topics: Humans; Thalamic Nuclei; Thalamus; Neurons; Organoids
PubMed: 37019105
DOI: 10.1016/j.stem.2023.03.007 -
Neuroscience and Biobehavioral Reviews Jul 2021The anterior thalamic nuclei are a vital node within hippocampal-diencephalic-cingulate circuits that support spatial learning and memory. Reflecting this... (Review)
Review
The anterior thalamic nuclei are a vital node within hippocampal-diencephalic-cingulate circuits that support spatial learning and memory. Reflecting this interconnectivity, the overwhelming focus of research into the cognitive functions of the anterior thalamic nuclei has been spatial processing. However, there is increasing evidence that the functions of the anterior thalamic nuclei extend beyond the spatial realm. This work has highlighted how these nuclei are required for certain classes of temporal discrimination as well as their importance for processing other contextual information; revealing parallels with the non-spatial functions of the hippocampal formation. Yet further work has shown how the anterior thalamic nuclei may be important for other forms of non-spatial learning, including a critical role for these nuclei in attentional mechanisms. This evidence signals the need to reconsider the functions of the anterior thalamic within the framework of their wider connections with sites including the anterior cingulate cortex that subserve non-spatial functions.
Topics: Anterior Thalamic Nuclei; Cognition; Hippocampus; Humans; Memory; Spatial Learning
PubMed: 33737105
DOI: 10.1016/j.neubiorev.2021.02.047 -
Neuroscience and Biobehavioral Reviews Dec 2020Two thalamic sites are of especial significance for understanding hippocampal - diencephalic interactions: the anterior thalamic nuclei and nucleus reuniens. Both nuclei... (Review)
Review
Two thalamic sites are of especial significance for understanding hippocampal - diencephalic interactions: the anterior thalamic nuclei and nucleus reuniens. Both nuclei have dense, direct interconnections with the hippocampal formation, and both are directly connected with many of the same cortical and subcortical areas. These two thalamic sites also contain neurons responsive to spatial stimuli while lesions within these two same areas can disrupt spatial learning tasks that are hippocampal dependent. Despite these many similarities, closer analysis reveals important differences in the details of their connectivity and the behavioural impact of lesions in these two thalamic sites. These nuclei play qualitatively different roles that largely reflect the contrasting relative importance of their medial frontal cortex interactions (nucleus reuniens) compared with their retrosplenial, cingulate, and mammillary body interactions (anterior thalamic nuclei). While the anterior thalamic nuclei are critical for multiple aspects of hippocampal spatial encoding and performance, nucleus reuniens contributes, as required, to aid cognitive control and help select correct from competing memories.
Topics: Anterior Thalamic Nuclei; Hippocampus; Humans; Mammillary Bodies; Midline Thalamic Nuclei; Neural Pathways; Neurons
PubMed: 33069688
DOI: 10.1016/j.neubiorev.2020.10.006 -
Brain and Behavior Apr 2023This study aimed to investigate the alterations in individual thalamic nuclei volumes in patients with occipital lobe epilepsy (OLE) compared with those of healthy...
INTRODUCTION
This study aimed to investigate the alterations in individual thalamic nuclei volumes in patients with occipital lobe epilepsy (OLE) compared with those of healthy controls, and to analyze the intrinsic thalamic network based on these volumes using graph theory.
METHODS
Thirty adult patients with newly diagnosed OLE and 42 healthy controls were retrospectively enrolled (mean age, 33.8 ± 17.0 and 32.2 ± 6.6 years, respectively). The study participants underwent brain magnetic resonance imaging with three-dimensional T1-weighted imaging. The right and left total thalamic and individual thalamic nuclei volumes were obtained using the FreeSurfer program. Then, the intrinsic thalamic network was calculated based on the individual thalamic nuclei volumes and graph theory using a BRAPH program.
RESULTS
There were no differences in the right and left whole-thalamic volumes between the two groups (0.445% vs. 0.469%, p = .142 and 0.481% vs. 0.490%, p = .575, respectively). However, significant differences were observed in the volumes of several thalamic nuclei between the two groups. The right medial geniculate and right suprageniculate nuclei volumes were increased (0.0077% vs. 0.0064%, p = .0003 and 0.0013% vs. 0.0010%, p = .0004, respectively), whereas the right and left parafascicular nuclei volumes were decreased in patients with OLE compared with those in healthy controls (0.0038% vs. 0.0048%, p < .0001 and 0.0037% vs. 0.0045%, p = .0001, respectively). There were no differences in the network measures regarding intrinsic thalamic network between the two groups.
CONCLUSION
We successfully demonstrated the alterations in individual thalamic nuclei volumes, especially the increased medial geniculate and suprageniculate, and decreased parafascicular nuclei volumes in patients with OLE compared with those of healthy controls despite no changes in the whole-thalamic volumes. These findings suggest an important role of the thalamus in the epileptic network of OLE.
Topics: Adult; Humans; Adolescent; Young Adult; Middle Aged; Retrospective Studies; Thalamus; Thalamic Nuclei; Epilepsies, Partial; Brain; Magnetic Resonance Imaging
PubMed: 36924055
DOI: 10.1002/brb3.2968 -
NeuroImage Nov 2022The thalamus is a central integration structure in the brain, receiving and distributing information among the cerebral cortex, subcortical structures, and the...
The thalamus is a central integration structure in the brain, receiving and distributing information among the cerebral cortex, subcortical structures, and the peripheral nervous system. Prior studies clearly show that the thalamus atrophies in cognitively unimpaired aging. However, the thalamus is comprised of multiple nuclei involved in a wide range of functions, and the age-related atrophy of individual thalamic nuclei remains unknown. Using a recently developed automated method of identifying thalamic nuclei (3T or 7T MRI with white-matter-nulled MPRAGE contrast and THOMAS segmentation) and a cross-sectional design, we evaluated the age-related atrophy rate for 10 thalamic nuclei (AV, CM, VA, VLA, VLP, VPL, pulvinar, LGN, MGN, MD) and an epithalamic nucleus (habenula). We also used T1-weighted images with the FreeSurfer SAMSEG segmentation method to identify and measure age-related atrophy for 11 extra-thalamic structures (cerebral cortex, cerebral white matter, cerebellar cortex, cerebellar white matter, amygdala, hippocampus, caudate, putamen, nucleus accumbens, pallidum, and lateral ventricle). In 198 cognitively unimpaired participants with ages spanning 20-88 years, we found that the whole thalamus atrophied at a rate of 0.45% per year, and that thalamic nuclei had widely varying age-related atrophy rates, ranging from 0.06% to 1.18% per year. A functional grouping analysis revealed that the thalamic nuclei involved in cognitive (AV, MD; 0.53% atrophy per year), visual (LGN, pulvinar; 0.62% atrophy per year), and auditory/vestibular (MGN; 0.64% atrophy per year) functions atrophied at significantly higher rates than those involved in motor (VA, VLA, VLP, and CM; 0.37% atrophy per year) and somatosensory (VPL; 0.32% atrophy per year) functions. A proximity-to-CSF analysis showed that the group of thalamic nuclei situated immediately adjacent to CSF atrophied at a significantly greater atrophy rate (0.59% atrophy per year) than that of the group of nuclei located farther from CSF (0.36% atrophy per year), supporting a growing hypothesis that CSF-mediated factors contribute to neurodegeneration. We did not find any significant hemispheric differences in these rates of change for thalamic nuclei. Only the CM thalamic nucleus showed a sex-specific difference in atrophy rates, atrophying at a greater rate in male versus female participants. Roughly half of the thalamic nuclei showed greater atrophy than all extra-thalamic structures examined (0% to 0.54% per year). These results show the value of white-matter-nulled MPRAGE imaging and THOMAS segmentation for measuring distinct thalamic nuclei and for characterizing the high and heterogeneous atrophy rates of the thalamus and its nuclei across the adult lifespan. Collectively, these methods and results advance our understanding of the role of thalamic substructures in neurocognitive and disease-related changes that occur with aging.
Topics: Adult; Aged; Aged, 80 and over; Aging; Atrophy; Cross-Sectional Studies; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Thalamic Nuclei; Thalamus; Young Adult
PubMed: 36007822
DOI: 10.1016/j.neuroimage.2022.119584 -
Communications Biology Nov 2022Almost all functional processing in the cortex strongly depends on thalamic interactions. However, in terms of functional interactions with the cerebral cortex, the...
Almost all functional processing in the cortex strongly depends on thalamic interactions. However, in terms of functional interactions with the cerebral cortex, the human thalamus nuclei still partly constitute a terra incognita. Hence, for a deeper understanding of thalamic-cortical cooperation, it is essential to know how the different thalamic nuclei are associated with cortical networks. The present work examines network-specific connectivity and task-related topical mapping of cortical areas with the thalamus. The study finds that the relay and higher-order thalamic nuclei show an intertwined functional association with different cortical networks. In addition, the study indicates that relay-specific thalamic nuclei are not only involved with relay-specific behavior but also in higher-order functions. The study enriches our understanding of interactions between large-scale cortical networks and the thalamus, which may interest a broader audience in neuroscience and clinical research.
Topics: Humans; Neural Pathways; Thalamic Nuclei; Cerebral Cortex; Thalamus
PubMed: 36333448
DOI: 10.1038/s42003-022-04126-w -
Epilepsy Research May 2022There is no doubt on the participation of the thalamus in the various types of genetic generalized epilepsies as evidenced by multiple non-invasive imaging studies in... (Review)
Review
There is no doubt on the participation of the thalamus in the various types of genetic generalized epilepsies as evidenced by multiple non-invasive imaging studies in humans as well as invasive studies in animal models of GGE. Based on human and mostly animal data gathered in early 2000 a so called 'three compartment model' on seizure generation was proposed conceptualizing the existence of a hyperexcitable cortical seizure onset zone providing excitation to relay cells of the relay thalamus and the inhibitory reticular thalamic nucleus (RTn). The interplay of corticothalamic excitation and feedforward inhibition via RTn is supposed to entrain thalamic relay neurons into synchronous, oscillatory activity for SWD sustainment. With the emergence of more fine-tuned experimental techniques and analyses, however, it becomes apparent that this model is too simplistic as the thalamus cannot be regarded as unity. Rather, different thalamic nuclei, being integrated in different thalamocortical and other subcortical subloops, need to be differentiated, which take over different functions for seizure generation, generalization and maintenance. Moreover, these networks are not necessarily the same for different classes of patients with GGE and can even be antagonistic between seizure types. This review will summarize data concerning different nuclei and their participation in GGE in order to extend this model and create a more detailed concept on seizure generation, generalization and maintenance.
Topics: Animals; Epilepsy, Absence; Epilepsy, Generalized; Humans; Seizures; Thalamic Nuclei; Thalamus
PubMed: 35427989
DOI: 10.1016/j.eplepsyres.2022.106918