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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 -
Epilepsia Oct 2022Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and... (Review)
Review
Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and real-world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide the selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS-ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death in epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7 to 10 years of follow-up for all modalities, albeit in uncontrolled follow-up or retrospective studies. A significant number of patients experience seizure-free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with comorbidities such as severe mood or sleep disorders, may influence the choice of modality. Programming has evolved-DBS is typically initiated at lower current/voltage than used in the pivotal trial, whereas target charge density is lower with RNS, however generalizable optimal parameters are yet to be defined. Noninvasive brain stimulation is an emerging stimulation modality, although it is currently not used widely. In summary, clinical practice has evolved from those established in pivotal trials. Guidance is now available for clinicians who wish to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.
Topics: Anterior Thalamic Nuclei; Deep Brain Stimulation; Drug Resistant Epilepsy; Epilepsy; Humans; Retrospective Studies; Seizures; Treatment Outcome; Vagus Nerve Stimulation
PubMed: 35700144
DOI: 10.1111/epi.17329 -
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 -
Trends in Neurosciences Jul 2021Early anatomical evidence suggested that the paraventricular nucleus of the thalamus (PVT) regulates arousal, as well as emotional and motivated behaviors. We discuss... (Review)
Review
Early anatomical evidence suggested that the paraventricular nucleus of the thalamus (PVT) regulates arousal, as well as emotional and motivated behaviors. We discuss recent studies using modern techniques which now confirm and expand the involvement of the rodent PVT in these functions. Despite the emerging notion that the PVT is implicated in various behavioral processes, a recurrent theme is that activity in this brain region depends on internal state information arriving from the hypothalamus and brainstem, and is influenced by prior experience. We propose that the primary function of the PVT is to detect homeostatic challenges by integrating information about prior experiences, competing needs, and internal state to guide adaptive behavioral responses aimed at restoring homeostasis.
Topics: Homeostasis; Humans; Midline Thalamic Nuclei; Neurons; Paraventricular Hypothalamic Nucleus; Thalamus
PubMed: 33775435
DOI: 10.1016/j.tins.2021.03.001 -
Neuron Jan 2021Interactions between the thalamus and prefrontal cortex (PFC) play a critical role in cognitive function and arousal. Here, we use anatomical tracing, electrophysiology,...
Interactions between the thalamus and prefrontal cortex (PFC) play a critical role in cognitive function and arousal. Here, we use anatomical tracing, electrophysiology, optogenetics, and 2-photon Ca imaging to determine how ventromedial (VM) and mediodorsal (MD) thalamus target specific cell types and subcellular compartments in layer 1 (L1) of mouse PFC. We find thalamic inputs make distinct connections in L1, where VM engages neuron-derived neurotrophic factor (NDNF+) cells in L1a and MD drives vasoactive intestinal peptide (VIP+) cells in L1b. These separate populations of L1 interneurons participate in different inhibitory networks in superficial layers by targeting either parvalbumin (PV+) or somatostatin (SOM+) interneurons. NDNF+ cells also inhibit the apical dendrites of L5 pyramidal tract (PT) cells to suppress action potential (AP)-evoked Ca signals. Lastly, NDNF+ cells mediate a unique form of thalamus-evoked inhibition at PT cells, selectively blocking VM-evoked dendritic Ca spikes. Together, our findings reveal how two thalamic nuclei differentially communicate with the PFC through distinct L1 micro-circuits.
Topics: Animals; Female; Inhibitory Postsynaptic Potentials; Male; Mediodorsal Thalamic Nucleus; Mice; Mice, Inbred C57BL; Nerve Net; Optogenetics; Prefrontal Cortex
PubMed: 33188733
DOI: 10.1016/j.neuron.2020.10.031 -
Brain : a Journal of Neurology Jul 2023Neuromodulation of the anterior nuclei of the thalamus (ANT) has shown to be efficacious in a subset of patients with refractory focal epilepsy. One important...
Neuromodulation of the anterior nuclei of the thalamus (ANT) has shown to be efficacious in a subset of patients with refractory focal epilepsy. One important uncertainty is to what extent thalamic subregions other than the ANT could be recruited more prominently in the propagation of focal onset seizures. We designed the current study to simultaneously monitor the engagement of the ANT, mediodorsal (MD) and pulvinar (PUL) nuclei during seizures in patients who could be candidates for thalamic neuromodulation. We studied 11 patients with clinical manifestations of presumed temporal lobe epilepsy (TLE) undergoing invasive stereo-encephalography (sEEG) monitoring to confirm the source of their seizures. We extended cortical electrodes to reach the ANT, MD and PUL nuclei of the thalamus. More than one thalamic subdivision was simultaneously interrogated in nine patients. We recorded seizures with implanted electrodes across various regions of the brain and documented seizure onset zones (SOZ) in each recorded seizure. We visually identified the first thalamic subregion to be involved in seizure propagation. Additionally, in eight patients, we applied repeated single pulse electrical stimulation in each SOZ and recorded the time and prominence of evoked responses across the implanted thalamic regions. Our approach for multisite thalamic sampling was safe and caused no adverse events. Intracranial EEG recordings confirmed SOZ in medial temporal lobe, insula, orbitofrontal and temporal neocortical sites, highlighting the importance of invasive monitoring for accurate localization of SOZs. In all patients, seizures with the same propagation network and originating from the same SOZ involved the same thalamic subregion, with a stereotyped thalamic EEG signature. Qualitative visual reviews of ictal EEGs were largely consistent with the quantitative analysis of the corticothalamic evoked potentials, and both documented that thalamic nuclei other than ANT could have the earliest participation in seizure propagation. Specifically, pulvinar nuclei were involved earlier and more prominently than ANT in more than half of the patients. However, which specific thalamic subregion first demonstrated ictal activity could not be reliably predicted based on clinical semiology or lobar localization of SOZs. Our findings document the feasibility and safety of bilateral multisite sampling from the human thalamus. This may allow more personalized thalamic targets to be identified for neuromodulation. Future studies are needed to determine if a personalized thalamic neuromodulation leads to greater improvements in clinical outcome.
Topics: Humans; Seizures; Brain; Epilepsy, Temporal Lobe; Electroencephalography; Drug Resistant Epilepsy; Anterior Thalamic Nuclei; Electrodes, Implanted
PubMed: 37137813
DOI: 10.1093/brain/awad121 -
ELife Mar 2023The paraventricular nucleus of the thalamus (PVT) is known to regulate various cognitive and behavioral processes. However, while functional diversity among PVT circuits...
The paraventricular nucleus of the thalamus (PVT) is known to regulate various cognitive and behavioral processes. However, while functional diversity among PVT circuits has often been linked to cellular differences, the molecular identity and spatial distribution of PVT cell types remain unclear. To address this gap, here we used single nucleus RNA sequencing (snRNA-seq) and identified five molecularly distinct PVT neuronal subtypes in the mouse brain. Additionally, multiplex fluorescent in situ hybridization of top marker genes revealed that PVT subtypes are organized by a combination of previously unidentified molecular gradients. Lastly, comparing our dataset with a recently published single-cell sequencing atlas of the thalamus yielded novel insight into the PVT's connectivity with the cortex, including unexpected innervation of auditory and visual areas. This comparison also revealed that our data contains a largely non-overlapping transcriptomic map of multiple midline thalamic nuclei. Collectively, our findings uncover previously unknown features of the molecular diversity and anatomical organization of the PVT and provide a valuable resource for future investigations.
Topics: Rats; Mice; Animals; Paraventricular Hypothalamic Nucleus; In Situ Hybridization, Fluorescence; Rats, Sprague-Dawley; Neural Pathways; Thalamus; Midline Thalamic Nuclei
PubMed: 36867023
DOI: 10.7554/eLife.81818 -
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 -
The Journal of Neuroscience : the... Oct 2020As one of the thalamic midline nuclei, the thalamic paraventricular nucleus (PVT) is considered to be an important signal integration site for many descending and...
As one of the thalamic midline nuclei, the thalamic paraventricular nucleus (PVT) is considered to be an important signal integration site for many descending and ascending pathways that modulate a variety of behaviors, including feeding, emotions, and drug-seeking. A recent study has demonstrated that the PVT is implicated in the acute visceral pain response, but it is unclear whether the PVT plays a critical role in the central processing of chronic pain. Here, we report that the neurons in the posterior portion of the PVT (pPVT) and their downstream pathway are involved in descending nociceptive facilitation regarding the development of neuropathic pain conditions in male rats. Lesions or inhibition of pPVT neurons alleviated mechanical allodynia induced by spared nerve injury (SNI). The excitability of pPVT-central amygdala (CeA) projection neurons was significantly increased in SNI rats. Importantly, selective optogenetic activation of the pPVT-CeA pathway induced obvious mechanical hypersensitivity in naive rats. In addition, we used rabies virus (RV)-based and cell-type-specific retrograde transsynaptic tracing techniques to define a novel neuronal circuit in which glutamatergic neurons in the vlPAG were the target of the pPVT-CeA descending facilitation pathway. Our data suggest that this pPVT-CeA-vlPAG circuit mediates central mechanisms of descending pain facilitation underlying persistent pain conditions. Studies have shown that the interactions between the posterior portion of the thalamic paraventricular nucleus (pPVT) and central amygdala (CeA) play a critical role in pain-related emotional regulation. However, most reports have associated this circuit with fear and anxiety behaviors. Here, an integrative approach of behavioral tests, electrophysiology, and immunohistochemistry was used to advance the novel concept that the pPVT-CeA pathway activation facilitates neuropathic pain processing. Using rabies virus (RV)-based and cell-type-specific retrograde transsynaptic tracing techniques, we found that glutamatergic neurons in the vlPAG were the target of the pPVT-CeA pathway. Thus, this study indicates the involvement of a pPVT-CeA-vlPAG pathway in a descending facilitatory mechanism underlying neuropathic pain.
Topics: Animals; Behavior, Animal; Central Amygdaloid Nucleus; Electrophysiological Phenomena; Hyperalgesia; Image Processing, Computer-Assisted; Male; Midline Thalamic Nuclei; Neural Pathways; Neuralgia; Neurons; Nociception; Optogenetics; Periaqueductal Gray; Rats; Rats, Sprague-Dawley
PubMed: 32958568
DOI: 10.1523/JNEUROSCI.2487-19.2020 -
Neuron Jan 2021Light exerts profound effects on cognitive functions across species, including humans. However, the neuronal mechanisms underlying the effects of light on cognitive...
Light exerts profound effects on cognitive functions across species, including humans. However, the neuronal mechanisms underlying the effects of light on cognitive functions are poorly understood. In this study, we show that long-term exposure to bright-light treatment promotes spatial memory through a di-synaptic visual circuit related to the nucleus reuniens (Re). Specifically, a subset of SMI-32-expressing ON-type retinal ganglion cells (RGCs) innervate CaMKIIα neurons in the thalamic ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), which in turn activate CaMKIIα neurons in the Re. Specific activation of vLGN/IGL-projecting RGCs, activation of Re-projecting vLGN/IGL neurons, or activation of postsynaptic Re neurons is sufficient to promote spatial memory. Furthermore, we demonstrate that the spatial-memory-promoting effects of light treatment are dependent on the activation of vLGN/IGL-projecting RGCs, Re-projecting vLGN/IGL neurons, and Re neurons. Our results reveal a dedicated subcortical visual circuit that mediates the spatial-memory-promoting effects of light treatment.
Topics: Animals; Lighting; Male; Mice; Mice, Inbred C57BL; Midline Thalamic Nuclei; Nerve Net; Organ Culture Techniques; Photoperiod; Spatial Memory; Visual Pathways
PubMed: 33171117
DOI: 10.1016/j.neuron.2020.10.023