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Allogeneic modified bone marrow-derived human mesenchymal stromal/stem cells (hMSC-SB623 cells) are in clinical development for the treatment of chronic motor deficits after traumatic brain injury and cerebral ischemic stroke. However, their exact mechanisms of action remain unclear. Here, we investigated the effects of this cell therapy on cortical network excitability, brain tissue, and peripheral blood at a chronic stage after ischemic stroke in a rat model. One month after focal cortical ischemic stroke, hMSC-SB623 cells or the vehicle solution were injected into the peri-stroke cortex. Starting one week after treatment, cortical excitability was assessed ex vivo. hMSC-SB623 cell transplants reduced stroke-induced cortical hyperexcitability, restoring cortical excitability to control levels. The histology of brain tissue revealed an increase of factors relevant to neuroregeneration, and synaptic and cellular plasticity. Whole-blood RNA sequencing and serum protein analyses showed that intra-cortical hMSC-SB623 cell transplantation reversed effects of stroke on peripheral blood factors known to be involved in stroke pathophysiology. Our findings demonstrate that intra-cortical transplants of hMSC-SB623 cells correct stroke-induced circuit disruptions even at the chronic stage, suggesting broad usefulness as a therapeutic for neurological conditions with network hyperexcitability. Additionally, the transplanted cells exert far-reaching immunomodulatory effects whose therapeutic impact remains to be explored., Competing Interests: Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: B.K., P.M.L., A.S., S.S.M., J.B., W.C.C., Y.A.Z., B.N., and Z.W. were/are SanBio, Inc., employees and/or paid consultants, and may have received stock options as part of their compensation. SanBio, Inc., filed a provisional patent application entitled, "Therapeutic methods and composition for restoring cortical excitability and neural plasticity after stroke" (inventors B.K., Y.A.Z, Z.W., and J.T.P.)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Inflammatory processes induced by brain injury are important for recovery; however, when uncontrolled, inflammation can be deleterious, likely explaining why most anti-inflammatory treatments have failed to improve neurological outcomes after brain injury in clinical trials. In the thalamus, chronic activation of glial cells, a proxy of inflammation, has been suggested as an indicator of increased seizure risk and cognitive deficits that develop after cortical injury. Furthermore, lesions in the thalamus, more than other brain regions, have been reported in patients with viral infections associated with neurological deficits, such as SARS-CoV-2. However, the extent to which thalamic inflammation is a driver or by-product of neurological deficits remains unknown. Here, we found that thalamic inflammation in mice was sufficient to phenocopy the cellular and circuit hyperexcitability, enhanced seizure risk, and disruptions in cortical rhythms that develop after cortical injury. In our model, down-regulation of the GABA transporter GAT-3 in thalamic astrocytes mediated this neurological dysfunction. In addition, GAT-3 was decreased in regions of thalamic reactive astrocytes in mouse models of cortical injury. Enhancing GAT-3 in thalamic astrocytes prevented seizure risk, restored cortical states, and was protective against severe chemoconvulsant-induced seizures and mortality in a mouse model of traumatic brain injury, emphasizing the potential of therapeutically targeting this pathway. Together, our results identified a potential therapeutic target for reducing negative outcomes after brain injury. more...

Although traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of mild TBI (mTBI), we found a chronic increase in C1q expression specifically in the corticothalamic system. Increased C1q expression colocalized with neuron loss and chronic inflammation and correlated with disruption in sleep spindles and emergence of epileptic activities. Blocking C1q counteracted these outcomes, suggesting that C1q is a disease modifier in mTBI. Single-nucleus RNA sequencing demonstrated that microglia are a source of thalamic C1q. The corticothalamic circuit could thus be a new target for treating TBI-related disabilities. more...

Visual perception in natural environments depends on the ability to focus on salient stimuli while ignoring distractions. This kind of selective visual attention is associated with gamma activity in the visual cortex. While the nucleus reticularis thalami (nRT) has been implicated in selective attention, its role in modulating gamma activity in the visual cortex remains unknown. Here, we show that somatostatin- (SST) but not parvalbumin-expressing (PV) neurons in the visual sector of the nRT preferentially project to the dorsal lateral geniculate nucleus (dLGN), and modulate visual information transmission and gamma activity in primary visual cortex (V1). These findings pinpoint the SST neurons in nRT as powerful modulators of the visual information encoding accuracy in V1 and represent a novel circuit through which the nRT can influence representation of visual information., Competing Interests: MH, BH, FC, AC, AC, IL, AC, MS, JP No competing interests declared, (© 2021, Hoseini et al.) more...

Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.) more...

The thalamic reticular nucleus (TRN) is optimally positioned to regulate information processing and state dynamics in dorsal thalamus. Distinct inputs depolarize TRN on multiple time scales, including thalamocortical afferents, corticothalamic 'feedback', and neuromodulation. Here, we systematically tested the concurrent and after-effects of depolarization duration on TRN firing in vivo using selective optogenetic drive. In VGAT-ChR2 mice, we isolated TRN single units (SU: N = 100 neurons) that responded at brief latency (≤5 ms) to stimulation. These units, and multi-unit activity (MUA) on corresponding electrodes, were analyzed in detail. Consistent with prior findings in relay neurons, after light cessation, burst-like events occurred in 74% of MUA sites, and 16% of SU. Increasing optical duration from 2 to 330 ms enhanced this burst probability, and decreased the latency to the first burst after stimulation. During stimulation, neurons demonstrated a 'plateau' firing response lasting 20-30 ms in response to light, but significant heterogeneity existed in the minimal stimuli required to drive this response. Two distinct types were evident, more sensitive 'non-linear' neurons that were driven to the plateau response by 2 or 5 ms pulses, versus 'linear' neurons that fired proportionally to optical duration, and reached the plateau with ∼20-ms optical drive. Non-linear neurons showed higher evoked firing rates and burst probability, but spontaneous rate did not differ between types. These findings provide direct predictions for TRN responses to a range of natural depolarizing inputs, and a guide for the optical control of this key structure in studies of network function and behavior., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.) more...

Integrative brain functions depend on widely distributed, rhythmically coordinated computations. Through its long-ranging connections with cortex and most senses, the thalamus orchestrates the flow of cognitive and sensory information. Essential in this process, the nucleus reticularis thalami (nRT) gates different information streams through its extensive inhibition onto other thalamic nuclei, however, we lack an understanding of how different inhibitory neuron subpopulations in nRT function as gatekeepers. We dissociated the connectivity, physiology, and circuit functions of neurons within rodent nRT, based on parvalbumin (PV) and somatostatin (SOM) expression, and validated the existence of such populations in human nRT. We found that PV, but not SOM, cells are rhythmogenic, and that PV and SOM neurons are connected to and modulate distinct thalamocortical circuits. Notably, PV, but not SOM, neurons modulate somatosensory behavior and disrupt seizures. These results provide a conceptual framework for how nRT may gate incoming information to modulate brain-wide rhythms., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Optogenetics provides an array of elements for specific biophysical control, while designer chemogenetic receptors provide a minimally invasive method to control circuits in vivo by peripheral injection. We developed a strategy for selective regulation of activity in specific cells that integrates opto- and chemogenetic approaches, and thus allows manipulation of neuronal activity over a range of spatial and temporal scales in the same experimental animal. Light-sensing molecules (opsins) are activated by biologically produced light through luciferases upon peripheral injection of a small molecule substrate. Such luminescent opsins, luminopsins, allow conventional fiber optic use of optogenetic sensors, while at the same time providing chemogenetic access to the same sensors. We describe applications of this approach in cultured neurons in vitro, in brain slices ex vivo, and in awake and anesthetized animals in vivo. more...