scholarly journals Activity of the Lateral Hypothalamus during Genetically Determined Absence Seizures

2021 ◽  
Vol 22 (17) ◽  
pp. 9466
Author(s):  
Péter Sere ◽  
Nikolett Zsigri ◽  
Timea Raffai ◽  
Szabina Furdan ◽  
Fanni Győri ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Lateral Hypothalamus ◽  
Brain Area ◽  
State Dependence ◽  
Absence Epilepsy ◽  
Absence Seizures ◽  
Spike Wave Discharges ◽  
Genetically Determined

(1) Background: Absence seizures (ASs) are sudden, transient lapses of consciousness associated with lack of voluntary movements and generalized 2.5–4 Hz spike-wave discharges (SWDs) in the EEG. In addition to the thalamocortical system, where these pathological oscillations are generated, multiple neuronal circuits have been involved in their modulation and associated comorbidities including the serotonergic system. Neuronal activity in one of the major synaptic input structures to the brainstem dorsal raphé nucleus (DRN), the lateral hypothalamus (LH), has not been characterized. (2) Methods: We used viral tract tracing and optogenetics combined with in vitro and in vivo electrophysiology to assess the involvement of the LH in absence epilepsy in a genetic rodent model. (3) Results: We found that a substantial fraction of LH neurons project to the DRN of which a minority is GABAergic. The LH to DRN projection can lead to monosynaptic iGluR mediated excitation in DRN 5-HT neurons. Neuronal activity in the LH is coupled to SWDs. (4) Conclusions: Our results indicate that a brain area involved in the regulation of autonomic functions and heavily innervating the RN is involved in ASs. The decreased activity of LH neurons during SWDs could lead to both a decreased excitation and disinhibition in the DRN. These results support a long-range subcortical regulation of serotonergic neuromodulation during ASs and further our understanding of the state-dependence of these seizures and some of their associated comorbidities.

scholarly journals Chemogenetic Activation of Feed-Forward Inhibitory Parvalbumin-Expressing Interneurons in the Cortico-Thalamocortical Network During Absence Seizures

2021 ◽  
Vol 15 ◽  
Author(s):  
Sandesh Panthi ◽  
Beulah Leitch
Keyword(s):  
Absence Epilepsy ◽  
Designer Drug ◽  
Absence Seizure ◽  
Absence Seizures ◽  
Feed Forward ◽  
Video Recordings ◽  
Intraperitoneal Dose ◽  
Spike Wave Discharges ◽  
The Impact

Parvalbumin-expressing (PV+) interneurons are a subset of GABAergic inhibitory interneurons that mediate feed-forward inhibition (FFI) within the cortico-thalamocortical (CTC) network of the brain. The CTC network is a reciprocal loop with connections between cortex and thalamus. FFI PV+ interneurons control the firing of principal excitatory neurons within the CTC network and prevent runaway excitation. Studies have shown that generalized spike-wave discharges (SWDs), the hallmark of absence seizures on electroencephalogram (EEG), originate within the CTC network. In the stargazer mouse model of absence epilepsy, reduced FFI is believed to contribute to absence seizure genesis as there is a specific loss of excitatory α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) at synaptic inputs to PV+ interneurons within the CTC network. However, the degree to which this deficit is directly related to seizure generation has not yet been established. Using chemogenetics and in vivo EEG recording, we recently demonstrated that functional silencing of PV+ interneurons in either the somatosensory cortex (SScortex) or the reticular thalamic nucleus (RTN) is sufficient to generate absence-SWDs. Here, we used the same approach to assess whether activating PV+ FFI interneurons within the CTC network during absence seizures would prevent or reduce seizures. To target these interneurons, mice expressing Cre recombinase in PV+ interneurons (PV-Cre) were bred with mice expressing excitatory Gq-DREADD (hM3Dq-flox) receptors. An intraperitoneal dose of pro-epileptic chemical pentylenetetrazol (PTZ) was used to induce absence seizure. The impact of activation of FFI PV+ interneurons during seizures was tested by focal injection of the “designer drug” clozapine N-oxide (CNO) into either the SScortex or the RTN thalamus. Seizures were assessed in PVCre/Gq-DREADD animals using EEG/video recordings. Overall, DREADD-mediated activation of PV+ interneurons provided anti-epileptic effects against PTZ-induced seizures. CNO activation of FFI either prevented PTZ-induced absence seizures or suppressed their severity. Furthermore, PTZ-induced tonic-clonic seizures were also reduced in severity by activation of FFI PV+ interneurons. In contrast, administration of CNO to non-DREADD wild-type control animals did not afford any protection against PTZ-induced seizures. These data demonstrate that FFI PV+ interneurons within CTC microcircuits could be a potential therapeutic target for anti-absence seizure treatment in some patients.

scholarly journals Homeostatic plasticity and external input shape neural network dynamics

2018 ◽  
Author(s):  
Johannes Zierenberg ◽  
Jens Wilting ◽  
Viola Priesemann
Keyword(s):  
Neural Network ◽  
Brain Area ◽  
External Input ◽  
Homeostatic Plasticity ◽  
Dynamic State ◽  
Network Topologies ◽  
Neural Network Dynamics ◽  
Spiking Activity

In vitro and in vivo spiking activity clearly differ. Whereas networks in vitro develop strong bursts separated by periods of very little spiking activity, in vivo cortical networks show continuous activity. This is puzzling considering that both networks presumably share similar single-neuron dynamics and plasticity rules. We propose that the defining difference between in vitro and in vivo dynamics is the strength of external input. In vitro, networks are virtually isolated, whereas in vivo every brain area receives continuous input. We analyze a model of spiking neurons in which the input strength, mediated by spike rate homeostasis, determines the characteristics of the dynamical state. In more detail, our analytical and numerical results on various network topologies show consistently that under increasing input, homeostatic plasticity generates distinct dynamic states, from bursting, to close-to-critical, reverberating and irregular states. This implies that the dynamic state of a neural network is not fixed but can readily adapt to the input strengths. Indeed, our results match experimental spike recordings in vitro and in vivo: the in vitro bursting behavior is consistent with a state generated by very low network input (< 0.1%), whereas in vivo activity suggests that on the order of 1% recorded spikes are input-driven, resulting in reverberating dynamics. Importantly, this predicts that one can abolish the ubiquitous bursts of in vitro preparations, and instead impose dynamics comparable to in vivo activity by exposing the system to weak long-term stimulation, thereby opening new paths to establish an in vivo-like assay in vitro for basic as well as neurological studies.

scholarly journals Respiratory alkalosis provokes spike-wave discharges in seizure-prone rats

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Kathryn A Salvati ◽  
George MPR Souza ◽  
Adam C Lu ◽  
Matthew L Ritger ◽  
Patrice Guyenet ◽  
...  
Keyword(s):  
Respiratory Alkalosis ◽  
Absence Epilepsy ◽  
Ph Sensitive ◽  
Absence Seizure ◽  
Patient Response ◽  
Absence Seizures ◽  
Intralaminar Nuclei ◽  
Highly Sensitive ◽  
Intralaminar Thalamus ◽  
Spike Wave Discharges

Hyperventilation reliably provokes seizures in patients diagnosed with absence epilepsy. Despite this predictable patient response, the mechanisms that enable hyperventilation to powerfully activate absence seizure-generating circuits remain entirely unknown. By utilizing gas exchange manipulations and optogenetics in the WAG/Rij rat, an established rodent model of absence epilepsy, we demonstrate that absence seizures are highly sensitive to arterial carbon dioxide, suggesting that seizure-generating circuits are sensitive to pH. Moreover, hyperventilation consistently activated neurons within the intralaminar nuclei of the thalamus, a structure implicated in seizure generation. We show that intralaminar thalamus also contains pH-sensitive neurons. Collectively, these observations suggest that hyperventilation activates pH-sensitive neurons of the intralaminar nuclei to provoke absence seizures.

scholarly journals FGCaMP7, an Improved Version of Fungi-Based Ratiometric Calcium Indicator for In Vivo Visualization of Neuronal Activity

2020 ◽  
Vol 21 (8) ◽  
pp. 3012 ◽  
Author(s):  
Natalia V. Barykina ◽  
Vladimir P. Sotskov ◽  
Anna M. Gruzdeva ◽  
You Kure Wu ◽  
Ruben Portugues ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Dynamic Range ◽  
Fluorescent Proteins ◽  
Confocal Imaging ◽  
Ion Concentration ◽  
Neuronal Cultures ◽  
Two Phase ◽  
Intracellular Environment

Genetically encoded calcium indicators (GECIs) have become a widespread tool for the visualization of neuronal activity. As compared to popular GCaMP GECIs, the FGCaMP indicator benefits from calmodulin and M13-peptide from the fungi Aspergillus niger and Aspergillus fumigatus, which prevent its interaction with the intracellular environment. However, FGCaMP exhibits a two-phase fluorescence behavior with the variation of calcium ion concentration, has moderate sensitivity in neurons (as compared to the GCaMP6s indicator), and has not been fully characterized in vitro and in vivo. To address these limitations, we developed an enhanced version of FGCaMP, called FGCaMP7. FGCaMP7 preserves the ratiometric phenotype of FGCaMP, with a 3.1-fold larger ratiometric dynamic range in vitro. FGCaMP7 demonstrates 2.7- and 8.7-fold greater photostability compared to mEGFP and mTagBFP2 fluorescent proteins in vitro, respectively. The ratiometric response of FGCaMP7 is 1.6- and 1.4-fold higher, compared to the intensiometric response of GCaMP6s, in non-stimulated and stimulated neuronal cultures, respectively. We reveal the inertness of FGCaMP7 to the intracellular environment of HeLa cells using its truncated version with a deleted M13-like peptide; in contrast to the similarly truncated variant of GCaMP6s. We characterize the crystal structure of the parental FGCaMP indicator. Finally, we test the in vivo performance of FGCaMP7 in mouse brain using a two-photon microscope and an NVista miniscope; and in zebrafish using two-color ratiometric confocal imaging.

Induction of Parkinsonian-Like Changes via Targeted Downregulation of Astrocytic Glutamate Transporter GLT-1 in the Striatum

2021 ◽  
pp. 1-20
Author(s):  
Chao Ren ◽  
Kai-Jie He ◽  
Hua Hu ◽  
Jin-Bao Zhang ◽  
Li-Guo Dong ◽  
...  
Keyword(s):  
Western Blotting ◽  
High Performance ◽  
Brain Area ◽  
Glutamate Transporter ◽  
Glutamate Excitotoxicity ◽  
Calcium Signal ◽  
Abnormal Gait ◽  
Pet Ct

Background: Previous investigations have suggested that decreased expression of glutamate transporter-1 (GLT-1) is involved in glutamate excitotoxicity and contribute to the development of Parkinson’s disease (PD), GLT-1 is decreased in animal models of PD. GLT-1 is mainly expressed in astrocytes, and the striatum is a GLT-1-rich brain area. Objective: The aim was to explore the function and mechanism of astrocytic GLT-1 in PD-like changes. Methods: In the study, PD-like changes and their molecular mechanism in rodents were tested by a behavioral assessment, micro-positron emission tomography/computed tomography (PET/CT), western blotting, immunohistochemical and immunofluorescence staining, and high performance liquid chromatography pre-column derivatization with O-pthaldialdehida after downregulating astrocytic GLT-1 in vivo and in vitro. Results: In vivo, after 6 weeks of brain stereotactic injection of adeno-associated virus into the striatum, rats in the astrocytic GLT-1 knockdown group showed poorer motor performance, abnormal gait, and depression-like feature; but no olfactory disorders. The results of micro-PET/CT and western blotting indicated that the dopaminergic system was impaired in astrocytic GLT-1 knockdown rats. Similarly, tyrosine hydroxylase (TH) positive immune-staining in neurons of astrocytic GLT-1 knockdown rats showed deficit in cell count. In vitro, knockdown of astrocytic GLT-1 via RNA interference led to morphological injury of TH-positive neurons, which may be related to the abnormal calcium signal induced by glutamate accumulation after GLT-1 knockdown. Furthermore, the GLT-1 agonist ceftriaxone showed a protective effect on TH-positive neuron impairment. Conclusion: The present findings may shed new light on the future prevention and treatment of PD based on blocking glutamate excitotoxicity.

scholarly journals 4009 Magneto-electric nanoparticles (MENs) cobalt ferrite-barrium titanate (CoFe2O4–BaTiO3) for non-invasive neuromodulation

2020 ◽  
Vol 4 (s1) ◽  
pp. 11-11
Author(s):  
Tyler Nguyen ◽  
Zoe Vriesman ◽  
Peter Andrews ◽  
Sehban Masood ◽  
M Stewart ◽  
...  
Keyword(s):  
Magnetic Field ◽  
Neuronal Activity ◽  
Calcium Imaging ◽  
Post Treatment ◽  
Calcium Signals ◽  
Whole Brain ◽  
Non Invasive ◽  
Cortical Regions

OBJECTIVES/GOALS: Our goal is to develop a non-invasive stimulation technique using magneto-electric nanoparticles (MENs) for inducing and enhancing neuronal activity with high spatial and temporal resolutions and minimal toxicity, which can potentially be used as a more effective approach to brain stimulation. METHODS/STUDY POPULATION: MENs compose of core-shell structures that are attracted to strong external magnetic field (~5000 Gauss) but produces electric currents with weaker magnetic field (~450 Gauss). MENs were IV treated into mice and drawn to the brain cortex with a strong magnetic field. We then stimulate MENs with a weaker magnetic field via electro magnet. With two photon calcium imaging, we investigated both the temporal and spatial effects of MENs on neuronal activity both in vivo and in vitro. We performed mesoscopic whole brain calcium imaging on awake animal to assess the MENs effects. Furthermore, we investigated the temporal profile of MENs in the vasculatures post-treatment and its toxicities to CNS. RESULTS/ANTICIPATED RESULTS: MENs were successfully localized to target cortical regions within 30 minutes of magnetic application. After wirelessly applying ~450 G magnetic field between 10-20 Hz, we observed a dramatic increase of calcium signals (i.e. neuronal excitability) both in vitro cultured neurons and in vivo treated animals. Whole brain imaging of awake mice showed a focal increase in calcium signals at the area where MENs localized and the signals spread to regions further away. We also found MENs stimulatory effects lasted up to 24 hours post treatment. MEN stimulation increases c-Fos expression but resulted in no inflammatory changes, up to one week, by assessing microglial or astrocytes activations. DISCUSSION/SIGNIFICANCE OF IMPACT: Our study shows, through controlling the applied magnetic field, MENs can be focally delivered to specific cortical regions with high efficacy and wirelessly activated neurons with high spatial and temporal resolution. This method shows promising potential to be a new non-invasive brain modulation approach disease studies and treatments.

scholarly journals Ps in the (Channel) Pod Are Not Alike …

2007 ◽  
Vol 7 (5) ◽  
pp. 136-137
Author(s):  
Yoav Noam ◽  
Tallie Z. Baram
Keyword(s):  
Neuronal Activity ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Phosphorylation Sites ◽  
Voltage Dependent ◽  
Activity Dependent ◽  
Stimulation Of ◽  
Cultured Hippocampal Neurons

Bidirectional Activity-Dependent Regulation of Neuronal Ion Channel Phosphorylation. Misonou H, Menegola M, Mohapatra DP, Guy LK, Park KS, Trimmer JS. J Neurosci 2006;26(52):13505–13514. Activity-dependent dephosphorylation of neuronal Kv2.1 channels yields hyperpolarizing shifts in their voltage-dependent activation and homoeostatic suppression of neuronal excitability. We recently identified 16 phosphorylation sites that modulate Kv2.1 function. Here, we show that in mammalian neurons, compared with other regulated sites, such as serine (S)563, phosphorylation at S603 is supersensitive to calcineurin-mediated dephosphorylation in response to kainate-induced seizures in vivo, and brief glutamate stimulation of cultured hippocampal neurons. In vitro calcineurin digestion shows that supersensitivity of S603 dephosphorylation is an inherent property of Kv2.1. Conversely, suppression of neuronal activity by anesthetic in vivo causes hyperphosphorylation at S603 but not S563. Distinct regulation of individual phosphorylation sites allows for graded and bidirectional homeostatic regulation of Kv2.1 function. S603 phosphorylation represents a sensitive bidirectional biosensor of neuronal activity.

scholarly journals Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro

2015 ◽  
Vol 112 (20) ◽  
pp. E2725-E2734 ◽  
Author(s):  
Cedric Bardy ◽  
Mark van den Hurk ◽  
Tameji Eames ◽  
Cynthia Marchand ◽  
Ruben V. Hernandez ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Basal Medium ◽  
Physiological Conditions ◽  
Synaptic Functions ◽  
Human Neurons ◽  
Nervous System Function ◽  
Neurophysiological Activity

Human cell reprogramming technologies offer access to live human neurons from patients and provide a new alternative for modeling neurological disorders in vitro. Neural electrical activity is the essence of nervous system function in vivo. Therefore, we examined neuronal activity in media widely used to culture neurons. We found that classic basal media, as well as serum, impair action potential generation and synaptic communication. To overcome this problem, we designed a new neuronal medium (BrainPhys basal + serum-free supplements) in which we adjusted the concentrations of inorganic salts, neuroactive amino acids, and energetic substrates. We then tested that this medium adequately supports neuronal activity and survival of human neurons in culture. Long-term exposure to this physiological medium also improved the proportion of neurons that were synaptically active. The medium was designed to culture human neurons but also proved adequate for rodent neurons. The improvement in BrainPhys basal medium to support neurophysiological activity is an important step toward reducing the gap between brain physiological conditions in vivo and neuronal models in vitro.

scholarly journals Full bandwidth electrophysiology of seizures and epileptiform activity enabled by flexible graphene micro-transistor depth neural probes

2021 ◽  
Author(s):  
Andrea Bonaccini Calia ◽  
Eduard Masvidal-Codina ◽  
Trevor M. Smith ◽  
Nathan Schäfer ◽  
Daman Rathore ◽  
...  
Keyword(s):  
High Frequency ◽  
Epileptiform Activity ◽  
Epileptic Activity ◽  
Absence Epilepsy ◽  
Neural Probes ◽  
Chemically Induced ◽  
Metal Microelectrode ◽  
Spike Wave Discharges ◽  
Implanted Devices

ABSTRACTMapping the entire frequency bandwidth of neuronal oscillations in the brain is of paramount importance for understanding physiological and pathological states. The ability to record simultaneously infraslow activity (<0.1 Hz) and higher frequencies (0.1-600 Hz) using the same recording electrode would particularly benefit epilepsy research. However, commonly used metal microelectrode technology is not well suited for recording infraslow activity. Here we use flexible graphene depth neural probes (gDNP), consisting of a linear array of graphene microtransistors, to concurrently record infraslow and high frequency neuronal activity in awake rodents. We show that gDNPs can reliably record and map with high spatial resolution seizures, post-ictal spreading depolarisation, and high frequency epileptic activity through cortical laminae to the CA1 layer of the hippocampus in a mouse model of chemically-induced seizures. We demonstrate functionality of chronically implanted devices over 10 weeks by recording with high fidelity spontaneous spike-wave discharges and associated infraslow activity in a rat model of absence epilepsy. Altogether, our work highlights the suitability of this technology for in vivo electrophysiology research, in particular, to examine the contributions of infraslow activity to seizure initiation and termination.

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