Mutations in ion channel genes have long been implicated in a spectrum of epilepsy syndromes. However, therapeutic decision-making is relatively complex for epilepsies associated with channelopathy. Therefore, in the present study, we used a patient-derived organoid model with a novel SCN2A mutation (p.E512K) to investigate the potential of utilizing such a model as a platform for preclinical testing of anti-seizure compounds. The electrophysiological properties of the variant Nav1.2 exhibited gain-of-function effects with increased current amplitude and premature activation. Immunofluorescence staining of patient-derived cortical organoids (COs) displayed normal neurodevelopment. Multielectrode array (MEA) recordings of patient-derived COs showed hyperexcitability with increased spiking and remarkable network bursts. Moreover, the application of patient-derived COs for preclinical drug testing using the MEA showed that they exhibit differential responses to various anti-seizure drugs and respond well to carbamazepine. Our results demonstrate that the individualized organoids have the potential to serve as a platform for preclinical pharmacological assessment.
Organoids/physiology* ; NAV1.2 Voltage-Gated Sodium Channel/genetics* ; Humans ; Anticonvulsants/pharmacology* ; Epilepsy/drug therapy* ; Mutation ; Cerebral Cortex/drug effects* ; Action Potentials/drug effects* ; Carbamazepine/pharmacology*

The retrosplenial cortex has been implicated in processing sensory information and spatial learning, with abnormal neural activity reported in association with psychedelics and in mouse and non-human primate models of autism spectrum disorders (ASDs). The direct role of the retrosplenial cortex in regulating social behaviors remains unclear. In this work, we reveal that neural activity in the retrosplenial agranular cortex (RSA), a subregion of the retrosplenial cortex, is initially activated, then quickly suppressed upon social contact. This up-down phase of RSA neurons is crucial for normal social behaviors. Parvalbumin-positive GABAergic neurons in the hippocampal CA1 region were found to send inhibitory projections to the RSA. Blocking these CA1-RSA inhibitory inputs significantly impaired social behavior. Notably, enhancing the CA1-RSA inhibitory input rescued the social behavior defects in an ASD mouse model. This work suggests a neural mechanism for the salience processing of social behavior and identifies a potential target for ASD intervention using neural modulation approaches.
Animals ; Social Behavior ; CA1 Region, Hippocampal/physiology* ; Mice ; Male ; Autism Spectrum Disorder/physiopathology* ; Mice, Inbred C57BL ; GABAergic Neurons/drug effects* ; Neural Inhibition/drug effects* ; Parvalbumins/metabolism* ; Neural Pathways/physiology* ; Cerebral Cortex/physiology*

General anesthesia plays a significant role in modern medicine. However, the precise mechanism of general anesthesia remains unclear, posing a key scientific challenge in anesthesiology. Advances in neuroscience techniques have enabled targeted manipulation of specific neural circuits and the capture of brain-wide neural activity at high resolution. These advances hold promise for elucidating the intricate mechanisms of action of general anesthetics. This review aims to summarize our current understanding of the role of cortical and subcortical nuclei in modulating general anesthesia, providing new evidence of cortico-cortical and thalamocortical networks in relation to anesthesia and consciousness. These insights contribute to a comprehensive understanding of the neural network mechanisms underlying general anesthesia.
Humans ; Anesthesia, General ; Animals ; Nerve Net/physiology* ; Cerebral Cortex/drug effects* ; Neural Pathways/drug effects* ; Thalamus/drug effects* ; Consciousness/drug effects*

While inflammatory bowel disease (IBD) might be a risk factor in the development of brain dysfunctions, the underlying mechanisms are largely unknown. Here, mice were treated with 5% dextran sodium sulfate (DSS) in drinking water and sacrificed on day 7. The serum level of IL-6 increased, accompanied by elevation of the IL-6 and TNF-α levels in cortical tissue. However, the endotoxin concentration in plasma and brain of mice with DSS-induced colitis showed a rising trend, but with no significant difference. We also found significant activation of microglial cells and reduction in occludin and claudin-5 expression in the brain tissue after DSS-induced colitis. These results suggested that DSS-induced colitis increases systemic inflammation which then results in cortical inflammation via up-regulation of serum cytokines. Here, we provide new information on the impact of colitis on the outcomes of cortical inflammation.
Animals ; Calcium-Binding Proteins ; metabolism ; Caspase 3 ; metabolism ; Cerebral Cortex ; pathology ; Claudin-5 ; metabolism ; Colitis ; chemically induced ; complications ; pathology ; Cytokines ; genetics ; metabolism ; Dextran Sulfate ; toxicity ; Disease Models, Animal ; Encephalitis ; etiology ; Gene Expression Regulation ; drug effects ; Mice ; Microfilament Proteins ; metabolism ; Occludin ; metabolism ; Polysaccharides ; blood ; toxicity ; Time Factors

OBJECTIVETo investigate acrylamide (ACR)-induced subacute neurotoxic effects on the central nervous system (CNS) at the synapse level in rats.

METHODSThirty-six Sprague Dawley (SD) rats were randomized into three groups, (1) a 30 mg/kg ACR-treated group, (2) a 50 mg/kg ACR-treated group, and (3) a normal saline (NS)-treated control group. Body weight and neurological changes were recorded each day. At the end of the test, cerebral cortex and cerebellum tissues were harvested and viewed using light and electron microscopy. Additionally, the expression of Synapsin I and P-Synapsin I in the cerebral cortex and cerebellum were investigated.

RESULTSThe 50 mg/kg ACR-treated rats showed a significant reduction in body weight compared with untreated individuals (P < 0.05). Rats exposed to ACR showed a significant increase in gait scores compared with the NS control group (P < 0.05). Histological examination indicated neuronal structural damage in the 50 mg/kg ACR treatment group. The active zone distance (AZD) and the nearest neighbor distance (NND) of synaptic vesicles in the cerebral cortex and cerebellum were increased in both the 30 mg/kg and 50 mg/kg ACR treatment groups. The ratio of the distribution of synaptic vesicles in the readily releasable pool (RRP) was decreased. Furthermore, the expression levels of Synapsin I and P-Synapsin I in the cerebral cortex and cerebellum were decreased in both the 30 mg/kg and 50 mg/kg ACR treatment groups.

CONCLUSIONSubacute ACR exposure contributes to neuropathy in the rat CNS. Functional damage of synaptic proteins and vesicles may be a mechanism of ACR neurotoxicity.

Acrylamide ; toxicity ; Animals ; Cerebellum ; cytology ; drug effects ; Cerebral Cortex ; cytology ; drug effects ; Drug Administration Schedule ; Gait ; Gene Expression Regulation ; drug effects ; Male ; Neurons ; drug effects ; Neurotoxicity Syndromes ; pathology ; Rats ; Rats, Sprague-Dawley ; Synapses ; drug effects ; Synapsins ; genetics ; metabolism ; Synaptic Vesicles ; drug effects ; physiology ; Weight Loss ; drug effects

OBJECTIVETo investigate the effect of corticosterone on the expression of the neuronal migration protein lissencephaly 1 (LIS1) in developing cerebral cortical neurons of fetal rats.

METHODSThe primary cultured cerebral cortical neurons of fetal Wistar rats were divided into control group, low-dose group, and high-dose group. The neurons were exposed to the medium containing different concentrations of corticosterone (0 μmol/L for the control group, 0.1 μmol/L for the low-dose group, and 1.0 μmol/L for the high-dose group). The neurons were collected at 1, 4, and 7 days after intervention. Western blot and immunocytochemical staining were used to observe the change in LIS1 expression in neurons.

RESULTSWestern blot showed that at 7 days after intervention, the low- and high-dose groups had significantly higher expression of LIS1 in the cytoplasm and nucleus of cerebral cortical neurons than the control group (P<0.05), and the high-dose group had significantly lower expression of LIS1 in the cytoplasm of cerebral cortical neurons than the low-dose group (P<0.05). Immunocytochemical staining showed that at 1, 4, and 7 days after corticosterone intervention, the high-dose group had a significantly lower mean optical density of LIS1 than the control group and the low-dose group (P<0.05). At 7 days after intervention, the low-dose group had a significantly lower mean optical density of LIS1 than the control group (P<0.05).

CONCLUSIONSCorticosterone downregulates the expression of the neuronal migration protein LIS1 in developing cerebral cortical neurons of fetal rats cultured in vitro, and such effect depends on the concentration of corticosterone and duration of corticosterone intervention.

1-Alkyl-2-acetylglycerophosphocholine Esterase ; analysis ; genetics ; Animals ; Cells, Cultured ; Cerebral Cortex ; drug effects ; metabolism ; Corticosterone ; pharmacology ; Dose-Response Relationship, Drug ; Female ; Fetus ; drug effects ; Microtubule-Associated Proteins ; analysis ; genetics ; Pregnancy ; Rats ; Rats, Wistar

OBJECTIVETo investigate the protective effect of histone acetylation against hypoxic-ischemic cortical injury in neonatal rats.

METHODSA total of 90 neonatal rats aged 3 days were divided into three groups: sham-operation, cortical injury model, and sodium butyrate (a histone deacetylase inhibitor) treatment. The rats in the model and the sodium butyrate treatment groups were intraperitoneally injected with lipopolysaccharide (0.05 mg/kg), and then right common carotid artery ligation was performed 2 hours later and the rats were put in a hypoxic chamber (oxygen concentration 6.5%) for 90 minutes. The rats in the sham-operation group were intraperitoneally injected with normal saline and the right common carotid artery was only separated and exposed without ligation or hypoxic treatment. The rats in the sodium butyrate treatment group were intraperitoneally injected with sodium butyrate (300 mg/kg) immediately after establishment of the cortical injury model once a day for 7 days. Those in the sham-operation and the model groups were injected with the same volume of normal saline. At 7 days after establishment of the model, Western blot was used to measure the protein expression of histone H3 (HH3), acetylated histone H3 (AH3), B-cell lymphoma/leukemia-2 (Bcl-2), Bcl-2-associated X protein (BAX), cleaved caspase-3 (CC3), and brain-derived neurotrophic factor (BDNF). Immunofluorescence assay was used to measure the expression of 5-bromo-2'-deoxyuridine (BrdU) as the cortex cell proliferation index.

RESULTSThe sodium butyrate treatment group had a significantly lower HH3/AH3 ratio than the model group (P<0.05), which suggested that the sodium butyrate treatment group had increased acetylation of HH3. Compared with the model group, the sodium butyrate treatment group had a significant increase in Bcl-2/Bax ratio, a significant reduction in CC3 expression, and a significant increase in BDNF expression (P<0.05). The sodium butyrate treatment group had a significant increase in the number of BrdU-positive cells in the cortex compared with the model group (P<0.05), and BrdU was mainly expressed in the neurons.

CONCLUSIONSIncreased histone acetylation may protect neonatal rats against cortical injury by reducing apoptosis and promoting regeneration of neurons. The mechanism may be associated with increased expression of BDNF.

Acetylation ; Animals ; Animals, Newborn ; Apoptosis ; drug effects ; Brain-Derived Neurotrophic Factor ; analysis ; Butyric Acid ; therapeutic use ; Cerebral Cortex ; pathology ; Female ; Histones ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo explore the protective effects of rutin against learning and memory impairment induced by trimethyltin (TMT) and investigate the possible mechanism.

METHODSForty 6- to 9-week-old male BALB/c mice were randomized equally into saline group (control), TMT group, TMT+rutin group, and rutin group. Mouse models of learning and memory impairment were establish by acute TMT (2.25 mg/kg) exposure. In TMT+rutin and rutin treatment groups, the mice received intraperitioneal injection of rutin (10 mg/kg) for 1 week before TMT exposure. Twenty-four hours after TMT exposure, Morris water maze test was employed to test the escape latency of the mice, and the synaptophysin expression in the hippocampus and cortex were analyzed by Western blotting.

RESULTSCompared that in TMT group, the escape latency of the mice in water maze test was significantly shorter in the other 3 groups (P<0.05); the escape latency in TMT +rutin group was similar with that in the control and rutin groups (P>0.05). Western blotting showed significantly decreased synaptophysin expression in the hippocampus and cortex in TMT group (P<0.05); synaptophysin expression in TMT +rutin group increased significantly compared with that in TMT group (P<0.05) but showed no statistical significance from that in rutin and control groups (P>0.05).

CONCLUSIONRutin pretreatment offers protective effect against TMT-induced learning and memory impairment in mice possibly by antagonizing decreased synaptophysin in the hippocampus and cortex.

Animals ; Cerebral Cortex ; drug effects ; metabolism ; Hippocampus ; drug effects ; metabolism ; Learning ; drug effects ; Male ; Memory Disorders ; chemically induced ; drug therapy ; Mice ; Mice, Inbred BALB C ; Neuroprotective Agents ; pharmacology ; Rutin ; pharmacology ; Synaptophysin ; metabolism ; Trimethyltin Compounds ; adverse effects

OBJECTIVETo investigate the changes of telemetry electrical activity in the infralimbic cortex (IL) of morphine-dependent rats with extinguished drug-seeking behavior.

METHODSSD rats were randomly divided into model group and control group and received operations of brain stereotaxic electrode embedding in the IL. The rats in the model group were induced to acquire morphine dependence and then received subsequent extinction training, and the changes of electrical activity in the IL were recorded with a physical wireless telemetry system.

RESULTSIn rats with morphine dependence, the time staying in the white box was significantly longer on days 1 and 2 after withdrawal than that before morphine injection and that of the control rats, but was obviously reduced on days 1 and 2 after extinction training to the control level. Compared with the control group, the morphine-dependent rats on day 2 following withdrawal showed significantly increased β wave and decreased δ wave when they stayed in the white box but significantly increased δ wave and decreased α wave and β wave when they shuttled from the black to the white box. On day 2 of extinction, the model rats, when staying in the white box, showed significantly decreased θ wave compared with that of the control rats group but decreased β wave and θ wave and increased δ wave compared with those in the withdrawal period. When they shuttled from black to white box, the model rats showed decreased δ wave and increased α wave and β wave compared with those in the withdrawal period.

CONCLUSIONMorphine-dependent rats have abnormal changes of electrical activity in the IL in drug-seeking extinction to affect their drug-seeking motive and inhibit the expression and maintenance of drug-seeking behaviors.

Animals ; Cerebral Cortex ; drug effects ; physiology ; Drug-Seeking Behavior ; physiology ; Electrophysiological Phenomena ; Extinction, Psychological ; Morphine ; pharmacology ; Morphine Dependence ; physiopathology ; Rats ; Rats, Sprague-Dawley ; Telemetry

OBJECTIVETo explore the role of P53 phosphorylation in neuron apoptosis of rats by chronic aluminum exposure.

METHODSA total of male 40 SD rats were divided randomly into 4 groups (n = 10/dose), the exposed groups were fed with normal diet with different concentration of AlCl3 · 6H2O for 6 months respectively. The dosage of low, middle and high groups were 10.73, 107.33, 1073.33 mg/kg in sequence. The control group received normal diet. The neuron apoptosis was measured by method of Tunel. The expressions of P53 and pP53-ser15 protein in the cortex were detected by Western-blot.

RESULTSTunel staining showed that the low, middle and high group rats had increased apoptosis rate than control group (P < 0.01). Western-blot test demonstrated that the expression of P53 protein in the cortex of high group rats were significantly higher than the control and low groups (P < 0.05). The expression of pP53-ser15 protein in the cortex of middle and high group rats were also higher than the control and low groups (P < 0.05).

CONCLUSIONChronic aluminum exposure can lead to over expression of P53 and pP53-ser15 protein in cerebral cortex, which maybe one of the most important mechanisms of neuron apoptosis induced by AlCl3.

Aluminum ; toxicity ; Aluminum Compounds ; toxicity ; Animals ; Apoptosis ; Cerebral Cortex ; metabolism ; Chlorides ; toxicity ; Male ; Neurons ; cytology ; drug effects ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Tumor Suppressor Protein p53 ; metabolism