Hydroxychloroquine (HCQ), a well-known antimalarial and anti-inflammatory drug, has demonstrated potential neuroprotective effects in ischemic stroke by inhibiting pyroptosis, a programmed cell death associated with inflammation. This study investigates the impact of HCQ on ischemic stroke pathology using both in vivo and in vitro models. In vivo, C57BL/6 mice subjected to middle cerebral artery occlusion (MCAO) were treated with HCQ. Neurological deficits, infarct volume, and the expression of pyroptosis markers were evaluated. The results demonstrated that HCQ significantly improved motor function and reduced infarct volume in the MCAO mouse model. In vitro, BV2 microglial cells exposed to lipopolysaccharide (LPS) and oxygen–glucose deprivation (OGD) were treated with HCQ. Western blot and immunofluorescence analyses revealed that HCQ effectively suppressed the expression of pyroptosis markers GSDMD and NLRP3 in both in vivo and in vitro models. These findings suggest that HCQ mitiga

Brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) are known to contribute to both protective and pronociceptive processes. However, their contribution to neuropathic pain after spinal cord injury (SCI) needs further investigation. In a recent study utilizing TrkBF616A mice, it was shown that systemic pharmacogenetic inhibition of TrkB signaling with 1NM-PP1 (1NMP) immediately after SCI delayed the onset of pain hypersensitivity, implicating maladaptive TrkB signaling in pain after SCI. To examine potential neural mechanisms underlying the behavioral outcome, patch-clamp recording was performed in small-diameter dissociated thoracic (T) dorsal root ganglia (DRG) neurons to evaluate TrkB signaling in uninjured mice and after T10 contusion SCI. Bath-applied 7,8-dihydroxyflavone (7,8-DHF), a selective TrkB agonist, induced a robust inward current in neurons from uninjured mice, which was attenuated by 1NMP treatment. SCI also decreased 7,8-DHF-induced curren

Single-nucleus RNA-sequencing (snRNA-seq) has revealed new levels of cellular organization and diversity within the human brain. However, full-length mRNA isoforms are not resolved in typical snRNA-seq analyses using short-read sequencing that cannot capture full-length transcripts. Here we combine standard 10x Genomics short-read snRNA-seq with targeted PacBio long-read snRNA-seq to examine isoforms of genes associated with neurological diseases at the single-cell level from prefrontal cortex samples of diseased and nondiseased human brain, assessing over 165,000 cells. Samples from 25 postmortem donors with Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), or Parkinson’s disease (PD), along with age-matched controls, were compared. Analysis of the short-read libraries identified shared and distinct gene expression changes across the diseases. The same libraries were then assayed using enrichment probes to target 50 disease-related genes followed by long-read PacBio sequencin

Selective modifications in the expression or function of dendritic ion channels regulate the propagation of synaptic inputs and determine the intrinsic excitability of a neuron. Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels open upon membrane hyperpolarization and conduct a depolarizing inward current ( I h). HCN channels are enriched in the dendrites of hippocampal pyramidal neurons where they regulate the integration of synaptic inputs. Synaptic plasticity can bidirectionally modify dendritic HCN channels in excitatory neurons depending on the strength of synaptic potentiation. In inhibitory neurons, however, the dendritic expression and modulation of HCN channels are largely unknown. In this study, we systematically compared the modulation of I h by synaptic potentiation in hippocampal CA1 pyramidal neurons and stratum radiatum (sRad) interneurons in mouse organotypic cultures. I h properties were similar in inhibitory and excitatory neurons and contributed to r

In an effort to increase access to neuroscience education in underserved communities, we created an educational program that utilizes a simple task to measure place preference of the cockroach ( Gromphadorhina portentosa ) and the open-source free software, SLEAP Estimates Animal Poses (SLEAP) to quantify behavior. Cockroaches ( n  = 18) were trained to explore a linear track for 2 min while exposed to either air, vapor, or vapor with nicotine from a port on one side of the linear track over 14 d. The time the animal took to reach the port was measured, along with distance traveled, time spent in each zone, and velocity. As characterizing behavior is challenging and inaccessible for nonexperts new to behavioral research, we created an educational program using the machine learning algorithm, SLEAP, and cloud-based (i.e., Google Colab) low-cost platforms for data analysis. We found that SLEAP was within a 0.5% margin of error when compared with manually scoring the data. Cockroaches wer

Chromatin regulation plays a crucial role in neocortical neurogenesis, and mutations in chromatin modifiers are linked to neurodevelopmental disorders. RBBP4 is a core subunit of several chromatin-modifying complexes; however, its functional role and genome-wide occupancy profile in the neocortical primordium are unknown. To address this, we performed RBBP4 knockdown using CRISPR/Cas9 on neocortical progenitors derived from mice of both sexes at embryonic age 12.5 during deep layer neurogenesis. Our study demonstrates that downregulation of RBBP4 in the E12.5 neocortical progenitors reduced neuronal output, specifically affecting CTIP2-expressing neurons. We demonstrate that RBBP4 plays an essential role in regulating neocortical progenitor proliferation. However, overexpression of RBBP4 alone was not sufficient to regulate neuronal fate. Genome-wide occupancy analysis revealed that RBBP4 primarily binds to distal regulatory elements, and neuron differentiation is a significant GO biol

The medial frontal cortex (mFC) and locus ceruleus (LC) are two brain areas that have been implicated in a range of cognitive phenomena, such as attention, memory, and decision-making. Regulators of these brain regions at the molecular level are not well understood but might help to elucidate underlying mechanisms of disorders that present with deficits in these cognitive domains. To probe this, we used chemogenetic stimulation of neurons in the LC with axonal projections to the prelimbic subregion (PrL) of the mFC and subsequent bulk RNA sequencing from the mouse PrL. We found that stimulation of this circuit caused an increase in transcription of a host of genes, including the Apoe gene. To investigate cell type-specific expression of Apoe in the PrL, we used a dual-virus approach to express either the excitatory DREADD receptor hM3Dq in LC neurons with projections to the PrL or a control virus and found that increases in Apoe expression in the PrL following depolarization of LC inpu

Certain structural brain connections have been confirmed to influence sleep duration in children. However, the causal relationships between all brain regions and children’s sleep duration remain unclear. A two-sample Mendelian randomization analysis was conducted using data from genome-wide association studies (GWAS) to examine the relationships between 206 structural connections and sleep duration in children. Sensitivity analyses were employed to validate the findings and assess the robustness of the causal inferences. Stronger connectivity from the left hemisphere (LH) control network to the accumbens ( β  = −0.15; 95% CI = [−0.30, −2.88 × 10−3]; p  = 0.05) and from the LH somatomotor network to the LH default network ( β  = −0.18; 95% CI = [−0.34, −0.03]; p  = 0.02) in white-matter structural connectivity (SC) were associated with shorter sleep durations. Conversely, increased white-matter SC from the LH dorsal attention network to the thalamus ( β  = 0.14; 95% CI = [8.45 × 10−4, 0