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Acta Medica Okayama Jun 2024Zolpidem, a non-benzodiazepine hypnotic, is primarily used to treat insomnia. In a previous study, pior treatment with non-benzodiazepine receptor agonists was...
Zolpidem, a non-benzodiazepine hypnotic, is primarily used to treat insomnia. In a previous study, pior treatment with non-benzodiazepine receptor agonists was associated with inflammation. The present study aimed to clarify the association between the effects of zolpidem and inflammation in mice treated with lipopolysaccharide (LPS), a known model of inflammation. We assessed the zolpidem-induced loss of righting reflex (LORR) duration 24 h after LPS treatment in mice. Additionally, the expressions of γ-aminobutyric acid (GABA)A receptor subunit and K+-Cl- cotransporter isoform 2 (KCC2) mRNA in the hippocampus and frontal cortex were examined in LPS-treated mice. Pretreatment with LPS was associated with significantly prolonged duration of zolpidem-induced LORR compared to control mice. This effect was significantly attenuated by administering bicuculline, a GABAA receptor antagonist, or flumazenil, a benzodiazepine receptor antagonist, in LPS-treated mice. Compared to controls, LPS-treated mice showed no significant change in the expression of GABAA receptor subunits in the hippocampus or frontal cortex. Bumetanide, an Na+-K+-2Cl- cotransporter isoform 1 blocker, attenuated the extended duration of zolpidem-induced LORR observed in LPS-treated mice. LPS significantly decreased Kcc2 mRNA expression in the hippocampus and the frontal cortex. These findings suggest that inflammation increases zolpidem-induced LORR, possibly through a reduction in KCC2 expression.
Topics: Animals; Zolpidem; Lipopolysaccharides; Mice; Pyridines; Male; Receptors, GABA-A; Symporters; Reflex, Righting; Hippocampus; K Cl- Cotransporters; Hypnotics and Sedatives; Inflammation; Frontal Lobe
PubMed: 38902210
DOI: 10.18926/AMO/67197 -
ENeuro Jun 2024Formation and retrieval of remote contextual memory depends on cortical engram neurons that are defined during learning. Manipulation of astrocytic G and G associated...
Formation and retrieval of remote contextual memory depends on cortical engram neurons that are defined during learning. Manipulation of astrocytic G and G associated G-protein coupled receptor (GPCR) signaling has been shown to affect memory processing, but little is known about the role of cortical astrocytic G-GPCR signaling in remote memory acquisition and the functioning of cortical engram neurons. We assessed this by chemogenetic manipulation of astrocytes in the medial prefrontal cortex (mPFC) of male mice, during either encoding or consolidation of a contextual fear memory, while simultaneously labeling cortical engram neurons. We found that stimulation of astrocytic G signaling during memory encoding and consolidation did not alter remote memory expression. In line with this, the size of the mPFC engram population and the recall-induced reactivation of these neurons was unaffected. Hence, our data indicate that activation of G-GPCR signaling in cortical astrocytes is not sufficient to alter memory performance and functioning of cortical engram neurons.
Topics: Animals; Astrocytes; Male; Prefrontal Cortex; Signal Transduction; Neurons; Fear; Mice, Inbred C57BL; GTP-Binding Protein alpha Subunits, Gs; Mice; Memory; Memory, Long-Term
PubMed: 38902023
DOI: 10.1523/ENEURO.0056-24.2024 -
PloS One 2024Based on the CRISP theory (Content Representation, Intrinsic Sequences, and Pattern completion), we present a computational model of the hippocampus that allows for...
Based on the CRISP theory (Content Representation, Intrinsic Sequences, and Pattern completion), we present a computational model of the hippocampus that allows for online one-shot storage of pattern sequences without the need for a consolidation process. In our model, CA3 provides a pre-trained sequence that is hetero-associated with the input sequence, rather than storing a sequence in CA3. That is, plasticity on a short timescale only occurs in the incoming and outgoing connections of CA3, not in its recurrent connections. We use a single learning rule named Hebbian descent to train all plastic synapses in the network. A forgetting mechanism in the learning rule allows the network to continuously store new patterns while forgetting those stored earlier. We find that a single cue pattern can reliably trigger the retrieval of sequences, even when cues are noisy or missing information. Furthermore, pattern separation in subregion DG is necessary when sequences contain correlated patterns. Besides artificially generated input sequences, the model works with sequences of handwritten digits and natural images. Notably, our model is capable of improving itself without external input, in a process that can be referred to as 'replay' or 'offline-learning', which helps in improving the associations and consolidating the learned patterns.
Topics: Neural Networks, Computer; Models, Neurological; Humans; Neuronal Plasticity; Learning; Hippocampus; Synapses
PubMed: 38900733
DOI: 10.1371/journal.pone.0304076 -
Addiction Biology Jun 2024A growing body of evidence indicates the existence of abnormal local and long-range functional connection patterns in patients with alcohol use disorder (AUD). However,...
A growing body of evidence indicates the existence of abnormal local and long-range functional connection patterns in patients with alcohol use disorder (AUD). However, it has yet to be established whether AUD is associated with abnormal interhemispheric and intrahemispheric functional connection patterns. In the present study, we analysed resting-state functional magnetic resonance imaging data from 55 individuals with AUD and 32 healthy nonalcohol users. For each subject, whole-brain functional connectivity density (FCD) was decomposed into ipsilateral and contralateral parts. Correlation analysis was performed between abnormal FCD and a range of clinical measurements in the AUD group. Compared with healthy controls, the AUD group exhibited a reduced global FCD in the anterior and middle cingulate gyri, prefrontal cortex and thalamus, along with an enhanced global FCD in the temporal, parietal and occipital cortices. Abnormal interhemispheric and intrahemispheric FCD patterns were also detected in the AUD group. Furthermore, abnormal global, contralateral and ipsilateral FCD data were correlated with the mean amount of pure alcohol and the severity of alcohol addiction in the AUD group. Collectively, our findings indicate that global, interhemispheric and intrahemispheric FCD may represent a robust method to detect abnormal functional connection patterns in AUD; this may help us to identify the neural substrates and therapeutic targets of AUD.
Topics: Humans; Male; Alcoholism; Magnetic Resonance Imaging; Adult; Brain; Middle Aged; Prefrontal Cortex; Thalamus; Case-Control Studies; Gyrus Cinguli; Brain Mapping; Young Adult
PubMed: 38899438
DOI: 10.1111/adb.13398 -
Addiction Biology Jun 2024The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced...
Correlation of striatal dopamine D2/3 receptor availability with GABA level in the anterior cingulate cortex in healthy controls but not in alcohol-dependent subjects and individuals at high risk: A multimodal magnetic resonance spectroscopy and positron emission tomography study.
BACKGROUND
The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced dopamine D2/3 receptors in the striatum of subjects with alcohol dependence (AD) compared to healthy controls have been found in previous studies. Furthermore, alterations of gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the anterior cingulate cortex (ACC) of AD subjects have been documented in several studies. However, the interaction between cortical Glu levels and striatal dopamine D2/3 receptors has not been investigated in AD thus far.
METHODS
This study investigated dopamine D2/3 receptor availability via 18F-fallypride positron emission tomography (PET) and GABA as well as Glu levels via magnetic resonance spectroscopy (MRS) in 19 detoxified AD subjects, 18 healthy controls (low risk, LR) controls and 19 individuals at high risk (HR) for developing AD, carefully matched for sex, age and smoking status.
RESULTS
We found a significant negative correlation between GABA levels in the ACC and dopamine D2/3 receptor availability in the associative striatum of LR but not in AD or HR individuals. Contrary to our expectations, we did not observe a correlation between Glu concentrations in the ACC and striatal D2/3 receptor availability.
CONCLUSIONS
The results may reflect potential regulatory cortical mechanisms on mesolimbic dopamine receptors and their disruption in AD and individuals at high risk, mirroring complex neurotransmitter interactions associated with the pathogenesis of addiction. This is the first study combining 18F-fallypride PET and MRS in AD subjects and individuals at high risk.
Topics: Humans; Positron-Emission Tomography; Gyrus Cinguli; Male; Alcoholism; Receptors, Dopamine D2; Adult; Female; Receptors, Dopamine D3; gamma-Aminobutyric Acid; Magnetic Resonance Spectroscopy; Middle Aged; Corpus Striatum; Case-Control Studies; Glutamic Acid; Benzamides
PubMed: 38899357
DOI: 10.1111/adb.13424 -
Brain and Behavior Jun 2024Social isolation stress (SIS) is a stressor known to trigger depressive behaviors. Psychiatric disorders are associated with neurobiological changes, such as...
BACKGROUND AND AIM
Social isolation stress (SIS) is a stressor known to trigger depressive behaviors. Psychiatric disorders are associated with neurobiological changes, such as neuroinflammation and an increase in nitric oxide (NO) signaling. Despite the well-established detrimental effects of SIS and the involvement of neuroinflammation and NO in depression, potential management strategies, especially resocialization, remain insufficiently explored. Our aim was to elucidate the effects of resocialization on depressive behaviors in socially isolated mice, with a focus on the possible involvement of neuroinflammation and nitrite in the hippocampus (HIP).
METHODS
We utilized 24 Naval Medical Research Institute male mice, maintained under both social and isolation conditions (SC and IC). After the isolation period, the mice were divided into two groups of eight, including the SIS group and a resocialized group. The SC group was kept without exposure to isolation stress. We conducted the open-field test, forced swimming test, and splash test to evaluate depressive behaviors. Additionally, nitrite levels, as well as the gene expression of interleukin (IL)-1β, tumor necrosis factor (TNF), and toll-like receptor 4 (TLR4) in the HIP, were measured.
RESULTS
The study found that resocialization significantly reduces depressive behaviors in SIS mice. The results suggest that the antidepressive effects of resocialization may be partially due to the modulation of the neuroinflammatory response and nitrite levels in the HIP. This is supported by the observed decrease in hippocampal gene expression of IL-1β, TLR4, and TNF, along with a reduction in nitrite levels following resocialization.
CONCLUSION
These insights could pave the way for new management strategies for depression, emphasizing the potential benefits of social interactions.
Topics: Animals; Social Isolation; Hippocampus; Mice; Male; Stress, Psychological; Depression; Nitrites; Neuroinflammatory Diseases; Behavior, Animal; Interleukin-1beta; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha
PubMed: 38898740
DOI: 10.1002/brb3.3604 -
CNS Neuroscience & Therapeutics Jun 2024Tooth loss is closely related to cognitive impairment, especially affecting cognitive functions involving hippocampus. The most well-known function of the hippocampus is...
BACKGROUND
Tooth loss is closely related to cognitive impairment, especially affecting cognitive functions involving hippocampus. The most well-known function of the hippocampus is learning and memory, and the mechanism behind is neuroplasticity, which strongly depends on the level of brain-derived neurotrophic factor (BDNF). While research has delved into the possible mechanisms behind the loss of teeth leading to cognitive dysfunction, there are few studies on the plasticity of sensory neural pathway after tooth loss, and the changes in related indicators of synaptic plasticity still need to be further explored.
METHODS
In this study, the bilateral maxillary molars were extracted in Sprague-Dawley rats of two age ranges (young and middle age) to establish occlusal support loss model; then, the spatial cognition was tested by Morris Water Maze (MWM). Quantitative real-time PCR (qPCR) and Western Blotting (WB) were used to detect BDNF, AKT, and functional proteins (viz., PSD95 and NMDAR) of hippocampal synapses. Golgi staining was used to observe changes in ascending nerve pathway. IF was used to confirm the location of BDNF and AKT expressed in hippocampus.
RESULTS
MWM showed that the spatial cognitive level of rats dropped after occlusal support loss. qPCR, WB, and IF suggested that the BDNF/AKT pathway was down-regulated in the hippocampus. Golgi staining showed the neurons of ascending sensory pathway decreased in numbers.
CONCLUSION
Occlusal support loss caused plastic changes in ascending nerve pathway and induced cognitive impairment in rats by down-regulating BDNF and synaptic plasticity.
Topics: Animals; Neuronal Plasticity; Rats, Sprague-Dawley; Cognitive Dysfunction; Brain-Derived Neurotrophic Factor; Rats; Male; Hippocampus; Maze Learning; Tooth Loss; Proto-Oncogene Proteins c-akt; Disks Large Homolog 4 Protein
PubMed: 38898731
DOI: 10.1111/cns.14750 -
Behavioral and Brain Functions : BBF Jun 2024Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication,...
BACKGROUND
Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model.
METHODS
Sociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala.
RESULTS
C58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using Bulk RNA-Seq and demonstrated oxytocin's beneficial effects on myelin gene expression.
LIMITATIONS
Our findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocin's effects need further examination to understand its' potential as an ASD therapeutic.
CONCLUSIONS
Our work demonstrates the C58/J mouse model's utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability.
Topics: Animals; Male; Microglia; Mice; Amygdala; Female; Oligodendroglia; Autism Spectrum Disorder; Mice, Inbred C57BL; Social Behavior; Gene Expression Profiling; Phenotype; Sex Characteristics; Transcriptome; Disease Models, Animal; Oxytocin
PubMed: 38898502
DOI: 10.1186/s12993-024-00240-3 -
The Journal of Headache and Pain Jun 2024The insula is an important part of the posttraumatic headache (PTH) attributed to mild traumatic brain injury (mTBI) neuropathological activity pattern. It is composed...
Connectivity of the insular subdivisions differentiates posttraumatic headache-associated from nonheadache-associated mild traumatic brain injury: an arterial spin labelling study.
OBJECTIVE
The insula is an important part of the posttraumatic headache (PTH) attributed to mild traumatic brain injury (mTBI) neuropathological activity pattern. It is composed of functionally different subdivisions and each of which plays different role in PTH neuropathology.
METHODS
Ninety-four mTBI patients were included in this study. Based on perfusion imaging data obtained from arterial spin labelling (ASL) perfusion magnetic resonance imaging (MRI), this study evaluated the insular subregion perfusion-based functional connectivity (FC) and its correlation with clinical characteristic parameters in patients with PTH after mTBI and non-headache mTBI patients.
RESULTS
The insular subregions of mTBI + PTH (mTBI patients with PTH) and mTBI-PTH (mTBI patients without PTH) group had positive perfusion-based functional connections with other insular nuclei and adjacent discrete cortical regions. Compared with mTBI-PTH group, significantly increased resting-state perfusion-based FC between the anterior insula (AI) and middle cingulate cortex (MCC)/Rolandic operculum (ROL), between posterior insula (PI) and supplementary motor area (SMA), and decreased perfusion-based FC between PI and thalamus were found in mTBI + PTH group. Changes in the perfusion-based FC of the left posterior insula/dorsal anterior insula with the thalamus/MCC were significant correlated with headache characteristics.
CONCLUSIONS
Our findings provide new ASL-based evidence for changes in the perfusion-based FC of the insular subregion in PTH patients attributed to mTBI and the association with headache features, revealing the possibility of potential neuroplasticity after PTH. These findings may contribute to early diagnosis of the disease and follow-up of disease progression.
Topics: Humans; Male; Female; Adult; Post-Traumatic Headache; Spin Labels; Brain Concussion; Magnetic Resonance Imaging; Middle Aged; Insular Cortex; Young Adult; Cerebral Cortex
PubMed: 38898386
DOI: 10.1186/s10194-024-01809-z -
Nature Communications Jun 2024Memory consolidation relies in part on the reactivation of previous experiences during sleep. The precise interplay of sleep-related oscillations (slow oscillations,...
Memory consolidation relies in part on the reactivation of previous experiences during sleep. The precise interplay of sleep-related oscillations (slow oscillations, spindles and ripples) is thought to coordinate the information flow between relevant brain areas, with ripples mediating memory reactivation. However, in humans empirical evidence for a role of ripples in memory reactivation is lacking. Here, we investigated the relevance of sleep oscillations and specifically ripples for memory reactivation during human sleep using targeted memory reactivation. Intracranial electrophysiology in epilepsy patients and scalp EEG in healthy participants revealed that elevated levels of slow oscillation - spindle activity coincided with the read-out of experimentally induced memory reactivation. Importantly, spindle-locked ripples recorded intracranially from the medial temporal lobe were found to be correlated with the identification of memory reactivation during non-rapid eye movement sleep. Our findings establish ripples as key-oscillation for sleep-related memory reactivation in humans and emphasize the importance of the coordinated interplay of the cardinal sleep oscillations.
Topics: Humans; Male; Female; Adult; Electroencephalography; Memory Consolidation; Epilepsy; Sleep Stages; Young Adult; Memory; Temporal Lobe; Sleep; Sleep, Slow-Wave
PubMed: 38898100
DOI: 10.1038/s41467-024-49572-8