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Genes Jun 2024Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid...
Multifactor Analyses of Frontal Cortex Lipids in the APP/PS1 Model of Familial Alzheimer's Disease Reveal Anomalies in Responses to Dietary n-3 PUFA and Estrogenic Treatments.
Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid alterations are linked to neurodegenerative diseases, especially Alzheimer's disease (AD). The complexity of the brain lipidome and its metabolic regulation has hampered the identification of critical processes associated with the onset and progression of AD. While most experimental studies have focused on the effects of known factors on the development of pathological hallmarks in AD, e.g., amyloid deposition, tau protein and neurofibrillary tangles, neuroinflammation, etc., studies addressing the causative effects of lipid alterations remain largely unexplored. In the present study, we have used a multifactor approach combining diets containing different amounts of polyunsaturated fatty acids (PUFAs), estrogen availabilities, and genetic backgrounds, i.e., wild type (WT) and APP/PS1 (FAD), to analyze the lipid phenotype of the frontal cortex in middle-aged female mice. First, we observed that severe n-3 PUFA deficiency impacts the brain n-3 long-chain PUFA (LCPUFA) composition, yet it was notably mitigated by hepatic de novo synthesis. n-6 LCPUFAs, ether-linked fatty acids, and saturates were also changed by the dietary condition, but the extent of changes was dependent on the genetic background and hormonal condition. Likewise, brain cortex phospholipids were mostly modified by the genotype (FAD>WT) with nuanced effects from dietary treatment. Cholesterol (but not sterol esters) was modified by the genotype (WT>FAD) and dietary condition (higher in DHA-free conditions, especially in WT mice). However, the effects of estrogen treatment were mostly observed in relation to phospholipid remodeling in a genotype-dependent manner. Analyses of lipid-derived variables indicate that nerve cell membrane biophysics were significantly affected by the three factors, with lower membrane microviscosity (higher fluidity) values obtained for FAD animals. In conclusion, our multifactor analyses revealed that the genotype, diet, and estrogen status modulate the lipid phenotype of the frontal cortex, both as independent factors and through their interactions. Altogether, the outcomes point to potential strategies based on dietary and hormonal interventions aimed at stabilizing the brain cortex lipid composition in Alzheimer's disease neuropathology.
Topics: Alzheimer Disease; Animals; Fatty Acids, Omega-3; Mice; Frontal Lobe; Female; Disease Models, Animal; Amyloid beta-Protein Precursor; Estrogens; Mice, Transgenic; Presenilin-1; Lipid Metabolism; Humans
PubMed: 38927745
DOI: 10.3390/genes15060810 -
Biomolecules Jun 2024Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular...
BACKGROUND
Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular level. We aimed to examine the effects of typical and atypical antipsychotics on human iPSC-derived neural progenitor cells (NPCs).
METHODS
Proliferation and neurite outgrowth were measured by live cell imaging, and gene expression levels related to neuronal identity were analyzed by RT-QPCR and immunocytochemistry during differentiation into hippocampal dentate gyrus granule cells following treatment of low- and high-dose antipsychotics (haloperidol, olanzapine, and risperidone).
RESULTS
Antipsychotics did not modify the growth properties of NPCs after 3 days of treatment. However, the characteristics of neurite outgrowth changed significantly in response to haloperidol and olanzapine. After three weeks of differentiation, mRNA expression levels of the selected neuronal markers increased (except for MAP2), while antipsychotics caused only subtle changes. Additionally, we found no changes in MAP2 or GFAP protein expression levels as a result of antipsychotic treatment.
CONCLUSIONS
Altogether, antipsychotic medications promoted neurogenesis in vitro by influencing neurite outgrowth rather than changing cell survival or gene expression. This study provides insights into the effects of antipsychotics on neuronal differentiation and highlights the importance of considering neurite outgrowth as a potential target of action.
Topics: Humans; Olanzapine; Risperidone; Neurogenesis; Hippocampus; Haloperidol; Antipsychotic Agents; Induced Pluripotent Stem Cells; Neural Stem Cells; Cell Differentiation; Cell Proliferation; Cells, Cultured; Neuronal Outgrowth
PubMed: 38927091
DOI: 10.3390/biom14060688 -
Biomolecules Jun 2024An epilepsy diagnosis reduces a patient's quality of life tremendously, and it is a fate shared by over 50 million people worldwide. Temporal lobe epilepsy (TLE) is... (Review)
Review
An epilepsy diagnosis reduces a patient's quality of life tremendously, and it is a fate shared by over 50 million people worldwide. Temporal lobe epilepsy (TLE) is largely considered a nongenetic or acquired form of epilepsy that develops in consequence of neuronal trauma by injury, malformations, inflammation, or a prolonged (febrile) seizure. Although extensive research has been conducted to understand the process of epileptogenesis, a therapeutic approach to stop its manifestation or to reliably cure the disease has yet to be developed. In this review, we briefly summarize the current literature predominately based on data from excitotoxic rodent models on the cellular events proposed to drive epileptogenesis and thoroughly discuss the major molecular pathways involved, with a focus on neurogenesis-related processes and transcription factors. Furthermore, recent investigations emphasized the role of the genetic background for the acquisition of epilepsy, including variants of neurodevelopmental genes. Mutations in associated transcription factors may have the potential to innately increase the vulnerability of the hippocampus to develop epilepsy following an injury-an emerging perspective on the epileptogenic process in acquired forms of epilepsy.
Topics: Epilepsy, Temporal Lobe; Humans; Animals; Hippocampus; Transcription Factors; Neurogenesis; Mutation
PubMed: 38927072
DOI: 10.3390/biom14060669 -
Behavioral and Brain Functions : BBF Jun 2024An intronic deletion within intron 2 of the DCDC2 gene encompassing the entire READ1 (hereafter, READ1d) has been associated in both children with developmental dyslexia...
BACKGROUND
An intronic deletion within intron 2 of the DCDC2 gene encompassing the entire READ1 (hereafter, READ1d) has been associated in both children with developmental dyslexia (DD) and typical readers (TRs), with interindividual variation in reading performance and motion perception as well as with structural and functional brain alterations. Visual motion perception -- specifically processed by the magnocellular (M) stream -- has been reported to be a solid and reliable endophenotype of DD. Hence, we predicted that READ1d should affect neural activations in brain regions sensitive to M stream demands as reading proficiency changes.
METHODS
We investigated neural activations during two M-eliciting fMRI visual tasks (full-field sinusoidal gratings controlled for spatial and temporal frequencies and luminance contrast, and sensitivity to motion coherence at 6%, 15% and 40% dot coherence levels) in four subject groups: children with DD with/without READ1d, and TRs with/without READ1d.
RESULTS
At the Bonferroni-corrected level of significance, reading skills showed a significant effect in the right polar frontal cortex during the full-field sinusoidal gratings-M task. Regardless of the presence/absence of the READ1d, subjects with poor reading proficiency showed hyperactivation in this region of interest (ROI) compared to subjects with better reading scores. Moreover, a significant interaction was found between READ1d and reading performance in the left frontal opercular area 4 during the 15% coherent motion sensitivity task. Among subjects with poor reading performance, neural activation in this ROI during this specific task was higher for subjects without READ1d than for READ1d carriers. The difference vanished as reading skills increased.
CONCLUSIONS
Our findings showed a READ1d-moderated genetic vulnerability to alterations in neural activation in the ventral attentive and salient networks during the processing of relevant stimuli in subjects with poor reading proficiency.
Topics: Humans; Dyslexia; Male; Child; Female; Magnetic Resonance Imaging; Parietal Lobe; Reading; Motion Perception; Frontal Lobe; Microtubule-Associated Proteins; Brain Mapping; Nerve Net; Photic Stimulation
PubMed: 38926731
DOI: 10.1186/s12993-024-00241-2 -
Nature Communications Jun 2024Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples,...
Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries offer more nuanced and accurate insights into the regulatory mechanisms of RNA editing in the human brain.
Topics: Humans; RNA Editing; Adenosine; Adenosine Deaminase; Brain; Inosine; RNA-Binding Proteins; Autopsy; Prefrontal Cortex; Postmortem Changes; Male
PubMed: 38926387
DOI: 10.1038/s41467-024-49268-z -
Zhongguo Dang Dai Er Ke Za Zhi =... Jun 2024To observe the effects of melatonin on autophagy in cortical neurons of neonatal rats with hypoxic-ischemic brain damage (HIBD) and to explore its mechanisms via the...
OBJECTIVES
To observe the effects of melatonin on autophagy in cortical neurons of neonatal rats with hypoxic-ischemic brain damage (HIBD) and to explore its mechanisms via the PI3K/AKT signaling pathway, aiming to provide a basis for the clinical application of melatonin.
METHODS
Seven-day-old Sprague-Dawley neonatal rats were randomly divided into a sham operation group, an HIBD group, and a melatonin group (=9 each). The neonatal rat HIBD model was established using the classic Rice-Vannucci method. Neuronal morphology in the neonatal rat cerebral cortex was observed with hematoxylin-eosin staining and Nissl staining. Autophagy-related protein levels of microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1 were detected by immunofluorescence staining and Western blot analysis. Phosphorylated phosphoinositide 3-kinase (p-PI3K) and phosphorylated protein kinase B (p-AKT) protein expression levels were measured by immunohistochemistry and Western blot. The correlation between autophagy and the PI3K pathway in the melatonin group and the HIBD group was analyzed using Pearson correlation analysis.
RESULTS
Twenty-four hours post-modeling, neurons in the sham operation group displayed normal size and orderly arrangement. In contrast, neurons in the HIBD group showed swelling and disorderly arrangement, while those in the melatonin group had relatively normal morphology and more orderly arrangement. Nissl bodies were normal in the sham operation group but distorted in the HIBD group; however, they remained relatively intact in the melatonin group. The average fluorescence intensity of LC3 and Beclin-1 was higher in the HIBD group compared to the sham operation group, but was reduced in the melatonin group compared to the HIBD group (<0.05). The number of p-PI3K and p-AKT cells decreased in the HIBD group compared to the sham operation group but increased in the melatonin group compared to the HIBD group (<0.05). LC3 and Beclin-1 protein expression levels were higher, and p-PI3K and p-AKT levels were lower in the HIBD group compared to the sham operation group (<0.05); however, in the melatonin group, LC3 and Beclin-1 levels decreased, and p-PI3K and p-AKT increased compared to the HIBD group (<0.05). The correlation analysis results showed that the difference of the mean fluorescence intensity of LC3 and Beclin-1 protein in the injured cerebral cortex between the melatonin and HIBD groups was negatively correlated with the difference of the number of p-PI3K and p-AKT cells between the two groups (<0.05).
CONCLUSIONS
Melatonin can inhibit excessive autophagy in cortical neurons of neonatal rats with HIBD, thereby alleviating HIBD. This mechanism is associated with the PI3K/AKT pathway.
Topics: Animals; Melatonin; Hypoxia-Ischemia, Brain; Rats, Sprague-Dawley; Rats; Proto-Oncogene Proteins c-akt; Animals, Newborn; Cerebral Cortex; Autophagy; Phosphatidylinositol 3-Kinases; Neurons; Signal Transduction; Male; Female
PubMed: 38926381
DOI: 10.7499/j.issn.1008-8830.2312053 -
Nature Communications Jun 2024The claustrum has been linked to attention and sleep. We hypothesized that this reflects a shared function, determining responsiveness to stimuli, which spans the axis...
The claustrum has been linked to attention and sleep. We hypothesized that this reflects a shared function, determining responsiveness to stimuli, which spans the axis of engagement. To test this hypothesis, we recorded claustrum population dynamics from male mice during both sleep and an attentional task ('ENGAGE'). Heightened activity in claustrum neurons projecting to the anterior cingulate cortex (ACCp) corresponded to reduced sensory responsiveness during sleep. Similarly, in the ENGAGE task, heightened ACCp activity correlated with disengagement and behavioral lapses, while low ACCp activity correlated with hyper-engagement and impulsive errors. Chemogenetic elevation of ACCp activity reduced both awakenings during sleep and impulsive errors in the ENGAGE task. Furthermore, mice employing an exploration strategy in the task showed a stronger correlation between ACCp activity and performance compared to mice employing an exploitation strategy which reduced task complexity. Our results implicate ACCp claustrum neurons in restricting engagement during sleep and goal-directed behavior.
Topics: Animals; Gyrus Cinguli; Male; Sleep; Neurons; Mice; Claustrum; Mice, Inbred C57BL; Behavior, Animal; Attention; Wakefulness
PubMed: 38926345
DOI: 10.1038/s41467-024-48829-6 -
Nature Communications Jun 2024During brain development, neural circuits undergo major activity-dependent restructuring. Circuit wiring mainly occurs through synaptic strengthening following the...
During brain development, neural circuits undergo major activity-dependent restructuring. Circuit wiring mainly occurs through synaptic strengthening following the Hebbian "fire together, wire together" precept. However, select connections, essential for circuit development, are transient. They are effectively connected early in development, but strongly diminish during maturation. The mechanisms by which transient connectivity recedes are unknown. To investigate this process, we characterize transient thalamocortical inputs, which depress onto somatostatin inhibitory interneurons during development, by employing optogenetics, chemogenetics, transcriptomics and CRISPR-based strategies in mice. We demonstrate that in contrast to typical activity-dependent mechanisms, transient thalamocortical connectivity onto somatostatin interneurons is non-canonical and involves metabotropic signaling. Specifically, metabotropic-mediated transcription, of guidance molecules in particular, supports the elimination of this connectivity. Remarkably, we found that this process impacts the development of normal exploratory behaviors of adult mice.
Topics: Animals; Interneurons; Somatostatin; Mice; Thalamus; Optogenetics; Signal Transduction; Male; Cerebral Cortex; Female; Mice, Inbred C57BL; Mice, Transgenic
PubMed: 38926335
DOI: 10.1038/s41467-024-49732-w -
Discovery Medicine Jun 2024Alzheimer's disease (AD) affects the brain and causes difficulties with cognition and emotions. At present, there are no viable therapies to halt or slow down the...
BACKGROUND
Alzheimer's disease (AD) affects the brain and causes difficulties with cognition and emotions. At present, there are no viable therapies to halt or slow down the advancement of AD. Metallothionein III (MT-III) exhibits antioxidant and anti-inflammatory characteristics, indicating possible therapeutic benefits. This study aimed to explore the influence of MT-III on AD pathological alterations and cognitive abilities.
METHODS
In this research, we employed the universally accepted AD mouse models (3xTg-AD) as test subjects and administrated vehicle or MT-III. The mice were subjected to the Morris water maze test to assess their spatial learning and memory capabilities. Moreover, to evaluate the consequent effects on neuronal groups in the hippocampus, the Nissl staining and neuronal nuclear antigen (NeuN) immunohistochemistry were used to identify the cellular morphology changes and density. Immunohistochemistry was also used to detect β-amyloid (Aβ) and glial fibrillary acidic protein (GFAP) to measure Aβ accumulation and astrocyte growth. Western blot was also used to measure Tau pathology-related PHD finger protein 1 (PHF-1), phosphorylated Tau (AT-8), and total Tau protein.
RESULTS
The administration of MT-III notably enhanced spatial learning and memory function in 3xTg-AD mice, as evidenced by the Morris water maze test ( < 0.01). According to immunohistochemistry and the obtained findings, it was observed that brain tissues of mice treated with MT-III showed a notable increase of Nissl bodies and NeuN intensity ( < 0.01) while a remarkable decrease in Aβ accumulation and GFAP ( < 0.01). Additionally, MT-III largely decreased levels of Tau phosphorylation-related PHF-1 and AT-8 ( < 0.01) and slightly reduced the level of Tau 5 ( < 0.05).
CONCLUSION
In summary, our research indicates that MT-III has the capacity to ameliorate pathological alterations in AD mouse models and safeguard their cognitive and emotional abilities. By decreasing β-amyloid accumulation and reducing the intensity of Tau pathology, MT-III protected hippocampal subfield neurons against pathological harm. Furthermore, MT-III reduced inflammation by inhibiting abnormal proliferation of astrocytes. Of utmost importance, MT-III greatly enhanced the cognitive abilities related to spatial learning and memory in mice, suggesting its promising therapeutic properties for AD.
Topics: Animals; Alzheimer Disease; Astrocytes; Mice; Disease Models, Animal; Metallothionein 3; Cell Proliferation; tau Proteins; Mice, Transgenic; Hippocampus; Amyloid beta-Peptides; Male; Humans; Maze Learning; Spatial Learning; Glial Fibrillary Acidic Protein
PubMed: 38926108
DOI: 10.24976/Discov.Med.202436185.112 -
Human Brain Mapping Jun 2024Neuroimaging studies have consistently demonstrated concurrent activation of the human precuneus and temporal pole (TP), both during resting-state conditions and various...
Neuroimaging studies have consistently demonstrated concurrent activation of the human precuneus and temporal pole (TP), both during resting-state conditions and various higher-order cognitive functions. However, the precise underlying structural connectivity between these brain regions remains uncertain despite significant advancements in neuroscience research. In this study, we investigated the connectivity of the precuneus and TP by employing parcellation-based fiber micro-dissections in human brains and fiber tractography techniques in a sample of 1065 human subjects and a sample of 41 rhesus macaques. Our results demonstrate the connectivity between the posterior precuneus area POS2 and the areas 35, 36, and TG of the TP via the fifth subcomponent of the cingulum (CB-V) also known as parahippocampal cingulum. This finding contributes to our understanding of the connections within the posteromedial cortices, facilitating a more comprehensive integration of anatomy and function in both normal and pathological brain processes. PRACTITIONER POINTS: Our investigation delves into the intricate architecture and connectivity patterns of subregions within the precuneus and temporal pole, filling a crucial gap in our knowledge. We revealed a direct axonal connection between the posterior precuneus (POS2) and specific areas (35, 35, and TG) of the temporal pole. The direct connections are part of the CB-V pathway and exhibit a significant association with the cingulum, SRF, forceps major, and ILF. Population-based human tractography and rhesus macaque fiber tractography showed consistent results that support micro-dissection outcomes.
Topics: Humans; Macaca mulatta; Temporal Lobe; Parietal Lobe; Animals; Diffusion Tensor Imaging; Male; Adult; Female; Neural Pathways; Young Adult; Axons; Connectome; White Matter; Gyrus Cinguli
PubMed: 38925589
DOI: 10.1002/hbm.26771