Disorder of neuroplasticity aggravates cognitive impairment via neuroinflammation associated with intestinal flora dysbiosis in chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) impairs cognitive function, yet its effects on brain structure and underlying mechanisms remain elusive. This study aims to explore the mechanisms behind cognitive impairment. METHODS: CHF models in rats were induced by ligation of the left anterior descending coronary artery. Cardiac function was analyzed by cardiac ultrasound and hemodynamics. ELISA, immunofluorescence, Western blot, Golgi staining and transmission electron microscopy were performed on hippocampal tissues. The alterations of intestinal flora under the morbid state were investigated via 16S rRNA sequencing. The connection between neuroinflammation and synapses is confirmed by a co-culture system of BV2 microglia and HT22 cells in vitro. Results: CHF rats exhibited deteriorated cognitive behaviors. CHF induced neuronal structural disruption, loss of Nissl bodies, and synaptic damage, exhibiting alterations in multiple parameters. CHF rats showed increased hippocampal levels of inflammatory cytokines and activated microglia and astrocytes. Furthermore, the study highlights dysregulated PDE4-dependent cAMP signaling and intestinal flora dysbiosis, closely associated with neuroinflammation, and altered synaptic proteins. In vitro, microglial neuroinflammation impaired synaptic plasticity via PDE4-dependent cAMP signaling. CONCLUSIONS: Neuroinflammation worsens CHF-related cognitive impairment through neuroplasticity disorder, tied to intestinal flora dysbiosis. PDE4 emerges as a potential therapeutic target. These findings provide insightful perspectives on the heart-gut-brain axis.

Hypersensitivity of the nicotinic acetylcholine receptor subunit (CHRNA2L9'S/L9'S) in female adolescent mice produces deficits in nicotine-induced facilitation of hippocampal-dependent learning and memory.

Adolescence is characterized by a critical period of maturation and growth, during which regions of the brain are vulnerable to long-lasting cognitive disturbances. Adolescent exposure to nicotine can lead to deleterious neurological and psychological outcomes. Moreover, the nicotinic acetylcholine receptor (nAChR) has been shown to play a functionally distinct role in the development of the adolescent brain. CHRNA2 encodes for the α2 subunit of nicotinic acetylcholine receptors associated with CA1 oriens lacunosum moleculare GABAergic interneurons and is associated with learning and memory. Previously, we found that adolescent male hypersensitive CHRNA2L9'S/L9' mice had impairments in learning and memory during a pre-exposure-dependent contextual fear conditioning task that could be rescued by low-dose nicotine exposure. In this study, we assessed learning and memory in female adolescent hypersensitive CHRNA2L9'S/L9' mice exposed to saline or a subthreshold dose of nicotine using a hippocampus-dependent task of pre-exposure-dependent contextual fear conditioning. We found that nicotine-treated wild-type female mice had significantly greater improvements in learning and memory than both saline-treated wild-type mice and nicotine-treated CHRNA2L9'S/L9' female mice. Thus, hyperexcitability of CHRNA2 in female adolescent mice ablated the nicotine-mediated potentiation of learning and memory seen in wild-types. Our results indicate that nicotine exposure during adolescence mediates sexually dimorphic patterns of learning and memory, with wild-type female adolescents being more susceptible to the effects of sub-threshold nicotine exposure. To understand the mechanism underlying sexually dimorphic behavior between hyperexcitable CHRNA2 mice, it is critical that further research be conducted.

Coping with the experience of frustration throughout life: Sex- and age-specific effects of early life stress on the susceptibility to reward devaluation.

Early life stress may lead to lifelong impairments in psychophysiological functions, including emotional and reward systems. Unpredicted decrease in reward magnitude generates a negative emotional state (frustration) that may be involved with susceptibility to psychiatric disorders. We evaluated in adolescents and adult rats of both sexes whether maternal separation (MS) alters the ability to cope with an unexpected reduction of reward later in life. Litters of Wistar rats were divided into controls (non handled - NH) or subjected to MS. Animals were trained to find sugary cereal pellets; later the amount was reduced. Increased latency to reach the reward-associated area indicates higher inability to regulate frustration. The dorsal hippocampus (dHC) and basolateral amygdala (BLA) were evaluated for protein levels of NMDA receptor subunits (GluN2A/GluN2B), synaptophysin, PSD95, SNAP-25 and CRF1. We found that adult MS males had greater vulnerability to reward reduction, together with decreased GluN2A and increased GluN2B immunocontent in the dHC. MS females and adolescents did not differ from controls. We concluded that MS enhances the response to frustration in males. The change in the ratio of GluN2A and GluN2B subunits in dHC could be related to a stronger, more difficult to update, memory of the aversive experience.

Predictive value of synaptic plasticity for functional decline in patients with multiple sclerosis.

Background: Previous research suggested that quadripulse (QPS)-induced synaptic plasticity is associated with both cognitive and motor function in patients with multiple sclerosis (MS) and does not appear to be reduced compared to healthy controls (HCs). Objective: This study aimed to explore the relationship between the degree of QPS-induced plasticity and clinically significant decline in motor and cognitive functions over time. We hypothesized that MS patients experiencing functional decline would exhibit lower levels of baseline plasticity compared to those without decline. Methods: QPS-induced plasticity was evaluated in 80 MS patients (56 with relapsing-remitting MS and 24 with progressive MS), and 69 age-, sex-, and education-matched HCs. Cognitive and motor functions, as well as overall disability status were evaluated annually over a median follow-up period of 2 years. Clinically meaningful change thresholds were predefined for each outcome measure. Linear mixed-effects models, Cox proportional hazard models, logistic regression, and receiver-operating characteristic analysis were applied to analyse the relationship between baseline plasticity and clinical progression in the symbol digit modalities test, brief visuospatial memory test revised (BVMT-R), nine-hole peg test (NHPT), timed 25-foot walk test, and expanded disability status scale. Results: Overall, the patient cohort showed no clinically relevant change in any functional outcome over time. Variability in performance was observed across time points in both patients and HCs. MS patients who experienced clinically relevant decline in manual dexterity and/or visuospatial learning and memory had significantly lower levels of synaptic plasticity at baseline compared to those without such decline (NHPT: ß = -0.25, p = 0.02; BVMT-R: ß = -0.50, p = 0.005). Receiver-operating characteristic analysis underscored the predictive utility of baseline synaptic plasticity in discerning between patients experiencing functional decline and those maintaining stability only for visuospatial learning and memory (area under the curve = 0.85). Conclusion: Our study suggests that QPS-induced plasticity could be linked to clinically relevant functional decline in patients with MS. However, to solidify these findings, longer follow-up periods are warranted, especially in cohorts with higher prevalences of functional decline. Additionally, the variability in cognitive performance in both patients with MS and HCs underscores the importance of conducting further research on reliable change based on neuropsychological tests.

Neurexin 3 Regulates Synaptic Connections Between Central Amygdala Neurons and Excitable Cells of the Lateral Parabrachial Nucleus in Rats with Varicella Zoster Induced Orofacial Pain.

Introduction: Herpes Zoster in humans is the result of varicella zoster virus (VZV) infection. Injecting rats with varicella zoster virus produces pain similar to herpes zoster "shingles" pain in humans. . In a previous study, orofacial pain was induced by injecting the whisker pad of male rats with VZV and the pain response increased after attenuating neurexin 3 (Nrxn3) expression in the central amygdala. Neurons descend from the central amygdala to the lateral parabrachial nucleus and orofacial pain signals ascend to the lateral parabrachial nucleus. GABAergic neurons within the central amygdala regulate pain by inhibiting activity within the lateral parabrachial nucleus. Attenuating Nrxn3 expression in the central amygdala increased GABA release in the lateral parabrachial nucleus suggesting Nrxn3 controls pain by regulating GABA release. Nrxn3 can also control synaptic connections between neurons, and we hypothesized that Nrxn3 knockdown in the central amygdala would reduce the number of GABAergic synaptic connections in the lateral parabrachial nucleus and increase VZV associated pain. Methods: To test this idea, the number of synaptic connections between GABAergic cells of the central amygdala and excitatory or dynorphin positive neurons within the lateral parabrachial nucleus were quantitated after infusion of a virus expressing synaptophysin. Synaptophysin is a synaptic vesicle protein that labels neuronal synaptic connections. These connections were measured in rats with and without whisker pad injection of VZV and knockdown of Nrxn3 within the central amygdala. Orofacial pain was measured using a place escape avoidance paradigm. Results: GABAergic synaptic connections were reduced in the lateral parabrachial nucleus after Nrxn3 knockdown. Rats with a reduction in the number of connections had an increase in VZV associated orofacial pain. Immunostaining with the pain marker prodynorphin indicated that the reduction in GABAergic connections was primarily associated with prodynorphin positive neurons. Discussion: The results suggest Nrxn3 reduces VZV associated orofacial pain, in part, by enhancing synaptic connections between GABA cells of the central amygdala and pain neurons within the lateral parabrachial nucleus.

Changes in hippocampal volume, synaptic plasticity and amylin sensitivity in an animal model of type 2 diabetes are associated with increased vulnerability to amyloid-beta in advancing age.

Type-2 diabetes (T2D) is a metabolic disorder that is considered a risk factor for Alzheimer's disease (AD). Cognitive impairment can arise due to hypoglycemia associated with T2D, and hyperamylinemia associated with insulin resistance can enhance AD pathology. We explored whether changes occur in the hippocampus in aging (6-12 months old) female V-Lep○b-/- transgenic (tg) mice, comprising an animal model of T2D. We also investigated whether an increase in vulnerability to Aß (1-42), a known pathological hallmark of AD, is evident. Using magnetic resonance imaging we detected significant decreases in hippocampal brain volume in female tg-mice compared to wild-type (wt) littermates. Long-term potentiation (LTP) was impaired in tg compared to wt mice. Treatment of the hippocampus with Aß (1-42) elicited a stronger debilitation of LTP in tg compared to wt mice. Treatment with an amylin antagonist (AC187) significantly enhanced LTP in wt and tg mice, and rescued LTP in Aß (1-42)-treated tg mice. Taken together our data indicate that a T2D-like state results in an increased vulnerability of the hippocampus to the debilitating effects of Aß (1-42) and that effects are mediated in part by changes in amylin receptor signaling.

Novel Leptin-Based Therapeutic Strategies to Limit Synaptic Dysfunction in Alzheimer's Disease.

Accumulation of hyper-phosphorylated tau and amyloid beta (Aß) are key pathological hallmarks of Alzheimer's disease (AD). Increasing evidence indicates that in the early pre-clinical stages of AD, phosphorylation and build-up of tau drives impairments in hippocampal excitatory synaptic function, which ultimately leads to cognitive deficits. Consequently, limiting tau-related synaptic abnormalities may have beneficial effects in AD. There is now significant evidence that the hippocampus is an important brain target for the endocrine hormone leptin and that leptin has pro-cognitive properties, as activation of synaptic leptin receptors markedly influences higher cognitive processes including learning and memory. Clinical studies have identified a link between the circulating leptin levels and the risk of AD, such that AD risk is elevated when leptin levels fall outwith the physiological range. This has fuelled interest in targeting the leptin system therapeutically. Accumulating evidence supports this possibility, as numerous studies have shown that leptin has protective effects in a variety of models of AD. Recent findings have demonstrated that leptin has beneficial effects in the preclinical stages of AD, as leptin prevents the early synaptic impairments driven by tau protein and amyloid ß. Here we review recent findings that implicate the leptin system as a potential novel therapeutic target in AD.

The Effects of Sevoflurane and Aß Interaction on CA1 Dendritic Spine Dynamics and MEGF10-Related Astrocytic Synapse Engulfment.

General anesthetics may accelerate the neuropathological changes related to Alzheimer's disease (AD), of which amyloid beta (Aß)-induced toxicity is one of the main causes. However, the interaction of general anesthetics with different Aß-isoforms remains unclear. In this study, we investigated the effects of sevoflurane (0.4 and 1.2 maximal alveolar concentration (MAC)) on four Aß species-induced changes on dendritic spine density (DSD) in hippocampal brain slices of Thy1-eGFP mice and multiple epidermal growth factor-like domains 10 (MEGF10)-related astrocyte-mediated synaptic engulfment in hippocampal brain slices of C57BL/6 mice. We found that both sevoflurane and Aß downregulated CA1-dendritic spines. Moreover, compared with either sevoflurane or Aß alone, pre-treatment with Aß isoforms followed by sevoflurane application in general further enhanced spine loss. This enhancement was related to MEGF10-related astrocyte-dependent synaptic engulfment, only in AßpE3 + 1.2 MAC sevoflurane and 3NTyrAß + 1.2 MAC sevoflurane condition. In addition, removal of sevoflurane alleviated spine loss in Aß + sevoflurane. In summary, these results suggest that both synapses and astrocytes are sensitive targets for sevoflurane; in the presence of 3NTyrAß, 1.2 MAC sevoflurane alleviated astrocyte-mediated synaptic engulfment and exerted a lasting effect on dendritic spine remodeling.

Gadd45A-mediated autophagy regulation and its impact on Alzheimer's disease pathogenesis: Deciphering the molecular Nexus.

BACKGROUND: The growth arrest and DNA damage-inducible 45 (Gadd45) gene has been implicated in various central nervous system (CNS) functions, both normal and pathological, including aging, memory, and neurodegenerative diseases. In this study, we examined whether Gadd45A deletion triggers pathways associated with neurodegenerative diseases including Alzheimer's disease (AD). METHODS: Utilizing transcriptome data from AD-associated hippocampus samples, we identified Gadd45A as a pivotal regulator of autophagy. Comprehensive analyses, including Gene Ontology enrichment and protein-protein interaction network assessments, highlighted Cdkn1A as a significant downstream target of Gadd45A. Experimental validation confirmed Gadd45A's role in modulating Cdkn1A expression and autophagy levels in hippocampal cells. We also examined the effects of autophagy on hippocampal functions and proinflammatory cytokine secretion. Additionally, a murine model was employed to validate the importance of Gadd45A in neuroinflammation and AD pathology. RESULTS: Our study identified 20 autophagy regulatory factors associated with AD, with Gadd45A emerging as a critical regulator. Experimental findings demonstrated that Gadd45A influences hippocampal cell fate by reducing Cdkn1A expression and suppressing autophagic activity. Comparisons between wild-type (WT) and Gadd45A knockout (Gadd45A-/-) mice revealed that Gadd45A-/- mice exhibited significant cognitive impairments, including deficits in working and spatial memory, increased Tau hyperphosphorylation, and elevated levels of kinases involved in Tau phosphorylation in the hippocampus. Additionally, Gadd45A-/- mice showed significant increases in pro-inflammatory cytokines and decreases autophagy markers in the brain. Neurotrophin levels and dendritic spine length were also reduced in Gadd45A-/- mice, likely contributing to the observed cognitive deficits. CONCLUSIONS: These findings support the direct involvement of the Gadd45A gene in AD pathogenesis, and enhancing the expression of Gadd45A may represent a promising therapeutic strategy for the treatment of AD.

Physical activity promotes brain development through serotonin during early childhood.

Early childhood serves as a critical period for neural development and skill acquisition when children are extremely susceptible to the external environment and experience. As a crucial experiential stimulus, physical activity is believed to produce a series of positive effects on brain development, such as cognitive function, social-emotional abilities, and psychological well-being. The World Health Organization recommends that children engage in sufficient daily physical activity, which has already been strongly advocated in the practice of preschool education. However, the mechanisms by which physical activity promotes brain development are still unclear. The role of neurotransmitters, especially serotonin, in promoting brain development through physical activity has received increasing attention. Physical activity has been shown to stimulate the secretion of serotonin by increasing the bioavailability of free tryptophan and enriching the diversity of gut microbiota. Due to its important role in modulating neuronal proliferation, differentiation, synaptic morphogenesis, and synaptic transmission, serotonin can regulate children's explicit cognitive and social interaction behavior in the early stages of life. Therefore, we hypothesized that serotonin emerges as a pivotal transmitter that mediates the relationship between physical activity and brain development during early childhood. Further systematic reviews and meta-analyses are needed to specifically explore whether the type, intensity, dosage, duration, and degree of voluntariness of PA may affect the role of serotonin in the relationship between physical activity and brain function. This review not only helps us understand the impact of exercise on development but also provides a solid theoretical basis for increasing physical activity during early childhood.

Region-Related Differences in Short-Term Synaptic Plasticity and Synaptotagmin-7 in the Male and Female Hippocampus of a Rat Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is an intellectual developmental disorder characterized, inter alia, by deficits in the short-term processing of neural information, such as sensory processing and working memory. The primary cause of FXS is the loss of fragile X messenger ribonucleoprotein (FMRP), which is profoundly involved in synaptic function and plasticity. Short-term synaptic plasticity (STSP) may play important roles in functions that are affected by FXS. Recent evidence points to the crucial involvement of the presynaptic calcium sensor synaptotagmin-7 (Syt-7) in STSP. However, how the loss of FMRP affects STSP and Syt-7 have been insufficiently studied. Furthermore, males and females are affected differently by FXS, but the underlying mechanisms remain elusive. The aim of the present study was to investigate possible changes in STSP and the expression of Syt-7 in the dorsal (DH) and ventral (VH) hippocampus of adult males and females in a Fmr1-knockout (KO) rat model of FXS. We found that the paired-pulse ratio (PPR) and frequency facilitation/depression (FF/D), two forms of STSP, as well as the expression of Syt-7, are normal in adult KO males, but the PPR is increased in the ventral hippocampus of KO females (6.4 ± 3.7 vs. 18.3 ± 4.2 at 25 ms in wild type (WT) and KO, respectively). Furthermore, we found no gender-related differences, but did find robust region-dependent difference in the STSP (e.g., the PPR at 50 ms: 50.0 ± 5.5 vs. 17.6 ± 2.9 in DH and VH of WT male rats; 53.1 ± 3.6 vs. 19.3 ± 4.6 in DH and VH of WT female rats; 48.1 ± 2.3 vs. 19.1 ± 3.3 in DH and VH of KO male rats; and 51.2 ± 3.3 vs. 24.7 ± 4.3 in DH and VH of KO female rats). AMPA receptors are similarly expressed in the two hippocampal segments of the two genotypes and in both genders. Also, basal excitatory synaptic transmission is higher in males compared to females. Interestingly, we found more than a twofold higher level of Syt-7, not synaptotagmin-1, in the dorsal compared to the ventral hippocampus in the males of both genotypes (0.43 ± 0.1 vs. 0.16 ± 0.02 in DH and VH of WT male rats, and 0.6 ± 0.13 vs. 0.23 ± 0.04 in DH and VH of KO male rats) and in the WT females (0.97 ± 0.23 vs. 0.31 ± 0.09 in DH and VH). These results point to the susceptibility of the female ventral hippocampus to FMRP loss. Importantly, the different levels of Syt-7, which parallel the higher score of the dorsal vs. ventral hippocampus on synaptic facilitation, suggest that Syt-7 may play a pivotal role in defining the striking differences in STSP along the long axis of the hippocampus.

Mitigating the Functional Deficit after Neurotoxic Motoneuronal Loss by an Inhibitor of Mitochondrial Fission.

Amyotrophic lateral sclerosis (ALS) is an extremely complex neurodegenerative disease involving different cell types, but motoneuronal loss represents its main pathological feature. Moreover, compensatory plastic changes taking place in parallel to neurodegeneration are likely to affect the timing of ALS onset and progression and, interestingly, they might represent a promising target for disease-modifying treatments. Therefore, a simplified animal model mimicking motoneuronal loss without the other pathological aspects of ALS has been established by means of intramuscular injection of cholera toxin-B saporin (CTB-Sap), which is a targeted neurotoxin able to kill motoneurons by retrograde suicide transport. Previous studies employing the mouse CTB-Sap model have proven that spontaneous motor recovery is possible after a subtotal removal of a spinal motoneuronal pool. Although these kinds of plastic changes are not enough to counteract the functional effects of the progressive motoneuron degeneration, it would nevertheless represent a promising target for treatments aiming to postpone ALS onset and/or delay disease progression. Herein, the mouse CTB-Sap model has been used to test the efficacy of mitochondrial division inhibitor 1 (Mdivi-1) as a tool to counteract the CTB-Sap toxicity and/or to promote neuroplasticity. The homeostasis of mitochondrial fission/fusion dynamics is indeed important for cell integrity, and it could be affected during neurodegeneration. Lesioned mice were treated with Mdivi-1 and then examined by a series of behavioral test and histological analyses. The results have shown that the drug may be capable of reducing functional deficits after the lesion and promoting synaptic plasticity and neuroprotection, thus representing a putative translational approach for motoneuron disorders.

Exploring the Effect of Arsenic-Containing Hydrocarbon on the Bidirectional Synaptic Plasticity of the Dorsal Hippocampus.

Arsenic-containing hydrocarbons (AsHCs) are common in marine organisms. However, there is little research on their effects on the central nervous system's advanced activities, such as cognition. Bidirectional synaptic plasticity dynamically regulates cognition through the balance of long-term potentiation (LTP) and long-term depression (LTD). However, the effects of AsHCs on bidirectional synaptic plasticity and the underlying molecular mechanisms remain unexplored. This study provides the first evidence that 15 µg As L-1 AsHC 360 enhances bidirectional synaptic plasticity, occurring during the maintenance phase rather than the baseline phase. Further calcium gradient experiments hypothesize that AsHC 360 may enhance bidirectional synaptic plasticity by affecting calcium ion levels. The enhancement of bidirectional synaptic plasticity by 15 µg As L-1 AsHC 360 holds significant implications in improving cognitive function, treating neuro-psychiatric disorders, promoting neural recovery, and enhancing brain adaptability.

PI3K/AKT signaling pathway: Molecular mechanisms and therapeutic potential in depression.

Depression is a serious global mental disorder. Numerous studies have found that depression may be closely related to decreased neurogenesis, neuroinflammation, neurotransmitter imbalance, and synaptic plasticity dysfunction. The pathogenesis of depression is complex and involves multiple signal transduction pathways and molecular changes. The PI3K/AKT pathway is an essential signaling pathways in neurons, which is widely expressed in emotion-related regions of the brain. Therefore, the PI3K/AKT pathway may play a moderating role in mood disorders. However, the role and mechanism of the PI3K/AKT signaling pathway in depression have not been fully described. This review systematically summarized the role of the PI3K/AKT signaling pathway in the pathogenesis of depression and discussed its potential in the treatment of depression. This will help in the treatment of depression and the development of antidepressants.

Cortico-basal ganglia plasticity in motor learning.

One key function of the brain is to control our body's movements, allowing us to interact with the world around us. Yet, many motor behaviors are not innate but require learning through repeated practice. Among the brain's motor regions, the cortico-basal ganglia circuit is particularly crucial for acquiring and executing motor skills, and neuronal activity in these regions is directly linked to movement parameters. Cell-type-specific adaptations of activity patterns and synaptic connectivity support the learning of new motor skills. Functionally, neuronal activity sequences become structured and associated with learned movements. On the synaptic level, specific connections become potentiated during learning through mechanisms such as long-term synaptic plasticity and dendritic spine dynamics, which are thought to mediate functional circuit plasticity. These synaptic and circuit adaptations within the cortico-basal ganglia circuitry are thus critical for motor skill acquisition, and disruptions in this plasticity can contribute to movement disorders.

Interaction between the Neuroprotective and Hyperglycemia Mitigation Effects of Walnut-Derived Peptide LVRL via the Wnt3a/ß-Catenin/GSK-3ß Pathway in a Type 2 Diabetes Mellitus Model.

The term type 3 diabetes mellitus (T3DM) has been considered for Alzheimer's disease (AD) due to the common molecular and cellular characteristics found between type 2 diabetes mellitus (T2DM) and cognitive deficits. However, the specific mechanism of T3DM remains elusive, especially the neuroprotective effects of dietary components in hyperglycemic individuals. In this study, a peptide, Leu-Val-Arg-Leu (LVRL), found in walnuts significantly improved memory decline in streptozotocin (STZ)- and high-fat-diet (HFD)-stimulated T2DM mouse models (p < 0.05). The LVRL peptide also mitigated hyperglycemia, enhanced synaptic plasticity, and ameliorated mitochondrial dysfunction, as demonstrated by Morris water maze tests, immunoblotting, immunofluorescence, immunohistochemistry, transmission electron microscopy, and cellular staining. A Wnt3a inhibitor, DKK1, was subsequently used to verify the possible role of the Wnt3a/ß-Catenin/GSK-3ß pathway in glucose-induced insulin resistance in PC12 cells. In vitro LVRL treatment dramatically modulated the protein expression of p-Tau (Ser404), Synapsin-1, and PSD95, elevated the insulin level, increased glucose consumption, and relieved the mitochondrial membrane potential, and MitoSOX (p < 0.05). These data suggested that peptides like LVRL could modulate the relationship between brain insulin and altered cognition status via the Wnt3a/ß-Catenin/GSK-3ß pathway.

The effects of different types of social interactions on the electrophysiology of neurons in the nucleus accumbens in rodents.

BORLAND, J.M., The effects of different types of social interactions on the electrophysiology of neurons in the nucleus accumbens in rodents, NEUROSCI BIOBEH REV 21(1) XXX-XXX, 2024.-Sociality shapes an organisms' life. The nucleus accumbens is a critical brain region for mental health. In the following review, the effects of different types of social interactions on the physiology of neurons in the nucleus accumbens is synthesized. More specifically, the effects of sex behavior, aggression, social defeat, pair-bonding, play behavior, affiliative interactions, parental behaviors, the isolation from social interactions and maternal separation on measures of excitatory synaptic transmission, intracellular signaling and factors of transcription and translation in neurons in the nucleus accumbens in rodent models are reviewed. Similarities and differences in effects depending on the type of social interaction is then discussed. This review improves the understanding of the molecular and synaptic mechanisms of sociality.

Corrigendum: Artemisinin reduces PTSD-like symptoms, improves synaptic plasticity, and inhibits apoptosis in rats subjected to single prolonged stress.

[This corrects the article DOI: 10.3389/fphar.2024.1303123.].

Dietary salt promotes cognitive impairment through repression of SIRT3/PINK1-mediated mitophagy and fission.

Dietary salt is increasingly recognized as an independent risk factor for cognitive impairment. However, the exact mechanisms are not yet fully understood. Mitochondria, which play a crucial role in energy metabolism, are implicated in cognitive function through processes such as mitochondrial dynamics and mitophagy. While mitochondrial dysfunction is acknowledged as a significant determinant of cognitive function, the specific relationship between salt-induced cognitive impairment and mitochondrial health has yet to be fully elucidated. Here, we explored the underlying mechanism of cognitive impairment of mice and N2a cells treated with high-salt focusing on the mitochondrial homeostasis with western blotting, immunofluorescence, electron microscopy, RNA sequencing, and more. We further explored the potential role of SIRT3 in salt-induced mitochondrial dysfunction and synaptic alteration through plasmid transfection and siRNA. High salt diet significantly inhibited mitochondrial fission and blocked mitophagy, leading to dysfunctional mitochondria and impaired synaptic plasticity. Our findings demonstrated that SIRT3 not only promote mitochondrial fission by modulating phosphorylated DRP1, but also rescue mitophagy through promoting PINK1/Parkin-dependent pathway. Overall, our data for the first time indicate that mitochondrial homeostasis imbalance is a driver of impaired synaptic plasticity in a cognitive impairment phenotype that is exacerbated by a long-term high-salt diet, and highlight the protective role of SIRT3 in this process.

Kainate receptors regulate synaptic integrity and plasticity by forming a complex with synaptic organizers in the cerebellum.

Kainate (KA)-type glutamate receptors (KARs) are implicated in various neuropsychiatric and neurological disorders through their ionotropic and metabotropic actions. However, compared to AMPA- and NMDA-type receptor functions, many aspects of KAR biology remain incompletely understood. Our study demonstrates an important role of KARs in organizing climbing fiber (CF)-Purkinje cell (PC) synapses and synaptic plasticity in the cerebellum, independently of their ion channel or metabotropic functions. The amino-terminal domain (ATD) of the GluK4 KAR subunit binds to C1ql1, provided by CFs, and associates with Bai3, an adhesion-type G protein-coupled receptor expressed in PC dendrites. Mice lacking GluK4 exhibit no KAR-mediated responses, reduced C1ql1 and Bai3 levels, and fewer CF-PC synapses, along with impaired long-term depression and oculomotor learning. Remarkably, introduction of the ATD of GluK4 significantly improves all these phenotypes. These findings demonstrate that KARs act as synaptic scaffolds, orchestrating synapses by forming a KAR-C1ql1-Bai3 complex in the cerebellum.