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Aim: The three‐phase enriched environment (EE) intervention paradigm has been shown to improve learning and memory function after cerebral ischemia, but the neuronal mechanisms are still unclear. This study aimed to investigate the hippocampal–cortical connectivity and the metabolic interactions between neurons and astrocytes to elucidate the underlying mechanisms of EE‐induced memory improvement after stroke. Methods: Rats were subjected to permanent middle cerebral artery occlusion (pMCAO) or sham surgery and housed in standard environment or EE for 30 days. Memory function was examined by Morris water maze (MWM) test. Magnetic resonance imaging (MRI) was conducted to detect the structural and functional changes. [18F]‐fluorodeoxyglucose (FDG) positron emission tomography (PET) was conducted to detect brain energy metabolism. PET‐based brain connectivity and network analysis was performed to study the changes of hippocampal–cortical connectivity. Astrocyte‐neuron metabolic coupling, including gap junction protein connexin 43 (Cx43), glucose transporters (GLUTs), and monocarboxylate transporters (MCTs), was detected by histological studies. Results: Our results showed EE promoted memory function improvement, protected structure integrity, and benefited energy metabolism after stroke. More importantly, EE intervention significantly increased functional connectivity between the hippocampus and peri‐hippocampal cortical regions, and specifically regulated the level of Cx43, GLUTs and MCTs in the hippocampus and cortex. Conclusions: Our results revealed the three‐phase enriched environment paradigm enhanced hippocampal–cortical connectivity plasticity and ameliorated post‐stroke memory deficits. These findings might provide some new clues for the development of EE and thus facilitate the clinical transformation of EE. [ABSTRACT FROM AUTHOR]

Purpose: In addition to peripheral neuronal dysfunction, conventional chemotherapy can be associated with other neurological treatment-limiting adverse effects, including cognitive dysfunction, memory impairment, and anxiety, which are referred to as "chemobrain". This study aimed to investigate the effects of doxorubicin (DOX) and paclitaxel (PAC) on learning and memory in rats using radial arm water maze (RAWM) and investigated a potential beneficial effect of vitamin E (Vit. E). Methods: Adult male rats were injected with four doses of 2 mg/kg/week DOX, or 2 mg/kg PAC every other day intraperitoneally. Vit. E was co-administered with these drugs in other groups to study its antioxidative effects. Using the RAWM, each rat was assessed for learning and memory performance through two sets of six trials separated by a 5-min rest period evaluating both short- and long-term effects on memory. Results: There was no deficit in learning or long-term memory in both drug groups compared to control. However, rats in both drug groups made significantly more errors in all short-term memory trials. This effect was mitigated when Vit. E was co-administered with either drug. Moreover, PAC (but not DOX) induced hippocampal lipid peroxidation by increasing the levels of standard biomarker thiobarbituric acid reactive substances (TBARS). Interestingly, Vit. E prevented PAC-induced hippocampal oxidative stress. Furthermore, both DOX and PAC were correlated with reduction in Brain-Derived Neurotrophic Factor (BDNF) expression levels in the hippocampus, which was overcome by the co-administration of Vit. E. Conclusion: There is a potential role of Vit. E in alleviating short-term memory impairment in rats exposed to chemotherapy, possibly by reducing hippocampal oxidative stress and neurodegeneration. [ABSTRACT FROM AUTHOR]

Multiple cognitive domains, including learning, memory, and psychomotor speed, show significant reductions with age. Likewise, several cerebrospinal fluid (CSF) neurodegenerative biomarkers, including total tau (t-tau, a marker of neuronal body injury) and neurofilament light chain (NfL, a marker of axonal injury) show age-related increases in normal aging. In the current study, we aimed to investigate whether the age-effect within different cognitive domains was mediated by age-associated CSF markers for neurodegenerative changes. We fitted 10 mediation models using structural equation modeling to investigate this in a cohort of 137 healthy adults, aged 40–80 years, from the Norwegian Dementia Disease Initiation (DDI) study. Here, t-tau and NfL were defined as mediators between age and different cognitive tests. The models showed that NfL mediated the age-effect for CERAD learning and memory recall (learning: β = −0.395, p < 0.05; recall: β = −0.261, p < 0.01). No such effect was found in the other models. Our findings suggest that the age-related lower performance in verbal learning and memory may be linked to NfL-associated neurodegenerative changes in cognitively healthy adults. • CSF NfL mediates the relationship between age and verbal learning and memory. • White matter pathology seems to have a prominent role in normal aging. • T-tau is not significantly associated to neuropsychological test performance. • SCD seems to be less important in detecting objective cognitive deficits. [ABSTRACT FROM AUTHOR]

• ROCK2 signalling mediates microglial proliferation in vitro and in vivo after TBI. • With resident microglia, ROCK2 inhibition modestly improves TBI outcomes. • Acute ROCK2 inhibition negatively interferes with microglial repopulation. • Acute ROCK2 inhibition annuls the beneficial effects of repopulating microglia. Traumatic brain injury (TBI) results in prolonged and non-resolving activation of microglia. Forced turnover of these cells during the acute phase of TBI aids recovery, but the cell-intrinsic pathways that underpin the pro-repair phenotype of these repopulating microglia remain unclear. Here, we show that selective targeting of ROCK2 with the small molecule inhibitor KD025 impairs the proliferative response of microglia after TBI as well as during genetically induced turnover of microglia. KD025 treatment abolished the substantial neuroprotective and cognitive benefits conferred by repopulating microglia, preventing these cells from replenishing the depleted niche during the early critical time window post-injury. Delaying KD025 treatment to the subacute phase of TBI allowed microglial repopulation to occur, but this did not enhance the benefits conferred by repopulating microglia. Taken together, our data indicate that ROCK2 mediates neuronal survival and microglial population dynamics after TBI, including the emergence of repopulating microglia with a pro-repair phenotype. ROCK2 is a novel mediatior of microglial proliferation with implications for neuroprotection after brain injury. [ABSTRACT FROM AUTHOR]

Novelty detection, crucial to episodic memory formation, is impaired in epileptic patients with mesial temporal lobe resection. Mismatch novelty detection, that activates the hippocampal CA1 area in humans and is vital for memory reformulation and reconsolidation, is also impaired in patients with hippocampal lesions. In this work, we investigated the response to mismatch novelty, as occurs with the new location of known objects in a familiar environment, in the Li2+-pilocarpine rat model of TLE and its correlation with hippocampal monoaminergic markers. Animals showing spontaneous recurrent seizures (SRSs) for at least 4 weeks at the time of behavioural testing showed impaired spatial learning in the radial arm maze, as described. Concurrently, SRS rats displayed impaired exploratory responses to mismatch novelty, yet novel object recognition was not significantly affected in SRS rats. While the levels of serotonin and dopamine transporters were mildly decreased in hippocampal membranes from SRS rats, the levels on the norepinephrine transporter, tyrosine hydroxylase and dopamine-β-hydroxylase were enhanced, hinting for an augmentation, rather than an impairment in noradrenergic function in SRS animals. Altogether, this reveals that mismatch novelty detection is particularly affected by hippocampal damage associated to the Li2+-pilocarpine model of epilepsy 4–8 weeks after the onset of SRSs and suggests that deficits in mismatch novelty detection may substantially contribute to cognitive impairment in MTLE. As such, behavioural tasks based on these aspects of mismatch novelty may prove useful in the development of cognitive therapy strategies aiming to rescue cognitive deficits observed in epilepsy. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is a common synthetic endocrine disruptor that can be utilized in the fabrication of materials such as polycarbonates and epoxy resins. Numerous studies have linked BPA to learning and memory problems, although the precise mechanism remains unknown. Gamma‐aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the vertebrate central nervous system, and it is intimately related to learning and memory. This study aims to evaluate whether altered cognitive behavior involves the GABA signaling pathway in male offspring of rats exposed to BPA during the prenatal and early postnatal periods. Pregnant rats were orally given BPA (0, 0.04, 0.4, and 4 mg/kg body weight (BW)/day) from the first day of pregnancy to the 21st day of breastfeeding. Three‐week‐old male rat offspring were selected for an open‐field experiment and a new object recognition experiment to evaluate the effect of BPA exposure on cognitive behavior. Furthermore, the role of GABA signaling markers in the cognition affected by BPA was investigated at the molecular level using western blotting and real‐time polymerase chain reaction (RT‐PCR). The research demonstrated that BPA exposure impacted the behavior and memory of male rat offspring and elevated the expression of glutamic acid decarboxylase 67 (GAD67), GABA type A receptors subunit (GABAARα1), and GABA vesicle transporter (VGAT) in the hippocampus while decreasing the expression levels of GABA transaminase (GABA‐T) and GABA transporter 1 (GAT‐1). These findings indicate that the alteration in the expression of GABA signaling molecules may be one of the molecular mechanisms by which perinatal exposure to BPA leads to decreased learning and memory in male rat offspring. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a leading cause of dementia in the elderly. Mitogen-activated protein kinase phosphatase 1 (MKP-1) plays a neuroprotective role in AD. However, the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, thereby repressing mRNA translation. Here, we reported that the microRNA-429-3p (miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3′-untranslated region (3′ UTR). Inhibition of miR-429-3p by its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ accumulation. More importantly, intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase (ERK1/2)-mediated GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

Aim: The increase in the frequency of thyroid diseases in old age makes it necessary to reveal the relationship between aging and irregularities in thyroid hormone levels. In the present study, the effects of experimental hypothyroidism and thyrotoxicosis induced in middle aged rats on spatial learning and memory performance were investigated. Materials and Methods: In this study, 45 Wistar albino 12-month-old rats weighing 400-450 g were used. The rats were divided into three groups according to thyroid hormone levels; euthyroid (n=16), hyperthyroid (n=16) and hypothyroid (n=13). Thyrotoxicosis was induced by intraperitoneal (i.p.). administration of L-thyroxine at a dose of 0.2 mg/kg/day. Hypothyroid state was induced by daily administration of 0.05% 6-n-propyl-thiouracil (PTU) in the drinking water of rats. Spatial memory and learning performance of rats were evaluated by Morris water maze test. Thyroid hormone levels were determined with a commercial ELISA kit. Results: One-way ANOVA test revealed that the mean distance to the platform (p

Due to global population growth, age-related disorders like cardiovascular disease and dementia are anticipated to increase. Recent data suggests a connection between cardiovascular disease and neurodegeneration, especially focusing on arterial stiffness (AS) and Alzheimer’s disease (AD). In light of this, we conducted a study to explore the impact of long-term nitric oxide synthase (NOS) isoform inhibition, which leads to AS, on neurobehavioral performance. We also compared these effects in an AD model and control mice. C57BL/6 and hAPP23+/− mice (an established AD model) were given 0.5 mg/mL N(G)-Nitro-L-Arginine Methyl Ester (L-NAME) in their drinking water for 16 weeks. Our findings indicate that chronic non-selective NOS inhibition increased AS and reduced spatiotemporal learning and memory in both C57BL/6 and hAPP23+/− mice. These effects were consistent across both groups, emphasizing the role of neuronal NOS (nNOS) in cognitive aging, regardless of genetic predisposition to AD.

Abstract As a kind of environmental noise, infrasonic noise has negative effects on various human organs. To date, research has shown that infrasound impairs cognitive function, especially the ability for learning and memory. Previously, we demonstrated that impaired learning and memory induced by infrasound was closely related with glia activation; however, the underlying mechanisms remain unclear. Connexin 43 hemichannels (Cx43 HCs), which are mainly expressed in hippocampal astrocytes, are activated under pathological conditions, lending support to the hypothesis that Cx43 HCs might function in the impaired learning and memory induced by infrasound. This study revealed that that blocking hippocampal Cx43 HCs or downregulating hippocampal Cx43 expression significantly alleviated impaired learning and memory induced by infrasound. We also observed that infrasound exposure led to the abundant release of glutamate and ATP through Cx43 HCs. In addition, the abundant release of glutamate and ATP depended on proinflammatory cytokines. Our finds suggested that the enhanced release of ATP and glutamate by astroglial Cx43 HCs may be involved in the learning and memory deficits caused by infrasound exposure.

In this paper, the author analyses learning as a function of the threshold between parties and ideas. Using Bakhtinian dialogic theory, literacy learning in particular is envisioned as a dialogue of the threshold. This instructional threshold is viewed both in pedagogical and biological terms. The physiological process of learning is described, making a biological case for instructional scaffolding and the gradual release of responsibility in the classroom. The dialogue of different disciplines serves as integration of several thresholds and further strengthening of learning. Curriculum integration is then promoted as a means to lasting learning.

Objective: To explore the therapeutic effects of ginseng total saponins (GTSs) on cognitive impairments in astronauts caused by prolonged exposure to microgravity environment. Methods: Fifty specific pathogen-free (SPF) male Wistar rats were randomized into control, hindlimb suspension (HLS), Huperzine A (HLS-Hup A 0.1 mg/kg), low-dose GTSs (HLS-GTSs 100 mg/kg), and high-dose GTSs (HLS-GTSs 200 mg/kg) groups, based on the completion time of reward-directed conditioning tasks. Except for rats in the control group, the others were subjected to HLS and treated with drugs (day 20 – 58), received reflex test under the condition of rewarding, and underwent Nissl body staining and Western blot detection on hippocampal. Results: After modeling, rats in HLS group exhibited a reduction in the number of lever presses and an increase in the completion time of the reward-directed operant conditioning task Ⅰ (P < 0.05) when compared with the control group, which were not substantially altered in the HLS-GTSs 100 and 200 mg/kg groups (P > 0.05). In the reward-directed operant conditioning task Ⅱ, the HLS group rats demonstrated a marked decrease in the number of lever presses (P < 0.05) and nose pokes (P < 0.01) when compared with the control group rats; the HLS-GTSs 100 mg/kg showed a significant increase in the number of lever presses and nose pokes (P < 0.05), while the HLS-GTSs 200 mg/kg demonstrated a significant reduction in completion time and an elevation in the number of lever presses (P < 0.05) when compared with the HLS group rats. In visual signal discrimination task, compared with the control group rats, the HLS group rats showed decrease in the indexes of the visual signal discrimination (P < 0.01), while HLS-GTSs 100 and 200 mg/kg groups exhibited manifest increase in it (P < 0.01). In reward extinction experiment, the number of lever presses in HLS rats significantly increased when compared with the control group (P < 0.01); compared with the HLS group, HLS-GTSs 100 and 200 mg/kg groups demonstrated a marked descrease (P < 0.05). The expressions of N-methyl-D-aspartic acid receptor 1 (NR1) and phosophorylated N-methyl-D-aspartic acid receptor 2B (p-NR2B) proteins were markedly decreased in rats in the HLS group (P < 0.05 and P < 0.01, respectively), while that of NR2B protein maintained the same (P > 0.05). GTSs increased the expression levels of p-NR2B (P < 0.01). Conclusion: GTSs improved the learning and memory ability of complex operations by regulating the NR1/NR2B phosphorylation pathways in rats.

Adult hippocampal neurogenesis is critical for learning and memory, and aberrant adult neurogenesis has been implicated in cognitive decline associated with aging and neurological diseases [J. T. Gonçalves, S. T. Schafer, F. H. Gage, Cell 167, 897–914 (2016)]. In previous studies, we observed that the delayed-rectifier voltage-gated potassium channel Kv1.1 controls the membrane potential of neural stem and progenitor cells and acts as a brake on neurogenesis during neonatal hippocampal development [S. M. Chou et al., eLife 10, e58779 (2021)]. To assess the role of Kv1.1 in adult hippocampal neurogenesis, we developed an inducible conditional knockout mouse to specifically remove Kv1.1 from adult neural stem cells via tamoxifen administration. We determined that Kv1.1 deletion in adult neural stem cells causes overproliferation and depletion of radial glia-like neural stem cells, prevents proper adult-born granule cell maturation and integration into the dentate gyrus, and moderately impairs hippocampus-dependent contextual fear learning and memory. Taken together, these findings support a critical role for this voltage-gated ion channel in adult neurogenesis.

Understanding the complexities of behavior is necessary to interpret neurophysiological data and establish animal models of neuropsychiatric disease. This understanding requires knowledge of the underlying information-processing structure-something often hidden from direct observation. Commonly, one assumes that behavior is solely governed by the experimenter-controlled rules that determine tasks. For example, differences in tasks that require memory of past actions are often interpreted as exclusively resulting from differences in memory. However, such assumptions are seldom tested. Here, we provide a comprehensive examination of multiple processes that contribute to behavior in a prevalent experimental paradigm. Using a combination of behavioral automation, hypothesis-driven trial design, and reinforcement learning modeling, we show that rats learn a spatial alternation task consistent with their drawing upon spatial preferences in addition to memory. Our approach also distinguishes learning based on established preferences from generalization of task structure, providing further insights into learning dynamics.

Objective: To investigate the underlying mechanism of the compound Bugansan Decoction (补肝散, BGSD) in intervening learning and memory in D-galactose (D-gal)-induced aging rats. Methods: A total of 40 rats were randomly assigned to four groups: control, model, BGSD [14.06 g/(kg·d)], and piracetam [0.4 g/(kg·d)] groups, with 10 rats in each group. D-gal [400 mg/(kg·d)] was injected intraperitoneally to establish the aging rat model. The rats' body weight, water intake, food intake, and gripping strength were recorded each week. The eight-arm maze and step-down test were used to measure the rats' capacity for learning and memory. Liver, thymus, spleen, and brain tissues were weighed to calculate the corresponding organ indices; serum malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were measured. Hematoxylin and eosin (HE) staining was adopted to observe the pathological changes of the hippocampus; enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in the hippocampus. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of receptors for advanced glycation end products (RAGE), nuclear factor-κB (NF-κB), TNF-α, IL-6, and IL-1β mRNA in the hippocampus. Western blot (WB) was employed to detect the expression levels of advanced glycation end products (AGEs), RAGE, and NF-κB protein in the hippocampus. Results: In D-gal-induced aging rats, BGSD significantly increased food intake, water intake, body weight, gripping strength, and organ indices (P < 0.05), and significantly decreased working memory error (WME), reference memory error (RME), and total memory errors (TE) in an eight-arm maze (P < 0.05). In the step-down test, step-down latency was prolonged and the frequency of errors dropped (P < 0.05). Additionally, BGSD could lessen the harm done to hippocampus neurons, increase serum SOD activity, lower MDA levels, and down-regulate the expression levels of the pro-inflammatory molecules TNF-α, IL-6, and IL-1β (P < 0.05). Further findings showed that BGSD significantly decreased hippocampal AGEs, RAGE, and NF-κB expression (P < 0.05). Conclusion: By blocking the AGEs/RAGE/NF-κB signaling pathway, BGSD may regulate the neuroinflammatory damage in D-gal-induced aging rats, and thus improve learning and memory.

A feature of the brains of intelligent animals is the ability to learn to respond to an ensemble of active neuronal inputs with a behaviorally appropriate ensemble of active neuronal outputs. Previously, a hypothesis was proposed on how this mechanism is implemented at the cellular level within the neocortical pyramidal neuron: the apical tuft or perisomatic inputs initiate “guess” neuron firings, while the basal dendrites identify input patterns based on excited synaptic clusters, with the cluster excitation strength adjusted based on reward feedback. This simple mechanism allows neurons to learn to classify their inputs in a surprisingly intelligent manner. Here, we revise and extend this hypothesis. We modify synaptic plasticity rules to align with behavioral time scale synaptic plasticity (BTSP) observed in hippocampal area CA1, making the framework more biophysically and behaviorally plausible. The neurons for the guess firings are selected in a voluntary manner via feedback connections to apical tufts in the neocortical layer 1, leading to dendritic Ca2+ spikes with burst firing, which are postulated to be neural correlates of attentional, aware processing. Once learned, the neuronal input classification is executed without voluntary or conscious control, enabling hierarchical incremental learning of classifications that is effective in our inherently classifiable world. In addition to voluntary, we propose that pyramidal neuron burst firing can be involuntary, also initiated via apical tuft inputs, drawing attention toward important cues such as novelty and noxious stimuli. We classify the excitations of neocortical pyramidal neurons into four categories based on their excitation pathway: attentional versus automatic and voluntary/acquired versus involuntary. Additionally, we hypothesize that dendrites within pyramidal neuron minicolumn bundles are coupled via depolarization cross-induction, enabling minicolumn functions such as the creation of powerful hierarchical “hyperneurons” and the internal representation of the external world. We suggest building blocks to extend the microcircuit theory to network-level processing, which, interestingly, yields variants resembling the artificial neural networks currently in use. On a more speculative note, we conjecture that principles of intelligence in universes governed by certain types of physical laws might resemble ours.

Summary: The orbitofrontal cortex, one of the key neocortical areas in valuation and emotion, is critical for cognitive flexibility but its role in the consolidation of recently acquired information remains unclear. Here, we demonstrate orbitofrontal offline replay in the context of a place-reward association task on a maze with varying goal locations. When switches in place-reward coupling were applied, replay was enhanced relative to sessions with stable contingencies. Moreover, replay strength was positively correlated with the subsequent overnight change in behavioral performance. Interrogating relationships between orbitofrontal and hippocampal activity, we found that orbitofrontal and hippocampal replay could occur independently but became coordinated during a type of cortical state with strong spiking activity. These findings reveal a structured form of offline orbitofrontal ensemble activity that is correlated with cognitive flexibility required to adapt to changing task contingencies, and becomes associated with hippocampal replay only during a specific state of high cortical excitability.

Brain infection by the parasite Toxoplasma gondii is thought to impair learning and memory, although the underlying mechanisms remain largely unknown. Recent studies suggest that perineuronal nets (PNNs) and their key regulator, matrix metalloproteinase-9 (MMP-9), have essential roles in synaptic plasticity associated with learning and memory. We investigated their roles in a chronic toxoplasmosis model using female mice. In mice with a high parasite burden of chronic infection, we found that MMP-9 expression was increased in the peripheral circulation and the brain. A correlation was found between the serum levels of MMP-9 and antibodies to the Toxoplasma matrix antigen MAG1, a surrogate marker for Toxoplasma tissue cysts in the brain. MMP-9 elevation was accompanied by increased expression of its endogenous regulators, TIMP-1 and NGAL. An increase in the levels of GSK-3α/β was observed, alongside a decrease in inhibitory GSK-3α/β (Ser-21/Ser-9) phosphorylation. MMP-9 expression was notably associated with the loss of PNNs but increased expression of the synaptic vesicle protein synaptophysin. There was a trend toward a negative correlation between MMP-9 and aggrecan expression, a critical PNN component. Together, these results suggest that chronic Toxoplasma infection can cause an increase in MMP-9 expression, resulting in the degradation of PNNs, which provides a possible mechanism for Toxoplasma-associated deficits in learning and memory.

The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brain's lipid landscape remain largely unexplored. The levels of saturated FFAs, particularly of myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the PLA1 isoform DDHD2 in mice dramatically reduces saturated FFA responses to memory acquisition across the brain. Furthermore, DDHD2 loss also decreases memory performance in reward-based learning and spatial memory models prior to the development of neuromuscular deficits that mirror human spastic paraplegia. Via pulldown-mass spectrometry analyses, we find that DDHD2 binds to the key synaptic protein STXBP1. Using STXBP1/2 knockout neurosecretory cells and a haploinsufficient STXBP1+/− mouse model of human early infantile encephalopathy associated with intellectual disability and motor dysfunction, we show that STXBP1 controls targeting of DDHD2 to the plasma membrane and generation of saturated FFAs in the brain. These findings suggest key roles for DDHD2 and STXBP1 in lipid metabolism and in the processes of synaptic plasticity, learning, and memory. Synopsis: The mechanisms by which neuronal activity affects lipid metabolism in the brain remain little understood. This study identifies the phospholipase A1 isoform DDHD2 and the key synaptic protein STXBP1 as important regulators of lipid metabolism in synaptic plasticity and long-term memory in mice. DDHD2 produces saturated free fatty acids (FFAs) in response to long-term memory acquisition. DDHD2 is targeted to the synapse via an interaction with STXBP1. Ablation of DDHD2 in mice diminishes saturated FFA responses to memory acquisition and leads to progressive neuromuscular and cognitive/memory deficits. STXBP1-haploinsufficient mice similarly exhibit reduced saturated FFAs. Ablation of phospholipase D1 has little effect on saturated FFAs and long-term memory. The phospholipase A1 isoform DDHD2 and the key synaptic protein STXBP1 control lipid metabolism in learning and long-term memory. [ABSTRACT FROM AUTHOR]

In 1984, Gary Lynch and Michel Baudry published in Science a novel biochemical hypothesis for learning and memory, in which they postulated that the calciumdependent protease, calpain, played a critical role in regulating synaptic properties and the distribution of glutamate receptors, thereby participating in memory formation in hippocampus. Over the following 40 years, much work has been done to refine this hypothesis and to provide convincing arguments supporting what was viewed at the time as a simplistic view of synaptic biochemistry. We have now demonstrated that the two major calpain isoforms in the brain, calpain-1 and calpain-2, execute opposite functions in both synaptic plasticity/learning and memory and in neuroprotection/neurodegeneration. Thus, calpain-1 activation is required for triggering long-term potentiation (LTP) of synaptic transmission and learning of episodic memory, while calpain-2 activation limits the magnitude of LTP and the extent of learning. On the other hand, calpain-1 is neuroprotective while calpain-2 is neurodegenerative, and its prolonged activation following various types of brain insults leads to neurodegeneration. The signaling pathways responsible for these functions have been identified and involve local protein synthesis, cytoskeletal regulation, and regulation of glutamate receptors. Human families with mutations in calpain-1 have been reported to have impairment in motor and cognitive functions. Selective calpain-2 inhibitors have been synthesized and clinical studies to test their potential use to treat disorders associated with acute neuronal damage, such as traumatic brain injury, are being planned. This review will illustrate the long and difficult journey to validate a bold hypothesis. [ABSTRACT FROM AUTHOR]

Background: Glucocorticoids (GCs) are steroidal hormones produced by the adrenal cortex. A physiological‐level GCs have a crucial function in maintaining many cognitive processes, like cognition, memory, and mood, however, both insufficient and excessive GCs impair these functions. Although this phenomenon could be explained by the U‐shape of GC effects, the underlying mechanisms are still not clear. Therefore, understanding the underlying mechanisms of GCs may provide insight into the treatments for cognitive and mood‐related disorders. Methods: Consecutive administration of corticosterone (CORT, 10 mg/kg, i.g.) proceeded for 28 days to mimic excessive GCs condition. Adrenalectomy (ADX) surgery was performed to ablate endogenous GCs in mice. Microinjection of 1 μL of Ad‐mTERT‐GFP virus into mouse hippocampus dentate gyrus (DG) and behavioral alterations in mice were observed 4 weeks later. Results: Different concentrations of GCs were shown to affect the cell growth and development of neural stem cells (NSCs) in a U‐shaped manner. The physiological level of GCs (0.01 μM) promoted NSC proliferation in vitro, while the stress level of GCs (10 μM) inhibited it. The glucocorticoid synthesis blocker metyrapone (100 mg/kg, i.p.) and ADX surgery both decreased the quantity and morphological development of doublecortin (DCX)‐positive immature cells in the DG. The physiological level of GCs activated mineralocorticoid receptor and then promoted the production of telomerase reverse transcriptase (TERT); in contrast, the stress level of GCs activated glucocorticoid receptor and then reduced the expression of TERT. Overexpression of TERT by AD‐mTERT‐GFP reversed both chronic stresses‐ and ADX‐induced deficiency of TERT and the proliferation and development of NSCs, chronic stresses‐associated depressive symptoms, and ADX‐associated learning and memory impairment. Conclusion: The bidirectional regulation of TERT by different GCs concentrations is a key mechanism mediating the U‐shape of GC effects in modulation of hippocampal NSCs and associated brain function. Replenishment of TERT could be a common treatment strategy for GC dysfunction‐associated diseases. [ABSTRACT FROM AUTHOR]

Almost 10 years ago Prichard et al. (2013) published a literature review on consistency of handedness. They described how consistency of handedness, typically measured by the Edinburgh Handedness Inventory (EHI), predicted outcomes in memory and decision-making paradigms better than direction of handedness. In the last 10 years, new research has extended these findings and added new theoretical perspectives. The goal of this short form review is to highlight and summarize some of these more intriguing findings and to encourage researchers in the fields of memory and decision making to incorporate handedness as a variable in future research. [ABSTRACT FROM AUTHOR]

Mesial temporal lobe epilepsy (MTLE), the most common form of focal epilepsy in adults, is often refractory to medication and associated with hippocampal sclerosis. Deep brain stimulation represents an alternative treatment option for drug-resistant patients who are ineligible for resective brain surgery. In clinical practice, closed-loop stimulation at high frequencies is applied to interrupt ongoing seizures, yet has (i) a high incidence of false detections; (ii) the drawback of delayed seizure-suppressive intervention; and (iii) limited success in sclerotic tissue. As an alternative, low-frequency stimulation (LFS) has been explored recently in patients with focal epilepsies. In preclinical epilepsy models, hippocampal LFS successfully prevented seizures when applied continuously. Since it would be advantageous to reduce the stimulation load, we developed a protocol for on-demand LFS. Given the importance of the hippocampus for navigation and memory, we investigated potential consequences of LFS on hippocampal function. To this end, we used the intrahippocampal kainate mouse model, which recapitulates the key features of MTLE, including spontaneous seizure activity and hippocampal sclerosis. Specifically, our online detection algorithm monitored epileptiform activity in hippocampal local field potential recordings and identified short epileptiform bursts preceding focal seizure clusters, triggering hippocampal LFS to stabilize the network state. To probe behavioural performance, we tested the acute influence of LFS on anxiety-like behaviour in the light-dark box test, spatial and non-spatial memory in the object location memory and novel object recognition test, as well as spatial navigation and long-term memory in the Barnes maze. On-demand LFS was almost as effective as continuous LFS in preventing focal seizure clusters but with a significantly lower stimulation load. When we compared the behavioural performance of chronically epileptic mice to healthy controls, we found that both groups were equally mobile, but epileptic mice displayed an increased anxiety level, altered spatial learning strategy and impaired memory performance. Most importantly, with the application of hippocampal LFS before behavioural training and test sessions, we could rule out deleterious effects on cognition and even show an alleviation of deficits in long-term memory recall in chronically epileptic mice. Taken together, our findings may provide a promising alternative to current therapies, overcoming some of their major limitations, and inspire further investigation of LFS for seizure control in focal epilepsy syndromes. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a leading cause of dementia in the elderly. Mitogen-activated protein kinase phosphatase 1 (MKP-1) plays a neuroprotective role in AD. However, the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, thereby repressing mRNA translation. Here, we reported that the microRNA-429-3p (miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3′-untranslated region (3′ UTR). Inhibition of miR-429-3p by its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and A β accumulation. More importantly, intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase (ERK1/2)-mediated GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containing α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting that miR-429 /MKP-1 pathway may be a novel therapeutic target for AD treatment. miR-429-3p inhibits MKP-1 expression by directly binding to its 3′UTR, consequently initiating ERK1/2-mediated hyperphosphorylation of GluA1 at S831, which ultimately leads to synaptic and cognitive dysfunction in AD. [Display omitted] [ABSTRACT FROM AUTHOR]

Cannabinoid receptors (CB1 and CB2) are promising targets for a better understanding of neurological diseases. Nevertheless, only a few ligands of CB have reached clinical application so far. Venoms are considered as interesting sources of novel biologically active compounds. Here, we describe an endocannabinoid-like molecule, oleoyl serotonin (OS), present in the venom of Stephanoconus snails. Using electrophysiological assays, it was shown that OS inhibits CB1 and CB2. Structure–activity relationship studies using a chimeric CB1/2 revealed that the domain encompassing the transmembrane helix V (TMHV)– intracellular loop 3 (ICL3)–TMHVI of the CB2 is critical for the binding and function of OS. We concluded that OS binds to sites of the CB2 that are different from the binding sites of the non-selective CB agonist WIN55,212-2. Behavioral assays in mice showed that OS counteracted learning and memory deficits caused by WIN55,212-2. Furthermore, a selectivity screening of OS showed high selectivity for CB over various ion channels and receptors. Overall, OS may represent a new approach to the prevention and treatment of learning and memory cognition impairment in neurological diseases. [ABSTRACT FROM AUTHOR]

In well-established first-order conditioning experiments, the concurrence of a sensory cue with reinforcement forms an association, allowing the cue to predict future reinforcement. In the insect mushroom body, a brain region central to learning and memory, such associations are encoded in the synapses between its intrinsic and output neurons. This process is mediated by the activity of dopaminergic neurons that encode reinforcement signals. In second-order conditioning, a new sensory cue is paired with an already established one that presumably activates dopaminergic neurons due to its predictive power of the reinforcement. We explored minimal circuit motifs in the mushroom body for their ability to support second-order conditioning using mechanistic models. We found that dopaminergic neurons can either be activated directly by the mushroom body’s intrinsic neurons or via feedback from the output neurons via several pathways. We demonstrated that the circuit motifs differ in their computational efficiency and robustness. Beyond previous research, we suggest an additional motif that relies on feedforward input of the mushroom body intrinsic neurons to dopaminergic neurons as a promising candidate for experimental evaluation. It differentiates well between trained and novel stimuli, demonstrating robust performance across a range of model parameters. [ABSTRACT FROM AUTHOR]

Down syndrome cell adhesion molecule (Dscam) gene encodes a cell adhesion molecule required for neuronal wiring. A remarkable feature of arthropod Dscam is massive alternative splicing generating thousands of different isoforms from three variable clusters of alternative exons. Dscam expression and diversity arising from alternative splicing have been studied during development, but whether they exert functions in adult brains has not been determined. Here, using honey bees, we find that Dscam expression is critically linked to memory retention as reducing expression by RNAi enhances memory after reward learning in adult worker honey bees. Moreover, alternative splicing of Dscam is altered in all three variable clusters after learning. Since identical Dscam isoforms engage in homophilic interactions, these results suggest a mechanism to alter inclusion of variable exons during memory consolidation to modify neuronal connections for memory retention. [ABSTRACT FROM AUTHOR]

The δ opioid receptor (DOR) inverse agonist has been demonstrated to improve learning and memory impairment in mice subjected to restraint stress. Here, we investigated the effects of SYK-623, a new DOR inverse agonist, on behavioral, immunohistochemical, and biochemical abnormalities in a mouse model of imipramine treatment-resistant depression. Male ddY mice received daily treatment of adrenocorticotropic hormone (ACTH) combined with chronic mild stress exposure (ACMS). SYK-623, imipramine, or the vehicle was administered once daily before ACMS. After three weeks, ACMS mice showed impaired learning and memory in the Y-maze test and increased immobility time in the forced swim test. SYK-623, but not imipramine, significantly suppressed behavioral abnormalities caused by ACMS. Based on the fluorescent immunohistochemical analysis of the hippocampus, ACMS induced a reduction in astrocytes and newborn neurons, similar to the reported findings observed in the postmortem brains of depressed patients. In addition, the number of parvalbumin-positive GABA neurons, which play a crucial role in neurogenesis, was reduced in the hippocampus, and western blot analysis showed decreased glutamic acid decarboxylase protein levels. These changes, except for the decrease in astrocytes, were suppressed by SYK-623. Thus, SYK-623 mitigates behavioral abnormalities and disturbed neurogenesis caused by chronic stress. [ABSTRACT FROM AUTHOR]

The transcription factor Olig2 is highly expressed throughout oligodendroglial development and is needed for the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes and remyelination. Although Olig2 overexpression in OPCs is a possible therapeutic target for enhancing myelin repair in ischemic stroke, achieving Olig2 overexpression in vivo remains a formidable technological challenge. To address this challenge, we employed lipid nanoparticle (LNP)-mediated delivery of Olig2 synthetically modified messenger RNA (mRNA) as a viable method for in vivo Olih2 protein overexpression. Specifically, we developed CD140a-targeted LNPs loaded with Olig2 mRNA (C-Olig2) to achieve targeted Olig2 protein expression within PDGFRα+ OPCs, with the goal of promoting remyelination for ischemic stroke therapy. We show that C-Olig2 promotes the differentiation of PDGFRα+ OPCs derived from mouse neural stem cells into mature oligodendrocytes in vitro, suggesting that mRNA-mediated Olig2 overexpression is a rational approach to promote oligodendrocyte differentiation and remyelination. Furthermore, when C-Olig2 was administered to a murine model of ischemic stroke, it led to improvements in blood‒brain barrier (BBB) integrity, enhanced remyelination, and rescued learning and cognitive deficits. Our comprehensive analysis, which included bulk RNA sequencing (RNA-seq) and single-nucleus RNA-seq (snRNA-seq), revealed upregulated biological processes related to learning and memory in the brains of mice treated with C-Olig2 compared to those receiving empty LNPs (Mock). Collectively, our findings highlight the therapeutic potential of multifunctional nanomedicine targeting mRNA expression for ischemic stroke and suggest that this approach holds promise for addressing various brain diseases. While Olig2 overexpression in OPCs represents a promising therapeutic avenue for enhancing remyelination in ischemic stroke, in vivo strategies for achieving Olig2 expression pose considerable technological challenges. The delivery of mRNA via lipid nanoparticles is considered aa viable approach for in vivo protein expression. In this study, we engineered CD140a-targeted LNPs loaded with Olig2 mRNA (C-Olig2) with the aim of achieving specific Olig2 overexpression in mouse OPCs. Our findings demonstrate that C-Olig2 promotes the differentiation of OPCs into oligodendrocytes in vitro, providing evidence that mRNA-mediated Olig2 overexpression is a rational strategy to foster remyelination. Furthermore, the intravenous administration of C-Olig2 into a murine model of ischemic stroke not only improved blood-brain barrier integrity but also enhanced remyelination and mitigated learning and cognitive deficits. These results underscore the promising therapeutic potential of multifunctional nanomedicine targeting mRNA expression in the context of ischemic stroke. [Display omitted] [ABSTRACT FROM AUTHOR]

Memory and learning allow animals to appropriate certain properties of nature with which they can navigate in it successfully. Memory is acquired slowly and consists of two major phases, a fragile early phase (short‐term memory, <4 h) and a more robust and long‐lasting late one (long‐term memory, >4 h). Erythropoietin (EPO) prolongs memory from 24 to 72 h when animals are trained for 5 min in a place recognition task but not when training lasted 3 min (short‐term memory). It is not known whether it promotes the formation of remote memory (≥21 days). We address whether the systemic administration of EPO can convert a short‐term memory into a long‐term remote memory, and the neural plasticity mechanisms involved. We evaluated the effect of training duration (3 or 5 min) on the expression of endogenous EPO and its receptor to shed light on the role of EPO in coordinating mechanisms of neural plasticity using a single‐trial spatial learning test. We administered EPO 10 min post‐training and evaluated memory after 24 h, 96 h, 15 days, or 21 days. We also determined the effect of EPO administered 10 min after training on the expression of arc and bdnf during retrieval at 24 h and 21 days. Data show that learning induces EPO/EPOr expression increase linked to memory extent, exogenous EPO prolongs memory up to 21 days; and prefrontal cortex bdnf expression at 24 h and in the hippocampus at 21 days, whereas arc expression increases at 21 days in the hippocampus and prefrontal cortex. [ABSTRACT FROM AUTHOR]

Background and aim: Early-life stressful situations and binge drinking have been thus far acknowledged as two burdensome conditions that potentially give rise to negative outcomes and then synergistically affect brain development. In this context, the hippocampus, with the greatest number of glucocorticoid receptors (GCRs) in the brain, is responsible for regulating negative responses to stress. Prolonged glucocorticoid (GC) exposure can accordingly cause oxidative stress (OS), leading to cognitive and emotional dysfunction. Against this background, melatonin, as a powerful antioxidant and hypothalamus–pituitary–adrenal (HPA) axis regulator, was administered in this study to ameliorate cognitive impairments induced by perinatal ethanol and stress exposure in adolescent male rat progeny. Methods: Wistar rat dams were exposed to ethanol (4 g/kg) and melatonin (10 mg/kg) from gestational day (GD) 6 to postnatal day (PND) 14 and then limited nesting material (LNS) from PND0 to PND14 individually or in combination. Maternal behavior was then investigated in mothers. Afterward, the plasma corticosterone (CORT) concentration, the OS marker, the corticotropin-releasing hormone receptor type 1 (CRHR1) expression, and the GCR and brain-derived neurotrophic factor (BDNF) levels were measured in the male pups. Moreover, behavioral tasks, including the elevated plus maze (EPM), the Morris water maze (MWM), the novel object recognition (NORT), and the object-location memory (OLM) tests were completed and assessed. Results: The quantity and quality of maternal care significantly decreased in the mothers with dual exposure to ethanol and stress. The plasma CORT concentration in the progeny also dropped in the Ethanol + LNS group, but the risk-taking behavior elevated significantly. The ethanol and stress exposure further revealed a significant fall in the GCR and CRHR1 expression levels, compared with stress alone. The results of learning and memory tasks also indicated a significant reduction in spatial learning and memory among animals exposed to ethanol and stress. The BDNF mRNA levels correspondingly increased in the Ethanol + LNS group, compared with LNS alone. In the presence of ethanol and stress, the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities correspondingly declined. On the other hand, the malondialdehyde (MDA) levels augmented in the hippocampus of the animals with ethanol and LNS dual exposure, as compared with the control group. Melatonin treatment (MT) thus improved nursing behaviors in dams, prevented OS, enhanced the CRHR1 and GCR expression, and reduced the BDNF levels to the similar ones in the control group. The animals in the Ethanol + LNS + MT group ultimately showed an ameliorated performance at behavioral tasks, including the memory and risk-taking behavior. Conclusion: It was concluded that MT could prevent stress response and memory impairments arising from dual exposure to ethanol and stress by inhibiting OS. [ABSTRACT FROM AUTHOR]

Objective: Excitotoxic damage results in cell death in several human neurodegenerative diseases. Epilepsy is one of the most common neurological disorders and it causes complications. To this end, we examined the protective role of allantoin (AL) in a model of excitotoxic neuronal death induced by intraperitoneal injection of kainic acid (KA) in mice. Methods: Two-month-old C57 male mice (n=35) were divided into five groups: control (received 0.9% saline), AL (received 10 mg/kg of AL), KA (received a single dose of 10 mg/kg of KA), KA+AL10 and KA+AL15 groups (received a single dose of 10 mg/kg of KA then were treated with 10 mg/kg of AL or 15 mg/kg respectively). On the 14th day of the experiment, learning and memory were tested using a shuttle-box. The number of intact neurons and damaged neural cells in hippocampal CA1 and CA3 were assessed by Nissl staining and Flour-J B immunohistochemistry, respectively. Results: The results showed that injection of KA decreased the latency time while administration of 10 mg/kg AL improved memory. In addition, there was a significant difference between KA and KA+AL10 mg/kg groups (p<0.01). The histological results revealed that the use of 10 mg/kg AL significantly increased the number of intact pyramidal cells in the hippocampal CA1 and CA3 regions compared with the KA group (p<0.01). Moreover, neurodegeneration of the hippocampal region was significantly decreased in the groups treated with AL compared with the KA group (p<0.05). Conclusion: This study indicated that AL at a concentration of 10 mg/kg/day improved neurodegenerative complications following temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

Honey bees have significant ecological and economic value as important pollinators, but they are continuously exposed to various environmental stressors, including insecticides, which can impair their health and cause colony decline. (1) Background: Cognitive abilities are vital for the functional maintenance of honey bees; however, it remains unknown if chronic, low-dose exposure to thiacloprid during the larval stage impairs the cognitive abilities of emerged adult honey bees. (2) Methods: To explore this question, honey bee larvae were fed 0, 0.5, and 1.0 mg/L thiacloprid during their developmental phase. Then, the cognitive (i.e., olfactory learning and memory) abilities of adult honey bees were quantified to assess the delayed impacts of early-stage thiacloprid exposure on adult honey bee cognition. Neural apoptosis and transcriptomic level were also evaluated to explore the neurological mechanisms underlying these effects. (3) Results: Our results revealed that chronic larval exposure to sublethal thiacloprid impaired the learning and memory abilities of adult honey bees by inducing neuronal apoptosis and transcriptomic alterations. (4) Conclusions: We highlighted a previously unknown impairment caused by thiacloprid in honey bees. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in reciprocal social interactions, deficits in communication, and restrictive and repetitive behaviors and interests. In previous studies, music has been identified as an intervention therapy for children with ASD. Objectives: The present study evaluated the effects of music on cognitive behavioral impairments in both sexes of adult rats exposed prenatally to Valproic acid. Methods: For induction of autism, pregnant female rats were pretreated with either saline or VPA (600 mg/kg.i.p.) at gestational day (GD) 12.5. Male and female offspring were divided into Saline.Non‐Music, VPA.Non‐Music, Saline.Music, and VPA.Music groups. The adult rats in the music groups were exposed to Mozart's piano sonata K.448 for 30 days (4 h/day), from postnatal day (PND) 60 to 90. Social interaction and Morris water maze (MWM) tasks were tested at PND 90. Results: Our results revealed that prenatal exposure to VPA decreased sociability and social memory performance in both sexes of adult rats. Moreover, prenatal exposure to VPA created learning and memory impairments in both sexes of adult rats in the MWM task. Music intervention improved sociability in both sexes of VPA‐exposed rats and social memory in both sexes of VPA‐exposed rats, especially in females. Furthermore, our results revealed that music ameliorated learning impairments in VPA‐exposed female rats in the MWM task. In addition, music improved spatial memory impairments in VPA‐exposed rats of both sexes, especially in females, which needs more investigation in molecular and histological fields in future studies. Conclusion: Music intervention improved sociability and social memory in adult VPA‐exposed rats, especially in female animals. Furthermore, music improved memory impairments in VPA‐exposed rats of both sexes. It seems that music had a better influence on female rats. However, future studies need more investigations in molecular and histological fields. [ABSTRACT FROM AUTHOR]

Apigenin is a flavone widely present in different fruits and vegetables and has been suggested to possess neuroprotective effects against some neurological disorders. In this study, we systematically reviewed preclinical studies that investigated the effects of apigenin on learning and memory, locomotion activity, anxiety-like behaviour, depressive-like behaviour and sensorimotor and motor coordination in rats and mice with impaired memory and behaviour. We searched SCOPUS, Web of Science, PubMed and Google Scholar for relevant articles. A total of 34 studies were included in this review. The included studies revealed that apigenin enhanced learning and memory and locomotion activity, exhibited anxiolytic effects, attenuated depressive-like behaviour and improved sensorimotor and motor coordination in animals with cognitive impairment and neurobehavioural deficit. Some of the molecular and biochemical mechanisms of apigenin include activation of the ERK/CREB/BDNF signalling pathway; modulation of neurotransmitter levels and monoaminergic, cholinergic, dopaminergic and serotonergic systems; inhibition of pro-inflammatory cytokine production; and attenuation of oxidative neuronal damage. These results revealed the necessity for further research using established doses and short or long durations to ascertain effective and safe doses of apigenin. These results also point to the need for a clinical experiment to ascertain the therapeutic effect of apigenin. [ABSTRACT FROM AUTHOR]

Introduction: Both sleep deprivation (SD) and inflammation can negatively affect cognitive function. This study aimed to investigate how SD impacts the brain's inflammatory response to lipopolysaccharide (LPS) and its subsequent effects on cognitive functions. Methods: To this end, male rats were tested through a Morris water maze (MWM) to assess their spatial learning and memory. Also, in vivo field potential recordings (to evaluate synaptic plasticity) were done in the Saline, SD, LPS1 (1 mg/kg/7 days), and LPS1+SD groups. Cytokine levels were measured using an enzyme-linked immunosorbent assay (ELISA). Results: Based on the results, the LPS1+SD group showed increased total distance and escape latency compared to the other groups in the MWM test. Besides, the LPS1+SD group exhibited a significant decrease in long-term potentiation (LTP) induction and maintenance in the CA1 area of the brain. Finally, the inflammatory cytokine interleukin-1β (IL-1β) levels were significantly higher in the LPS1+SD group than in the Saline group. Conclusion: These findings suggest that the combined effects of SD and brain inflammatory response can have more harmful effects on cognitive function, LTP, and inflammatory factors than either SD or LPS1 alone. [ABSTRACT FROM AUTHOR]

AbstractAimMaterials and MethodsResultsFormaldehyde is a chemical that lies behind the various systemical failures in organism. Many products that people use contain formaldehyde. Owing to its tissue fixative properties, scientists who work in life sciences are exposed to this substance more than others. Several studies have shown that formaldehyde affects the CA1 and CA3 regions of the hippocampus, which play crucial roles in memory consolidation. In this study, we aimed to investigate anxiety levels and indicate the short and long term effects of formaldehyde and sex-related differences by exposing formaldehyde to male and female rats.Formaldehyde (10 mg/kg) was administered intraperitoneally for 7 days for acute exposure and 30 days for chronic exposure. Cognitive assessment was performed using fear conditioning, elevated plus maze, and Morris water maze tests. TUNEL staining was used to identify apoptosis in the brains obtained after decapitation.Exposure to intraperitoneal formaldehyde does not impair learning and memory in acute and chronic periods and has no effect on depression or anxiety. After acute exposure, apoptosis was observed in the hippocampal CA1 and CA3 regions in males. When the cognitive test results were examined, no differences were found between the experimental and control groups. There was also no significant difference between males and females. [ABSTRACT FROM AUTHOR]

Chronic stress may induce learning and memory deficits that are associated with a depression-like state in Drosophila melanogaster. The molecular and neural mechanisms underlying the etiology of chronic stress–induced learning deficit (CSLD) remain elusive. Here, we show that the autophagy-lysosomal pathway, a conserved cellular signaling mechanism, is associated with chronic stress in Drosophila, as indicated by time-series transcriptome profiling. Our findings demonstrate that chronic stress induces the disruption of autophagic flux, and chronic disruption of autophagic flux could lead to a learning deficit. Remarkably, preventing the disruption of autophagic flux by up-regulating the basal autophagy level is sufficient to protect against CSLD. Consistent with the essential role of the dopaminergic system in modulating susceptibility to CSLD, dopamine neuronal activity is also indispensable for chronic stress to induce the disruption of autophagic flux. By screening knockout mutants, we found that neuropeptide F, the Drosophila homolog of neuropeptide Y, is necessary for normal autophagic flux and promotes resilience to CSLD. Moreover, neuropeptide F signaling during chronic stress treatment promotes resilience to CSLD by preventing the disruption of autophagic flux. Importantly, neuropeptide F receptor activity in dopamine neurons also promotes resilience to CSLD. Together, our data elucidate a mechanism by which stress-induced excessive dopaminergic activity precipitates the disruption of autophagic flux, and chronic disruption of autophagic flux leads to CSLD, while inhibitory neuropeptide F signaling to dopamine neurons promotes resilience to CSLD by preventing the disruption of autophagic flux. [ABSTRACT FROM AUTHOR]

As a kind of environmental noise, infrasonic noise has negative effects on various human organs. To date, research has shown that infrasound impairs cognitive function, especially the ability for learning and memory. Previously, we demonstrated that impaired learning and memory induced by infrasound was closely related with glia activation; however, the underlying mechanisms remain unclear. Connexin 43 hemichannels (Cx43 HCs), which are mainly expressed in hippocampal astrocytes, are activated under pathological conditions, lending support to the hypothesis that Cx43 HCs might function in the impaired learning and memory induced by infrasound. This study revealed that that blocking hippocampal Cx43 HCs or downregulating hippocampal Cx43 expression significantly alleviated impaired learning and memory induced by infrasound. We also observed that infrasound exposure led to the abundant release of glutamate and ATP through Cx43 HCs. In addition, the abundant release of glutamate and ATP depended on proinflammatory cytokines. Our finds suggested that the enhanced release of ATP and glutamate by astroglial Cx43 HCs may be involved in the learning and memory deficits caused by infrasound exposure. [ABSTRACT FROM AUTHOR]

Interleukin 18 (IL18) was originally identified as an inflammation-induced cytokine that is secreted by immune cells. An increasing number of studies have focused on its non-immunological functions, with demonstrated functions for IL18 in energy homeostasis and neural stability. IL18 is reportedly required for lipid metabolism in the liver and brown adipose tissue. Furthermore, IL18 (Il18) deficiency in mice leads to mitochondrial dysfunction in hippocampal cells, resulting in depressive-like symptoms and cognitive impairment. Microarray analyses of Il18−/− mice have revealed a set of genes with differential expression in liver, brown adipose tissue, and brain; however, the impact of IL18 deficiency in these tissues remains uncertain. In this review article, we discuss these genes, with a focus on their relationships with the phenotypic disease traits of Il18−/− mice. [ABSTRACT FROM AUTHOR]

Mammalian target of rapamycin (mTOR) pathway has emerged as a key molecular mechanism underlying memory processes. Although mTOR inhibition is known to block memory processes, it remains elusive whether and how an enhancement of mTOR signaling may improve memory processes. Here we found in male mice that the administration of VO-OHpic, an inhibitor of the phosphatase and tensin homolog (PTEN) that negatively modulates AKT-mTOR pathway, enhanced auditory fear memory for days and weeks, while it left short-term memory unchanged. Memory enhancement was associated with a long-lasting increase in immaturetype dendritic spines of pyramidal neurons into the auditory cortex. The persistence of spine remodeling over time arose by the interplay between PTEN inhibition and memory processes, as VO-OHpic induced only a transient immature spine growth in the somatosensory cortex, a region not involved in long-term auditory memory. Both the potentiation of fear memories and increase in immature spines were hampered by rapamycin, a selective inhibitor of mTORC1. These data revealed that memory can be potentiated over time by the administration of a selective PTEN inhibitor. In addition to disclosing new information on the cellular mechanisms underlying long-term memory maintenance, our study provides new insights on the molecular processes that aid enhancing memories over time. [ABSTRACT FROM AUTHOR]

Introduction: Neuroinflammation is a common feature of many psychiatric disorders as well as a common underlying mechanism of neurodegenerative diseases. Sex has been shown to strongly influence the development as well as the clinical expression of these pathologies. However, there is still a neglect regarding the consideration of sex effects in rodent experiments, and a substantial underrepresentation of females in studies. This work set out to expand our knowledge of neuroinflammatory mechanisms in female mice, at both a behavioral and molecular level. Methods: This study used GFAP-IL6 mice, a model of chronic neuroinflammation, in which interleukin-6 (IL6) is overexpressed in the central nervous system under the control of the glial fibrillary acidic protein (GFAP) promoter. We evaluated aged (11-15-month-old) wild type-like (WT) and GFAP-IL6 female mice in behavioral tests assessing anxiety (elevated plus-maze, EPM, Light/dark box), and spatial learning and memory (Y-maze, YM and Barnes Maze, BM) and associative learning (fear conditioning, FC). We also examined gene expression of markers linked to neuroinflammation, neurodegeneration and neurotransmission via RT-qPCR in brain regions involved in motor control, anxiety, learning and memory. Results: Female GFAP-IL6 mice exhibited reduced anxiety-like behavior in the EPM, and hypolocomotion in the light-dark test and EPM. Short-term memory impairment was evident in the YM but associative learning in FC was intact in GFAP-IL6 mice, suggesting domain-specific cognitive deficits in female GFAP- IL6 mice. In the BM, all mice showed intact learning and memory, but GFAP- IL6 mice exhibited higher latencies to enter the escape hole than WT mice. We analyzed the search strategy and found differences in the way GFAP-IL6 mice searched for the escape hole compared to WTs. RT-qPCR showed increased mRNA levels for molecules involved in pro-inflammatory pathways in the cerebellum, motor cortex, hippocampus, and amygdala in GFAP-IL6 mice. Of the regions examined, the cerebellum and the hippocampus showed upregulation of neuroinflammatory makers as well as dysregulation of glutamatergic and GABAergic neurotransmission gene expression in GFAP-IL6 mice compared to WTs. Conclusion: In conclusion, we showed that chronic neuroinflammation via IL6 overexpression in aged female mice led to a less anxious-like phenotype, hypolocomotion and impaired intermediate-term spatial learning and memory in the YM. [ABSTRACT FROM AUTHOR]

Maternal exposure to inflammation may represent a major risk factor for neuropsychiatric disorders with associated cognitive dysfunction in offspring in later life. Growing evidence has suggested that resveratrol exerts a beneficial effect on cognitive impairment via its anti-inflammatory and antioxidant properties and by ameliorating synaptic dysfunction. However, how resveratrol affects maternal immune activation-induced cognitive dysfunction and the underlying mechanisms are unclear. In the present study, pregnant dams were given an intraperitoneal injection of lipopolysaccharide (LPS; 50 μg/kg) on gestational day 15. Subsequently, the offspring mice were treated or not with resveratrol (40 mg/kg) from postnatal day (PND) 60 to PND 88. Male offspring were selected for the evaluation of cognitive function using the Morris water maze test. The hippocampal levels of pro-inflammatory cytokines were examined by ELISA. The mRNA and protein levels of sirtuin-1 (SIRT1), brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD-95), and synaptophysin (SYP) were determined by RT-qPCR and western blot, respectively. The results showed that male offspring mice exposed to LPS in utero exhibited learning and memory impairment. Additionally, the levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) were increased while those of SIRT1, BDNF, PSD-95, and SYP were decreased in male offspring of LPS-treated mothers. Treatment with resveratrol reversed cognitive impairment and attenuated the increase in the levels of pro-inflammatory cytokines induced by maternal immune activation in the offspring mice. Furthermore, resveratrol reversed the deleterious effects of maternal immune activation on SIRT1, BDNF, PSD-95, and SYP levels in the hippocampus. Collectively, our results suggested that resveratrol can effectively improve learning and memory impairment induced by maternal immune activation via the modulation of inflammation and synaptic dysfunction. [ABSTRACT FROM AUTHOR]

Activation of neuronal protein synthesis upon learning is critical for the formation of long-term memory. Here, we report that learning in the contextual fear conditioning paradigm engenders a decrease in eIF2a (eukaryotic translation initiation factor 2) phosphorylation in astrocytes in the hippocampal CA1 region, which promotes protein synthesis. Genetic reduction of eIF2a phosphorylation in hippocampal astrocytes enhanced contextual and spatial memory and lowered the threshold for the induction of long-lasting plasticity by modulating synaptic transmission. Thus, learning-induced dephosphorylation of eIF2a in astrocytes bolsters hippocampal synaptic plasticity and consolidation of long-term memories. [ABSTRACT FROM AUTHOR]

Objectives In the present study, we investigated the pattern of cognitive difficulties in hospitalized patients due to COVID-19 and its relation with the clinical features of the disease. Method Forty hospitalized patients with COVID-19 [mean age: 46.98 years (SD = 9.30); mean years of education: 13.65 (SD = 2.07) and 40 sex-, age- and education-matched healthy controls completed a set of neuropsychological measures administered by telephone. Participants' premorbid intellectual skills and patients' anxiety and depressive symptoms were also evaluated. The association of COVID-19-related biomarkers [oxygen saturation (SpO2), C-reactive protein (CRP), D-dimer and ferritin levels] with neuropsychological performances was examined with a series of hierarchical multiple linear regression analyses, after controlling for demographic and clinical characteristics, psychological distress and premorbid intellectual skills. Results Patients performed worse than healthy participants on measures of verbal memory, attention and working memory. SpO2 levels were associated with patients' performance on verbal and working memory, whereas CRP levels were associated with performance on verbal memory, abstract reasoning and verbal fluency, after controlling for demographic and clinical characteristics. Ferritin levels predicted performance on the verbal fluency test, whereas D-dimer levels did not predict any of the neuropsychological measures. Conclusions Cognitive difficulties in verbal memory, attention and working memory were noted in patients with COVID-19. Markers of hyperinflammation predicted patients' performance above and beyond demographic characteristics, duration of symptoms, length of hospitalization and psychological distress. [ABSTRACT FROM AUTHOR]

The present study focused on examining the impact of vitamin C (Vit C) administration on the function of memory and the status of oxidative stress (OS) in the hippocampal area of the brain using an unpredictable chronic mild stress (UCMS) model in rats. To this end, 50 male Wistar rats (11-12 weeks of age at the start of the study) were assigned to five groups of six animals, including control, UCMS, UCMS + Vit C 50 mg/Kg, UCMS + Vit C 100 mg/Kg, and UCMS + Vit C 400 mg/Kg. The animals received daily intraperitoneal injections of Vit C at a certain time (9 am) before the initiation of a stressor. UCMS, including a progression of typical stressors, was applied for four weeks. Subsequently, using the passive avoidance (PA) and Morris water maze (MWM) tests were performed to investigate learning and memory. Eventually, hippocampal tissues were evaluated in terms of OS criteria. The results revealed that the latency to enter the dark chamber (P < 0. 01 and P < 0.05, PA test) and the time spent in the target quadrant (P < 0.0001, MWM test) were shorter in the UCMS group, while latency to discover the platform was longer (P < 0.05 and P < 0.001, MWM test) compared to the control group. However, UCMS decreased the content of thiol (P < 0.0001), as well as the activities of catalase (P < 0.0001) and superoxide dismutase (P < 0.0001), whereas the concentration of malondialdehyde (P < 0.01) increased in the hippocampal region of the brain in comparison to the control group. Interestingly, Vit C treatment reversed the mentioned effects of UCMS. Therefore, the latency to enter the dark chamber (P < 0. 05 and P < 0.01,1 and 24 h after the shock, PA test, UCMS + Vit C 400) and the time spent in the target quadrant (P < 0. 01 and P < 0.05, MWM test, UCMS + Vit C 400 and UCMS + Vit C 100, respectively) were longer in the UCMS + Vit C groups. Moreover, Vit C increased the content of thiol (P < 0.05, UCMS + Vit C 400), as well as the activity of catalase (P < 0.001, UCMS + Vit C 400) and superoxide dismutase (P < 0.0001, UCMS + Vit C 400, UCMS + Vit C 100), whereas the concentration of malondialdehyde (P < 0. 05 and P < 0.01, UCMS + Vit C 100, UCMS + Vit C 400) decreased in the hippocampal region of the brain in comparison to the UCMS group. Overall, these results suggest that Vit C could reverse UCMS-induced learning and memory impairment possibly through the modulation of brain OS. Key points Memory and learning impairments were induced by unpredictable chronic mild stress (UCMS) Vitamin C could prevent cognitive impairments caused by UCMS in rats by attenuation of oxidative stress in the brain. [ABSTRACT FROM AUTHOR]

Main Problem: N‐acetylaspartylglutamate (NAAG) has neuroprotective effects in traumatic brain injury (TBI) by activating metabotropic glutamate receptor 3 (mGluR3) and reducing glutamate release. Glutamate carboxypeptidase II (GCPII) is the primary enzyme responsible for the hydrolysis of NAAG. It remains unclear whether glutamate carboxypeptidase III (GCPIII), a homolog of GCPII, can partially compensate for GCPII's function. Methods: GCPII−/−, GCPIII−/−, and GCPII/III−/− mice were generated using CRISPR/Cas9 technology. Mice brain injury model was established through moderate controlled cortical impact (CCI). The relationship between GCPII and GCPIII was explored by analyzing injury response signals in the hippocampus and cortex of mice with different genotypes at the acute (1 day) and subacute (7 day) phase after TBI. Results: In this study, we found that deletion of GCPII reduced glutamate production, excitotoxicity, and neuronal damage and improved cognitive function, but GCPIII deletion had no significant neuroprotective effect. Additionally, there was no significant difference in the neuroprotective effect between the combination of GCPII and GCPIII deletion and GCPII deletion alone. Conclusion: These results suggest that GCPII inhibition may be a therapeutic option for TBI, and that GCPIII may not act as a complementary enzyme to GCPII in this context. [ABSTRACT FROM AUTHOR]

Purpose: To examine associations between parameters of psychological well-being, injury characteristics, cardiovascular autonomic nervous system (ANS) control, and cognitive performance in persons with spinal cord injury (SCI) compared with age-matched uninjured controls. This is an observational, cross-sectional study including a total of 94 participants (52 with SCI and 42 uninjured controls: UIC). Cardiovascular ANS responses were continuously monitored at rest and during administration of the Paced Auditory Serial Addition Test (PASAT). Self-report scores on the SCI-Quality of Life questionnaires are reported for depression, anxiety, fatigue, resilience, and positive affect. Participants with SCI performed significantly more poorly on the PASAT compared with the uninjured controls. Although not statistically significant, participants with SCI tended to report more psychological distress and less well-being than the uninjured controls. In addition, when compared with uninjured controls, the cardiovascular ANS responses to testing were significantly altered in participants with SCI; however, these responses to testing did not predict PASAT performance. Self-reported levels of anxiety were significantly related to PASAT score in the SCI group, but there was no significant relationship between PASAT and the other indices of SCI-Quality of Life. Future investigations should more closely examine the relationship among cardiovascular ANS impairments, psychological disorders, and cognitive dysfunction to better elucidate the underpinnings of these deficits and to guide interventions aimed at improving physiological, psychological, and cognitive health after SCI. Tetraplegia, paraplegia, blood pressure variability, cognitive, mood. [ABSTRACT FROM AUTHOR]

Investigation of spatial memory entails studying the process for encoding and retrieving spatial information in working memory that is required for animal and human survival. Synaptic plasticity in the hippocampus is necessary for working memory. Physical activity stimulates the N-methyl-D-aspartate receptor (NMDAR) and subsequently increases NR2A or NR2B subunits of NMDAR-enabling synaptic plasticity in the hippocampus. Reduction of NMDAR and the postsynaptic density (PSD)-95 protein can be found in learning and memory impairment. An increasing amount of evidence has shown that peripheral physical activity has an enhancing effect on learning and memory and elevates the expression of brain-derived neurotrophic factor (BDNF). However, the mechanisms of physical activity that improve working memory have not been fully understood. In the current study, we study the potential effects of peripheral physical activity on spatial memory and synaptic plasticity-related proteins. Physical activity was performed by having the rats do voluntary wheel running throughout P25--P40. The Morris water maze task was performed on P40 for 6 days to study spatial memory. The hippocampal protein expression was ascertained by Western blot analysis. We found that physical activity enhanced spatial memory and BDNF, PSD-95, NR2A, and NR2B levels in the hippocampus. Physical activity can be effective in improving the central synaptic plasticity-related proteins that are essential for learning and memory. Peripheral physical activity is a promising candidate for further investigation as a potential treatment for learning and memory impairment. [ABSTRACT FROM AUTHOR]