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• Type 1 diabetes reduces exploration without reducing novelty-seeking motivation. • Deletion of TNFR1 attenuates the reduction in gait speed induced by type 1 diabetes. • Type 1 diabetes induces anxiety-like behavior in the first week post-streptozotocin. • Deletion of TNFR1 induces working memory impairment in normoglycemic mice. Type 1 diabetes mellitus (T1D) is associated with cognitive impairments in humans. A well-established animal model of T1D is induced through the administration of streptozotocin (STZ), a glucose analog that induces pancreatic β-cell death, resulting in hyperglycemia and cognitive impairment linked to neuroinflammation and oxidative stress. Tumor necrosis factor (TNF)-α, a key inflammatory mediator, is elevated in the central nervous system (CNS) of diabetic animals. In this study, we utilized TNFR1 knockout mice to investigate the role of TNFR1 signaling in short-term T1D-related cognitive impairment. Our findings showed that diabetic animals did not develop cognitive damage within the first 2 weeks of T1D but exhibited reduced exploration in all behavioral tests. Our findings suggest that this reduction in exploration was attributable to motor impairment, as there was no reduction in motivated novelty-seeking behavior. Additionally, deletion of TNFR1 signaling attenuated gait speed impairment in diabetic mice, but did not affect other motor-related or exploratory behaviors. [ABSTRACT FROM AUTHOR]

The aggregation of Amyloid- β (A β) peptides is associated with neurodegeneration in Alzheimer's disease (AD). We previously identified novel naphtalene derivatives, including the lead compound Amylovis-201, able to form thermodynamically stable complexes with A β species, peptides and fibrils. As the drug showed a chemical scaffold coherent for an effective interaction with the σ 1 receptor chaperone and as σ 1 agonists are currently developed as potent neuroprotectants in AD, we investigated the pharmacological action of Amylovis-201 on the σ 1 receptor. We report that Amylovis-201 is a potent σ 1 agonist by several in silico , in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action at σ 1 receptors. Furthermore, we show for the first time that classical σ 1 receptor agonist (PRE-084), and antagonist (NE-100) are able to interact and disaggregate A β 25–35 fibrils. Interestingly, Amylovis-201 was the only compound inhibiting A β 25–35 aggregates formation. Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent and σ 1 receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD. Amylovis-201, known to interfere with Amyloid- β aggregation, also acts as a sigma-1 agonist in vitro and in vivo. The drug is therefore a dual-acting compound with synergic extracellular and intracellular modes of action. [Display omitted] [ABSTRACT FROM AUTHOR]

Sleep is considered closely related to cognitive function, and cognitive impairment is the main clinical manifestation of Alzheimer's disease (AD). Sleep disturbance in AD patients is more severe than that in healthy elderly individuals. Additionally, sleep deprivation reportedly increases the activity of the hypothalamic orexin system and the risk of AD. To investigate whether intervention with the orexin system can improve sleep disturbance in AD and its impact on AD pathology. In this study, six-month-old amyloid precursor protein/presenilin 1 mice were subjected to six weeks of chronic sleep deprivation and injected intraperitoneally with almorexant, a dual orexin receptor antagonist (DORA), to investigate the effects and mechanisms of sleep deprivation and almorexant intervention on learning and memory in mice with AD. We found that sleep deprivation aggravated learning and memory impairment and increased brain β-amyloid (Aβ) deposition in mice with AD. The application of almorexant can increase the total sleep time of sleep-deprived mice and reduce cognitive impairment and Aβ deposition, which is related to the improvement in Aquaporin-4 polarity. Thus, DORA may be an effective strategy for delaying the progression of AD patients by improving the sleep disturbances. • Almorexant intervention can alleviate chronic sleep deprivation-induced AD learning and memory impairment and Aβ deposition. • The mechanism may be related to mitigating the damage to AQP4 polarity caused by sleep deprivation. • Orexin dual receptor antagonists can be an effective strategy for improving sleep in AD, and slowing pathological progression. [ABSTRACT FROM AUTHOR]

Neuronal activity is the basis of information encoding and processing in the brain. During neuronal activation, intracellular ATP (adenosine triphosphate) is generated to meet the high-energy demands. Simultaneously, ATP is secreted, increasing the extracellular ATP concentration and acting as a homeostatic messenger that mediates cell–cell communication to prevent aberrant hyperexcitability of the nervous system. In addition to the confined release and fast synaptic signaling of classic neurotransmitters within synaptic clefts, ATP can be released by all brain cells, diffuses widely, and targets different types of purinergic receptors on neurons and glial cells, making it possible to orchestrate brain neuronal activity and participate in various physiological processes, such as sleep and wakefulness, learning and memory, and feeding. Dysregulation of extracellular ATP leads to a destabilizing effect on the neural network, as found in the etiopathology of many psychiatric diseases, including depression, anxiety, schizophrenia, and autism spectrum disorder. In this review, we summarize advances in the understanding of the mechanisms by which extracellular ATP serves as an intercellular signaling molecule to regulate neural activity, with a focus on how it maintains the homeostasis of neural networks. In particular, we also focus on neural activity issues that result from dysregulation of extracellular ATP and propose that aberrant levels of extracellular ATP may play a role in the etiopathology of some psychiatric diseases, highlighting the potential therapeutic targets of ATP signaling in the treatment of these psychiatric diseases. Finally, we suggest potential avenues to further elucidate the role of extracellular ATP in intercellular communication and psychiatric diseases. [ABSTRACT FROM AUTHOR]

• PI3K/Akt signaling pathway is related to anti-apoptosis and pro-axonal regeneration. • The PI3K/Akt pathway is a potential key pathway for the treatment of PSCI in TCM. • Moxibustion can activate the PI3K/Akt signaling pathway to function. • Moxibustion can promote axonal regeneration and improve learning and memory of PSCI. This study aimed to investigate whether moxibustion could affect PI3K/Akt pathway to regulate Transforming acidic coiled-coil containing protein 3 (TACC3) and promote axonal regeneration to improve learning and memory function in middle cerebral artery occlusion (MCAO) rats. Sixty SD rats were randomly divided into 4 groups: sham-operated control group (SC), model control group (MC), model + moxibustion group (MM), and model + inhibitor + moxibustion group (MIM). The rats in MC, MM, and MIM groups were made into MCAO models, and PI3K inhibitor LY294002 was injected into the rats in MIM group before modeling; while the rats in SC group were only treated with artery separation without monofilament inserting. After that, the rats in MM and MIM groups were intervented with moxibustion. We used the Zea-Longa scale, micro-Magnetic Resonance Imaging (micro-MRI), Morris water maze (MWM), TUNEL, western blot (WB), immunofluorescence and immunohistochemistry to evaluate the neurological deficits, cerebral infarct volume, learning and memory, apoptotic cell percentage in the hippocampal, the expression level of axonal regeneration and PI3K/AKt related proteins, the expression level of TACC3. The detection of 2 h after surgery showed the result before moxibustion and 7 days after the intervention showed the results after moxibustion. After 7 d of intervention, the scores of Zea-Longa and the cerebral infarct volume, the escape latency, the percentage of apoptosis cells of MM group were lower than that of MC and MIM groups; the frequency of rats crossed the previous platform location, PI3K, p-Akt/t-Akt and TACC3, the level of GAP-43 in MM group was more than MC and MIM groups (P < 0.05). While no statistical difference existed between MIM group and MC group (P > 0.05). Moxibustion can promote axonal regeneration and improve learning and memory of Post-stroke cognitive impairment via activating the PI3K/AKT signaling pathway and TACC3. [ABSTRACT FROM AUTHOR]

Fish experiencing harvest mortality often evolve a fast life-history that prioritizes investment in current versus future reproduction, thereby potentially limiting energetic investment in the brain. Fisheries may also select for shy fish that are less willing to learn, or directly select fish with poor cognitive ability. The resulting evolutionary changes can alter the cognitive performance of individuals and affect fish populations and fisheries quality. [ABSTRACT FROM AUTHOR]

The methylazoxymethanol acetate (MAM) rodent model is used to study aspects of schizophrenia. However, numerous studies that have employed this model have used only males, resulting in a dearth of knowledge on sex differences in brain function and behaviour. The purpose of this study was to determine whether differences exist between male and female MAM rats in neuronal oscillatory function within and between the prefrontal cortex (PFC), ventral hippocampus (vHIP) and thalamus, behaviour, and in proteins linked to schizophrenia neuropathology. We showed that female MAM animals exhibited region-specific alterations in theta power, elevated low and high gamma power in all regions, and elevated PFC-thalamus high gamma coherence. Male MAM rats had elevated beta and low gamma power in PFC, and elevated vHIP-thalamus coherence. MAM females displayed impaired reversal learning whereas MAM males showed impairments in spatial memory. Glycogen synthase kinase-3 (GSK-3) was altered in the thalamus, with female MAM rats displaying elevated GSK-3α phosphorylation. Male MAM rats showed higher expression and phosphorylation GSK-3α, and higher expression of GSK-β. Sex-specific changes in phosphorylated Tau levels were observed in a region-specific manner. These findings demonstrate there are notable sex differences in behaviour, oscillatory network function, and GSK-3 signaling in MAM rats, thus highlighting the importance of inclusion of both sexes when using this model to study schizophrenia. [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]

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]

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]

The breast cancer 1 ( Brca1 ) susceptibility gene regulates the repair of reactive oxygen species (ROS)-mediated DNA damage, which is implicated in neurodevelopmental disorders. Alcohol (ethanol, EtOH) exposure during pregnancy causes fetal alcohol spectrum disorders (FASD), including abnormal brain function, associated with enhanced ROS-initiated DNA damage. Herein, oxidative DNA damage in fetal brains and neurodevelopmental disorders were enhanced in saline-exposed +/- vs. +/+ Brca1 littermates. A single EtOH exposure during gestation further enhanced oxidative DNA damage, altered the expression of developmental/DNA damage response genes in fetal brains, and resulted in neurodevelopmental disorders, all of which were BRCA1-dependent. Pretreatment with the ROS inhibitor phenylbutylnitrone (PBN) blocked DNA damage and some neurodevelopmental disorders in both saline- and EtOH-exposed progeny, corroborating a ROS-dependent mechanism. Fetal BRCA1 protects against altered gene expression and neurodevelopmental disorders caused by both physiological and EtOH-enhanced levels of ROS formation. BRCA1 deficiencies may enhance the risk for FASD. [Display omitted] • Phenylbutylnitrone (PBN) blocks reactive oxygen species (ROS) formation. • Low fetal BRCA1 and ethanol (EtOH) enhance ROS-mediated fetal brain DNA damage. • Low BRCA1 and EtOH alter fetal brain gene expression in Brca1 knockout mice. • Low BRCA1 and in utero EtOH cause neurodevelopmental disorders in progeny. • BRCA1-and EtOH-dependent DNA damage and disorders blocked by PBN. [ABSTRACT FROM AUTHOR]

While calpains have long been implicated in neurodegeneration, no calpain inhibitor has been developed for the treatment of neurodegeneration. This is partly due to the lack of understanding of the specific functions of most of the 15 members of the calpain family. Work from our laboratory over the last 5–10 years has revealed that calpain-1 and calpain-2, two of the major calpain isoforms in the brain, play opposite roles in both synaptic plasticity/learning and memory and neuroprotection/neurodegeneration. Thus, calpain-1 activation is required for triggering certain forms of synaptic plasticity and for learning some types of information and is neuroprotective. In contrast, calpain-2 activation limits the extent of synaptic plasticity and of learning and is neurodegenerative. These results have been validated with the use of calpain-1 knock-out mice and mice with a selective calpain-2 deletion in excitatory neurons of the forebrain. Through a medicinal chemistry campaign, we have identified a number of selective calpain-2 inhibitors and shown that these inhibitors do facilitate learning of certain tasks and are neuroprotective in a number of animal models of acute neurodegeneration. One of these inhibitors, NA-184, is currently being developed for the treatment of traumatic brain injury, and clinical trials are being planned. [ABSTRACT FROM AUTHOR]

• The hyperactive ITPR1-D2594K mutation causes motor deficits and muscle weakness. • ITPR1 hyperactivity enhances the response to thermal and mechanical stimulation. • R-carvedilol attenuates the enhanced pain response in the ITPR1-D2594K mice. • The ITPR1-D2594K mutation has little effect on hippocampal learning and memory. Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) is an intracellular Ca2+ release channel important for a number of fundamental cellular functions. Consistent with its critical physiological significance, mutations in ITPR1 are associated with disease. Surprisingly, nearly all the disease-associated ITPR1 mutations characterized to date are loss of function. Despite the paucity of ITPR1 gain-of-function (GOF) mutations, enhanced ITPR1 function as a result of dysregulation by ITPR1 interacting proteins is thought to be associated with ataxia, learning and memory impairments, Alzheimer's disease (AD) progression, and chronic pain. However, direct evidence for the role of ITPR1 GOF in disease is lacking. To determine whether GOF in ITPR1 itself has pathological ramifications, we employed a newly developed mouse model expressing an ITPR1 mutation in the gating domain of the channel, D2594K, that markedly increased the channel's sensitivity to activation by IP 3. Behavioral studies showed that the ITPR1-D2594K+/- mutant mice displayed motor deficits and reduced muscle strength. However, the ITPR1-D2594K+/- mutation did not significantly alter hippocampal learning and memory and did not change learning and memory impairments when crossed with the 5xFAD AD model mice. On the other hand, ITPR1-D2594K+/- mice exhibited increased sensitivity to thermal and mechanical stimulation compared to WT. Interestingly, R-carvedilol treatment attenuated the enhanced thermal and mechanical nociception in ITPR1-D2594K+/- mice. Thus, the ITPR1-D2594K+/- mutation in the channel's gating domain has a marked impact on motor movements and pain perception, but little effect on hippocampal learning and memory. [ABSTRACT FROM AUTHOR]

Objective : Electroacupuncture (EA) in the treating principle of "soothing the liver and regulating the kidney" was applied to intervion the rats with post-traumatic stress disorder (PTSD), and its effect on anxiety-like behavior, spatial learning and memory ability, and expressions of synaptophysin (SYN) and postsynaptic dense 95 (PSD95) in hippocampus of rats were observed to explore the underlying mechanism. Methods : Twenty-four male SD rats were randomly divided into control group, model group, and EA group, with 8 rats in each group. There was no intervention in the control group. The rest 16 rats were prepared for modeling. The single-prolonged stress & shock (SPS&S) method was used to establish the PTSD models. There was no intervention in the model group after modeling. In the EA group, "Bǎihuì (百会GV20)"" Shéntíng (神庭GV24)""Gānshū (肝俞BL18)""Shènshū (肾俞BL23)" were manipulated with EA stimulation, intensity 1 mA, frequency 2/100 Hz, disperse-dense wave, and treatment was performed once a day, 20 min each time, for a total of 21 days. Open field test, elevated plus maze and Morris water maze tests were used to observe the behavioral differences of rats in each group. Immunohistochemical method was used to observe the differences of positive expressions of proteins SYN and PSD95 in hippocampus. Results : In the open field test, compared with the control group, the total traveling distance, the percentage of the time spent in the central cell and the numbers of the central cells crossing in the model group were all decreased (all P < 0.05). Compared with the model group, these indicators in the EA group were significantly all increased (all P < 0.05). In the elevated plus maze test, compared with the control group, the percentages of open arm staying time and entering times in the model group were both decreased (both P < 0.05). Compared with the model group, these indicators in the EA group were both significantly increased (both P < 0.05). The results of Morris water maze test showed that compared with the control group, the escape latency time and travelled distance of rats in the model group were all increased from day1 to day 4 (all P < 0.05), and the percentage of staying time in the target quadrant was decreased (P < 0.05). Compared with the model group, the escape latency time and travelled distance of EA group were both significantly shortened (both P < 0.05), and the percentage of staying time in the target quadrant was significantly increased (P < 0.05). The immunohistochemical results showed that, compared with the control group, the positive expressions of SYN and PSD95 in the hippocampus of the model group were significantly down-regulated (both P < 0.05). Compared with the model group, the positive expressions of SYN and PSD95 in the hippocampus of the EA group were significantly up-regulated (both P < 0.05). Conclusions : EA in the treating principle of "soothing the liver and regulating the kidney" can effectively relieve anxiety-like behavior and improve spatial learning and memory ability of rats with PTSD, and the mechanism is related to the up-regulation of the expressions of SYN and PSD95 in the hippocampus. [ABSTRACT FROM AUTHOR]

Excessive exercise leads to body fatigue and destroys the balance of the oxidation/oxidation resistance system in the body, thus damaging the central nervous system and reducing learning and memory ability. Nrf2 is an important transcription factor that regulates the cell oxidative stress response. Therefore, the research and development of natural antioxidants with the effect of regulating Nrf2-related signalling pathways to improve central fatigue caused by body fatigue has application value. Methods and results: Cordyceps militaris polysaccharides were extracted, isolated and purified via DEAE-cellulose 52 and Sepharose CL-6B columns to obtain two saccharides, Cordyceps militaris acidic polysaccharides (CMPB) and CMPB-b. The results of behavioural tests showed that compared with the model group, the learning and memory abilities of the CMPB-H group (800 mg/kg) mice were remarkably improved in the dark avoidance and Morris water maze tasks (p < 0.01), and the levels of fatigue metabolites and oxidative stress in the body were obviously decreased (p < 0.01). The expression level of BDNF, PI3K, Nrf2 and HO-1 proteins in the hippocampus were significantly increased (p < 0.01). In vitro experiments, compared with the PC12 oxidative stress model group, CMPB-b high-dose group (100 μg/mL) had remarkably improved oxidative stress. CMPB-b also obviously promoted the phosphorylation of PI3K and AKT proteins (p < 0.01) and the nuclear translocation of Nrf2 (p < 0.01), and significantly increased the expression of HO-1 (p < 0.01). Conclusion: CMPB can alleviate the fatigue state of high-intensity swimming mice and improve the learning and memory impairment of exercise-fatigue mice by regulating the Nrf2-related signalling pathway. Its antioxidant active component CMPB-b exerts in vitro antioxidative neurological damage by the same mechanism. Our systematic studies provide strong supporting evidence for the future use of Cordyceps militaris acidic polysaccharides in health products to improve resistance to fatigue. [ABSTRACT FROM AUTHOR]

Cognitive functions are increasingly understood to involve coordinated activity patterns between multiple brain regions, and their disruption by neuropsychiatric disorders is similarly complex. Closed-loop neurostimulation can directly modulate neural signals with temporal and spatial precision. How to leverage such an approach to effectively identify and target distributed neural networks implicated in mediating cognition remains unclear. We review current conceptual and technical advances in this area, proposing that devices that enable large-scale acquisition, integrated processing, and multiregion, arbitrary waveform stimulation will be critical for mechanistically driven manipulation of cognitive processes in physiological and pathological brain networks. Cognitive processes require coordinated communication between multiple brain regions. Physiological activity patterns governing such interactions may represent an effective focus for manipulating these processes. The diversity of network disruptions that occur in patients with neuropsychiatric disorders remains incompletely characterized and may necessitate personalized therapeutic approaches. Neural interface devices that enable large-scale acquisition and multiregion, arbitrary waveform stimulation will be critical to test hypotheses about mechanisms of cognition. Advances in materials science and engineering increase the information that can be derived from neural interface devices without increasing potential for implantation-related morbidity. Concurrent advances in architecture for signal processing, data communication, and power management are necessary to permit real-world implementation of closed-loop devices in both animal models and human subjects. [ABSTRACT FROM AUTHOR]

The aim of this study is to elucidate the underlying mechanism through which glial cell line-derived neurotrophic factor (GDNF) improves cognitive deficits in adults resulting from neonatal surgical interventions. Newborn Sprague–Dawley rats, regardless of gender, were randomly allocated into seven groups on postnatal day 7 as follows (n =15): (1) Control group (not subjected to anesthesia, surgery, or any pharmaceutical interventions); (2) GDNF group (received intracerebroventricular injection of GDNF); (3) Surgery group (underwent right carotid artery exposure under anesthesia with 3 % sevoflurane); (4) Surgery plus GDNF group; (5) Surgery plus GDNF and type II JAK inhibitor NVP-BBT594 (BBT594) group (administered intraperitoneal injection of BBT594); (6) BBT group; and (7) Surgery plus BBT group. Starting from postnatal day 33, all rats underwent Barnes maze and fear conditioning tests, followed by decapitation under sevoflurane anesthesia for subsequent analyses. The left hemibrains underwent Golgi staining, while the right hemibrains were used for hippocampal protein extraction to assess Protein kinase Mζ (PKMζ) and Kalirin expression through western blotting. GDNF demonstrated a mitigating effect on spatial learning and memory impairment, as well as context-related fear memory impairment, reductions in dendritic total lengths, and spinal density within the hippocampus induced by surgical intervention. Notably, all of these ameliorative effects of GDNF were reversed upon administration of the RET inhibitor BBT594. Additionally, GDNF alleviated the downregulation of protein expression of PKMζ and Kalirin in the hippocampus of rats subjected to surgery, subsequently reversed by BBT594. The effective impact of GDNF on learning and memory impairment caused by surgical intervention appears to be mediated through the RET pathway. Moreover, GDNF may exert its influence by upregulating the expression of PKMζ and Kalirin, consequently enhancing the development of dendrites and dendritic spines. • Glial cell line-derived neurotrophic factor ameliorates cognitive deficits resulting from neonatal surgical interventions in rats. • The neuroprotective effects of GDNF are mediated through the RET pathway. • The neuroprotective effects of GDNF are associated with the modulation of downstream effectors PKMζ and Kalirin. [ABSTRACT FROM AUTHOR]

Rosemary (Rosmarinus officinalis L.) is a rich source of dietary bioactive compounds such as rosmarinic acid and carnosol with a large repertoire of pharmacological properties, including anti-inflammatory and neuroprotective activities. In the present study, we investigated rosemary as a potential new therapeutic agent for cognitive function and other symptoms of aging. In this present study, we have aimed to investigate the effects of oral administration of rosemary extract (RME) on learning and memory in the context of other biomarkers-related cognitive function and neurotransmitter levels in senescent accelerated prone 8 (SAMP8) mouse, a model of accelerating aging and Alzheimer's disease. The Morris water maze (MWM) test showed improved spatial learning and memory behavior in RME treated SAMP8 mouse. Moreover, RME decreased Aβ 42 and inflammatory cytokine levels and increased BDNF, Sirt1, and neurotransmitter levels in SAMP8 mouse. Whole-genome microarray analysis revealed that RME significantly increased gene expression related to oligodendrocyte differentiation, myelination, and ATP production in the hippocampus and decreased gene expression related to stress, neuroinflammation, and apoptosis. Also, in the SAMP8 hippocampus, RME significantly increased Olig1 and Olig2 expression. Altogether, our study is the first to report improvement of spatial learning and memory of RME, modulation of genes important for oligodendrogenesis, and Anti-neuroinflammatory effect by suppressing Aβ 42 levels in mouse brain and thus highlights the prospects of RME in the treatment of cognitive dysfunction and aging. • Oral administration of RME improved spatial learning and memory in SAMP8 mice. • Oral administration of RME induced the increase of oligodendrogenesis-related genes in hippocampus of SAMP8 mice. • RME treatment increased BDNF and Sirt1 levels in hippocampus and cortex of SAMP8 mice. • RME treatment regulated the levels of inflammatory cytokines in hippocampus and cortex of SAMP8 mice. [ABSTRACT FROM AUTHOR]

Despite evidence that aerobic exercise benefits the aging brain, in particular the hippocampus and memory, controlled clinical trials have not comprehensively evaluated effects of aerobic exercise training on human memory in older adults. The central goal of this study was to determine chronic effects of moderate-to-vigorous intensity aerobic exercise on the hippocampus and memory in non-demented, inactive adults ages 55–80 years. We determine effects of aerobic exercise training with a 6-month randomized controlled trial (RCT) comparing 150 min/week of home-based, light intensity exercise with progressive moderate-to-vigorous intensity aerobic exercise. For the first time in a large trial, we examined temporal mechanisms by determining if individual differences in the rapid, immediate effects of moderate intensity exercise on hippocampal-cortical connectivity predict chronic training-related changes over months in connectivity and memory. We examined physiological mechanisms by testing the extent to which chronic training-related changes in cardiorespiratory fitness are a critical factor to memory benefits. The Exercise Effects on Brain Connectivity and Learning from Minutes to Months (Brain-EXTEND) trial is conceptually innovative with advanced measures of hippocampal-dependent learning and memory processes combined with novel capture of the physiological changes, genetic components, and molecular changes induced by aerobic exercise that change hippocampal-cortical connectivity. Given that hippocampal connectivity deteriorates with Alzheimer's and aerobic exercise may contribute to reduced risk of Alzheimer's, our results could lead to an understanding of the physiological mechanisms and moderators by which aerobic exercise reduces risk of this devastating and costly disease. [ABSTRACT FROM AUTHOR]

Mutations in SYNGAP1 are a common genetic cause of intellectual disability (ID) and a risk factor for autism. SYNGAP1 encodes a synaptic GTPase-activating protein (GAP) that has both signaling and scaffolding roles. Most pathogenic variants of SYNGAP1 are predicted to result in haploinsufficiency. However, some affected individuals carry missense mutations in its calcium/lipid binding (C2) and GAP domains, suggesting that many clinical features result from loss of functions carried out by these domains. To test this hypothesis, we targeted the exons encoding the C2 and GAP domains of SYNGAP. Rats heterozygous for this deletion exhibit reduced exploration and fear extinction, altered social investigation, and spontaneous seizures—key phenotypes shared with Syngap heterozygous null rats. Together, these findings indicate that the reduction of SYNGAP C2/GAP domain function is a main feature of SYNGAP haploinsufficiency. This rat model provides an important system for the study of ID, autism, and epilepsy. [Display omitted] • Generated rat model with heterozygous deletion of SYNGAP C2/GAP domains (Syngap +/Δ-GAP ) • Homozygous lethality indicates C2/GAP domains are essential for survival • Syngap +/Δ-GAP rats exhibit seizures, reduced exploration, and impaired fear extinction • These key phenotypes are shared between Syngap +/Δ-GAP and Syngap heterozygous null mutant rats Katsanevaki et al. use a combination of molecular, cellular, circuit, and behavioral approaches to demonstrate phenotypic similarities between two distinct Syngap rat models. These findings highlight the importance of C2/GAP protein domains in the pathophysiology associated with SYNGAP1 -related intellectual disability. [ABSTRACT FROM AUTHOR]

This systematic review explored the impact of maternal immune activation (MIA) on learning and memory behavior in offspring, with a particular focus on sexual dimorphism. We analyzed 20 experimental studies involving rodent models (rats and mice) exposed to either lipopolysaccharide (LPS) or POLY I:C during gestation following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our findings reveal that most studies report a detrimental impact of MIA on the learning and memory performance of offspring, highlighting the significant role of prenatal environmental factors in neurodevelopment. Furthermore, this review underscores the complex effects of sex, with males often exhibiting more pronounced cognitive impairment compared to females. Notably, a small subset of studies report enhanced cognitive function following MIA, suggesting complex, context-dependent outcomes of prenatal immune challenges. This review also highlights sex differences caused by the effects of MIA in terms of cytokine responses, alterations in gene expression, and differences in microglial responses as factors that contribute to the cognitive outcomes observed. • Maternal immune activation (MIA) can impair offspring learning and memory. • MIA negatively impacts cognition in rodents. • Males are more susceptible to cognitive deficits. • Some studies show improved cognition after MIA. • Sex differences in immune responses may explain cognitive outcomes. [ABSTRACT FROM AUTHOR]

Cataglyphis desert ants are skilled visual navigators. Here, I present a brief overview of multisensory learning and neuronal plasticity in ants, with a particular focus on the transition from the dark nest interior to performing first foraging trips. This highlights desert ants as experimental models for studying neuronal mechanisms underlying behavioral development into successful navigators. [ABSTRACT FROM AUTHOR]

Impairment of synaptic plasticity is closely correlated with a range of pathological conditions, such as cognitive deficits. However, how synaptic efficacy is regulated remains incompletely understood. Here, we report that the epigenetic factor JADE2 was indispensable for the maintenance of hippocampal synaptic plasticity and cognitive functions in mice. We used the Morris water maze and the fear conditioning test to examine learning-related behaviors. In addition, Western blotting, viral-mediated JADE2 manipulations, RNA sequencing, and electrophysiological recordings were used to address our questions. JADE2 expression is increased upon enhanced neuronal activity in vitro and in vivo. Knockdown or genetic deletion of Jade2 in hippocampal CA1 results in impaired structural and functional synaptic plasticity, leading to memory impairment, whereas overexpression of JADE2 in CA1 neurons facilitates hippocampal-dependent learning and memory. Mechanistically, our data show that JADE2 modulates synaptic functions mainly by transcriptional activation of cytoskeletal regulator Rac1 , and this activity is dependent on its interaction with histone acetyltransferase HBO1. Finally, we demonstrate that restoring RAC1 expression in Jade2 knockout mice could rescue the deficits in synaptic plasticity and learning-related behaviors. Our findings reveal that JADE2 plays a critical role in regulating synaptic plasticity and memory formation, suggesting that activity-dependent epigenetic regulation is an important molecular mechanism in controlling synaptic plasticity. [ABSTRACT FROM AUTHOR]

Lead (Pb) and manganese (Mn) are common neurotoxins. However, individuals are subject to co-exposures in real life, and it is therefore important to study these metals in combination. Weaning Sprague-Dawley rats were given ad libitum access to drinking water solutions containing Pb (100 mg/L), Mn (2.5 mg/mL) or a mixture, and each treatment had its own minocycline (50 mg/(kg•day)) supplement group. The results showed a significant difference in spatial memory and induction levels of hippocampal long-term potentiation (LTP) in all exposure groups when compared with controls. The combined-exposure group exhibited the most pronounced effect when compared with each of the single-metal exposure groups. Microglia displayed activation at day 3 after exposure alone or in combination, while astrocytes showed activation at day 5, accompanied by decreased expression levels of GLAST, GLT-1, and GS. Furthermore, the levels of glutamate in the synaptic cleft increased significantly. When microglial activation was inhibited by minocycline, the activation of astrocytes and the expression of GLAST, GLT-1, and GS were both reversed. In addition, upon minocycline treatment, hippocampal LTP impairment and cognitive injury were significantly alleviated in each of the exposure groups. These results suggest that combined exposure to Pb and Mn can cause greater effects on cognition and synaptic plasticity when compared to single-metal exposure groups. The reason may involve abnormal activation of microglia leading to excessive regulation of astrocytes, resulting in glutamate reuptake dysfunction in astrocytes and leading to perturbed cognition and synaptic plasticity. [Display omitted] [ABSTRACT FROM AUTHOR]

Mounting evidence indicates that histone modifications are involved in aging-associated cognitive decline (AACD) and can be transmitted to offspring over multiple generations under conditions of stress. Here, we investigated the effects of maternal sub-chronic inflammation caused by lipopolysaccharide (LPS) on AACD and histone modifications in the F1 and F2 generations of experimental mice as well as the potential sex specificity of intergenerational effects. In brief, F0-generation CD-1 dams were exposed to LPS (50 µg/kg) or saline (CON) during late pregnancy. Subsequently, F1 males and females (at 2 months-of-age) from the LPS treatment group were mated with non-littermates from the LPS group or wild-type mice to produce F2 generations of parental- (F2-LPS 2), paternal- (F2M-LPS 1) and maternal-origin (F2F-LPS 1) mice. Then, CON-F1 males and females were mated with wild-type mice to generate F2 generations of paternal- (F2M-CON 1) and maternal-origin (F2F-CON 1). Next, we evaluated the cognitive ability and levels of hippocampal H4K12ac and H3K9me3 in the F1 and F2 offspring at 3- and 13 months-of-age. Overall, F1 male and female LPS groups presented with elevated corticosterone (P < 0.001, P = 0.036, P = 0.025, 0.012, respectively) and cytokine responses, poorer cognitive performance (all P < 0.05) and H3K9 hypermethylation and H4K12 hypoacetylation in the dorsal hippocampus (all P < 0.05); these issues were carried over to the F2 generation via the parents, predominantly in the paternal lineage. Moreover, the levels of H3K9me3 and H4K12ac were significant correlated with cognitive performance (all P < 0.05), regardless of whether inflammatory insults had been incurred directly or indirectly. These findings indicated that gestational inflammatory insults in the F0 generation accelerated AACD in the F2 generation, along with H3K9 hypermethylation and H4K12 hypoacetylation in the hippocampus, and that these issues were derived from the F1 parents, especially from the F1 fathers. • Gestational inflammatory insult accelerated AACD in F1 and F2 generations. • The F2 offspring dyscognitive was lineage-dependent, mainly derived from F1 fathers. • The hippocampal H3K9me3 and H4K12ac levels changed with age in F1 and F2. • The levels of H3K9me3 and H4K12ac were related with the cognitive performance. [ABSTRACT FROM AUTHOR]

Cyanidin-3-O-glucoside (C3G) is the main kind of anthocyanins that has been reported to possess neuroprotective potentials. In this study, the protection effects of C3G on Pb-induced neurotoxicity and underlying mechanisms were demonstrated. Integrated biomarker responses (IBR) were employed to comprehensively evaluate the neuroprotection of C3G. Results showed that C3G apparently ameliorated the behavioral impairments of Pb-induced rats, and decreased Pb concentrations in the brains and blood. C3G suppressed Pb-induced oxidative damage by increasing Superoxide dismutase (SOD), Glutathione peroxidase (GSH-Px) activity, and decreasing Malondialdehyde (MDA) content in brains. C3G may exhibit its neuroprotection via upregulating neurotransmitters levels, protecting the N-methyl- D -aspartic acid (NMDA) receptor function, promoting Ca2+ influx and modifying the Ca2+ dependent processes like protein kinases, signaling molecules, transcription factors and immediate early genes (IEGs). IBR revealed that C3G could dose-dependently improve Pb-induced cognitive impairment and nerve injury. Collectively, this report indicated that C3G could improve Pb-induced cognitive functional impairment by improving oxidative stress and mediating the cAMP-PKA-CREB signaling pathway. [Display omitted] • Investigating neuroprotective effect of C3G in Pb-induced rats. • IBR was employed to evaluate the neuroprotective effect of C3G. • C3G ameliorated Pb-induced learning and memory impairments. • C3G suppressed Pb-induced oxidative damage. • C3G regulated Pb-induced neurotoxicity through cAMP-PKA-CREB pathway. [ABSTRACT FROM AUTHOR]

Regulating energy metabolism is critical to maintain homeostasis of cellular and systemic functions. In the brain, specialised centres for energy storage regulation finely communicate with the periphery and integrate signals about internal states. As a result, the behavioural responses can be directly adjusted accordingly to the energetic demands. In the fruit fly Drosophila melanogaster , one of these regulatory centres is the mushroom bodies (MBs), a brain region involved in olfactory memory. The integration of metabolic cues by the MBs has a crucial impact on learned behaviour. In this review, we explore recent advances supporting the interplay between energy metabolism and memory establishment, as well as the instructive role of energy during the switch between memory phases. Memory consolidation is one of the most complex functions in the brain, and it involves energy-demanding processes, such as the synthesis of new proteins. Recent studies in Drosophila have provided functional insights about the link between energy metabolism and long-term memory establishment. At the cellular level, neurons of the mushroom bodies (MBs) (a memory centre) overlap with circuits that regulate energy metabolism. Specific MB neurons are involved in energy storage regulation and food perception. Artificially interfering with the activity of those neurons results in changes in body weight, food-intake behaviour, and metabolic processes. Internal states, such as hunger and satiety, and the integration of metabolic factors by MBs affects learning and memory outcome. In addition to metabolic supply, energy is also implemented as an instructive cue. The level of energy is translated into neural activity, and can act as a gate between different memory phases. [ABSTRACT FROM AUTHOR]

• TLR4 deletion improves behavioral dysfunction in aged mice. • TLR4 deletion enhanced the learning and memory ability of aged mice. • TLR4 deletion improves the integrity of blood–brain barrier in aged mice. • TLR4 deletion inhibits the release of proinflammatory factors in aged mice. • TLR4 deletion had no effect on the visual acuity of aged mice. Toll-like receptor-4 (TLR4), a member of the TLR family, plays a key role in inflammation-related diseases of the nervous system. TLR4 knockout mice are widely used in various neurological disease studies, and there is a clear correlation between inflammation and behavior. Therefore, elucidating the effect of TLR4 on neurobehavioral function is essential, and the related mechanisms need to be explored. Male TLR4 knockout (TLR4−/−) and wild-type (TLR4+/+) mice of different ages (4, 8, and 16 months) were used for behavioral experiments. Synaptic spine, blood–brain barrier (BBB) integrity, memory regulatory proteins, cortical blood flow, and inflammatory factor examinations were also conducted to explore the possible mechanism by which TLR4 works. Here, we found that compared with 16-m-old TLR4+/+ mice, age-matched TLR4−/− mice had better learning and memory abilities, increased expression of neuronal synaptic spines, and increased memory-related regulatory proteins in the hippocampus. TLR4 knockout significantly attenuated the fear response in 16-m-old mice. The TLR4−/− mice also had better blood–brain barrier integrity, increased expression of tight junction-associated proteins, increased cerebral cortical blood flow and reduced proinflammatory cytokine expression in the cortex and cerebrospinal fluid. Our results suggest that TLR4 deletion ameliorates significant neurobehavioral dysfunction during the aging stage, as well as multiple abnormalities in brain function and structure due to alterations in tight junction-associated proteins and inflammatory factors. [ABSTRACT FROM AUTHOR]

The hippocampus is thought to be a vulnerable target of microwave exposure. The aim of the present study was to investigate whether 20-hydroxyecdysone (20E) acted as a fate regulator of adult rat hippocampal neural stem cells (NSCs). Furthermore, we investigated if 20E attenuated high power microwave (HMP) radiation-induced learning and memory deficits. Sixty male Sprague-Dawley rats were randomly divided into three groups: normal controls, radiation treated, and radiation+20E treated. Rats in the radiation and radiation+20E treatment groups were exposed to HPM radiation from a microwave emission system. The learning and memory abilities of the rats were assessed using the Morris water maze test. Primary adult rat hippocampal NSCs were isolated in vitro and cultured to evaluate their proliferation and differentiation. In addition, hematoxylin & eosin staining, western blotting, and immunofluorescence were used to detect changes in the rat brain and the proliferation and differentiation of the adult rat hippocampal NSCs after HPM radiation exposure. The results showed that 20E induced neuronal differentiation of adult hippocampal NSCs from HPM radiation-exposed rats via the Wnt3a/β-catenin signaling pathway in vitro. Furthermore, 20E facilitated neurogenesis in the subgranular zone of the rat brain following HPM radiation exposure. Administration of 20E attenuated learning and memory deficits in HPM radiation-exposed rats and frizzled-related protein (FRZB) reduced the 20E-induced nuclear translocation of β-catenin, while FRZB treatment also reversed 20E-induced neuronal differentiation of NSCs in vitro. These results suggested that 20E was a fate regulator of adult rat hippocampal NSCs, where it played a role in attenuating HPM radiation-induced learning and memory deficits. [ABSTRACT FROM AUTHOR]

Neuroinflammation plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Anisomycin is a pyrrolidine antibiotic isolated from Streptomyces griseolus , which is an efficient anti-inflammatory agent that functions both in vivo and in vitro. However, it is not clear whether anisomycin can exert neuroprotective effect in AD. In the present study, anisomycin was intragastrically administrated to female triple-transgenic AD (3xTg-AD) model mice, then Morris water maze test was used to observe the long-term spatial memory of mice, the in vivo hippocampal field potential recording was performed to evaluate the synaptic plasticity, the Western blot and immunofluorescence were employed to detect pathological changes, and the bioinformatics analysis was used to predict the potential target of anisomycin exerting effects in AD. The results showed that anisomycin ameliorated the long-term spatial memory deficits, improved LTP depression and increased the expression of PSD-95, reduced the Aβ and tau pathologies, and alleviated the activation of microglia and astrocytes in the brains of 3xTg-AD mice. In addition, the results from bioinformatics analysis showed that the potential target of anisomycin focused on inflammatory pathway. These results indicated that anisomycin exerts neuroprotective effects in 3xTg-AD mice by alleviating neuroinflammation, but the potential mechanism of anisomycin exerting neuroprotective effects needs to be further investigated. [Display omitted] • Anisomycin improves cognitive dysfunction and synaptic plasticity in 3xTg-AD mice. • Anisomycin reduces Aβ and tau pathologies in the brains of 3xTg-AD mice. • Anisomycin exerts neuroprotective effects in AD by alleviating neuroinflammation. [ABSTRACT FROM AUTHOR]

It is to investigate the effects of β-asarone on learning and memory, hippocampal morphology, synaptophysin (SYP) and postsynaptic density 95(PSD95) protein expression, N-methyl-D-aspartic acid receptor 2B (NR2B)- Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) - Extracellular signal-regulated kinase (ERK) / Cyclic-AMP response element binding protein (CREB) signal in hippocampus of rats with exhaustive exercise-induced fatigue. Fifty Sprague-Dawley male rats were randomly divided into five groups: normal group, exercise group, exercise and β-asarone (2.5, 10, 40 mg/kg)–treated groups. The learning and memory in rats were tested by Morris water maze experiment. We measured the hippocampal morphology by Nissl staining. The levels of SYP, PSD95, NR2B, CaMKII, ERK1/2, CREB, p-NR2B, p-CaMKII, p-ERK1/2 and p-CREB expression were measured by western blot analysis. The results demonstrated that β-asarone (10, 40 mg/kg) treatment significantly decreased the latency to find the platform, increased the time spent in the target quadrant and the number of crossing the platform of rats with exhaustive exercise-induced fatigue. β-asarone (10, 40 mg/kg) treatment increased the cell density in the hippocampus CA1 region, significantly up-regulated NR2B-CaMKII-ERK/CREB signal and improved the protein expression levels of SYP and PSD95 in hippocampus of rats with exhaustive exercise-induced fatigue. It suggests that β-asarone could improve learning and memory of rats with exhaustive exercise-induced fatigue. The mechanism might be related to β-asarone protecting the morphology of hippocampus, increasing the protein expression levels of SYP and PSD95 and up-regulating NR2B-CaMKII-ERK/CREB signal in hippocampus of rats with exhaustive exercise-induced fatigue. [ABSTRACT FROM AUTHOR]

Agrochemicals play a vital role in protecting crops and enhancing agricultural production by reducing threats from pests, pathogens and weeds. The toxicological status of honey bees can be influenced by a number of factors, including pesticides. While extensive research has focused on the lethal and sublethal effects of insecticides on individual bees and colonies, it is important to recognise that fungicides and herbicides can also affect bees' health. Unfortunately, in the field, honey bees are exposed to mixtures of compounds rather than single substances. This study aimed to evaluate the effects of a commercial fungicide and a commercial herbicide, both individually and in combination, on honey bees. Mortality assays, biomarkers and learning and memory tests were performed, and the results were integrated to assess the toxicological status of honey bees. Neurotoxicity (acetylcholinesterase and carboxylesterase activities), detoxification and metabolic processes (glutathione S-transferase and alkaline phosphatase activities), immune system function (lysozyme activity and haemocytes count) and genotoxicity biomarkers (Nuclear Abnormalities assay) were assessed. The fungicide Sakura® was found to activate detoxification enzymes and affect alkaline phosphatase activity. The herbicide Elegant 2FD and the combination of both pesticides showed neurotoxic effects and induced detoxification processes. Exposure to the herbicide/fungicide mixture impaired learning and memory in honey bees. This study represents a significant advance in understanding the toxicological effects of commonly used commercial pesticides in agriculture and contributes to the development of effective strategies to mitigate their adverse effects on non-target insects. [Display omitted] • Effects of commercial fungicide and herbicide, single and in combination, were evaluated. • Mortality assay, biomarkers and learning and memory tests were performed on honey bees. • Neurotoxic effects after both mixture treatments could be attributed to the herbicide. • Herbicide and pesticide mixtures compromise honey bees' behaviour. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 (FGF21) is one endogenous metabolic molecule that functions as a regulator in glucose and lipid homeostasis. However, the effect of FGF21 on L-lactate homeostasis and its mechanism remains unclear until now. Forty-five Six-week-old male C57BL/6 mice were divided into three groups: control, L-lactate, and FGF21 (1.5 mg/kg) groups. At the end of the treatment, nuclear magnetic resonance-based metabolomics, and key proteins related to L-lactate homeostasis were determined respectively to evaluate the efficacy of FGF21 and its mechanisms. The results showed that, compared to the vehicle group, the L-lactate-treated mice displayed learning and memory performance impairments, as well as reduced hippocampal ATP and NADH levels, but increased oxidative stress, mitochondrial dysfunction, and apoptosis, which suggesting inhibited L-lactate-pyruvate conversion in the brain. Conversely, FGF21 treatment ameliorated the L-lactate accumulation state, accompanied by restoration of the learning and memory defects, indicating enhanced L-lactate uptake and utilization in hippocampal neurons. We demonstrated that maintaining constant L-lactate-pyruvate flux is essential for preserving neuronal bioenergetic and redox levels. FGF21 contributed to preparing the brain for situations of high availability of L-lactate, thus preventing neuronal vulnerability in metabolic reprogramming. [Display omitted] • L-lactate availability is essential for neuronal function. • L-lactate-pyruvate axis maintains hippocampal metabolic microenvironment. • FGF21-mediated L-lactate homeostasis relies on MCT2 expression. [ABSTRACT FROM AUTHOR]

Lead is a neurotoxic contaminant that exists widely in the environment. Although lead neurotoxicity has been found to be tightly linked to gut microbiota disturbance, the effect of host metabolic disorders caused by gut microbiota disturbance on lead neurotoxicity has not been investigated. In this work, the results of new object recognition tests and Morris water maze tests showed that chronic low-dose lead exposure caused learning and memory dysfunction in mice. The results of 16 S rRNA sequencing of cecal contents and fecal microbiota transplantation showed that the neurotoxicity of lead could be transmitted through gut microbiota. The results of untargeted metabolomics and bile acid targeted metabolism analysis showed that the serum bile acid metabolism profile of lead-exposed mice was significantly changed. In addition, supplementation with TUDCA or INT-777 significantly alleviated chronic lead exposure-induced learning and memory impairment, primarily through inhibition of the NLRP3 inflammasome in the hippocampus to relieve neuroinflammation. In conclusion, our findings suggested that dysregulation of host bile acid metabolism may be one of the mechanisms of lead-induced neurotoxicity, and supplementation of specific bile acids may be a possible therapeutic strategy for lead-induced neurotoxicity. [Display omitted] • Chronic lead exposure disrupts gut microbiota associated host bile acid metabolic homeostasis. • TUDCA and INT-777 supplementation alleviate lead-induced learning and memory impairment. • TUDCA and INT-777 attenuate lead-induced neuroinflammation by inhibiting NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]

• The expression mechanism of long-term potentiation is now explained in molecular term by AMPA-R trafficking. • However the mechanism to maintain the enhanced transmission despite protein diffusion and turnover still remains elusive. • A recent emergence of liquid-liquid phase separation of synaptic molecules including CaMKII might explain this. Long-term potentiation (LTP) of synaptic transmission is considered to be a cellular counterpart of learning and memory. Activation of postsynaptic NMDA type glutamate receptor (NMDA-R) induces trafficking of AMPA type glutamate receptors (AMPA-R) and other proteins to the synapse in sequential fashion. At the same time, the dendritic spine expands for long-term and modulation of actin underlies this (structural LTP or sLTP). How these changes persist despite constant diffusion and turnover of the component proteins have been the central focus of the current LTP research. Signaling triggered by Ca2+-influx via NMDA-R triggers kinase including Ca2+/calmodulin-dependent protein kinase II (CaMKII). CaMKII can sustain longer-term biochemical signaling by forming a reciprocally-activating kinase-effector complex with its substrate proteins including Tiam1, thereby regulating persistence of the downstream signaling. Furthermore, activated CaMKII can condense at the synapse through the mechanism of liquid-liquid phase separation (LLPS). This increases the binding capacity at the synapse, thereby contributing to the maintenance of enlarged protein complexes. It may also serve as the synapse tag, which captures newly synthesized proteins. [ABSTRACT FROM AUTHOR]

• AS-IV could not only improve the memory of aging rats, but also reduce the inflammatory response in the hippocampus. • AS-IV attenuated the expression of AGEs, RAGE and NF-κB in the aging rats. • AS-IV improves age-related memory disorders, which possibly associates with neuroinflammation mediated by AGEs/RAGE/NF-κB axis. We investigated the effects of astragaloside IV (AS-IV) on memory function in aging rats mimicked by D-galactose administration and explored the potential molecular mechanisms. Twenty-seven male rats were randomly divided into control group (N = 9), model group (N = 9), and AS-IV treated group (N = 9). Aging model was stimulated by D-galactose (400 mg/kg/d, i.p. , dissolved in saline) for 8 weeks in rats. The general status of the rats was observed weekly. Learning and memory function was determined using the eight-arm radical maze and step-down test. Pathological changes in the hippocampal CA1 region were determined by hematoxylin and eosin staining. Organ indexes, superoxide dismutase (SOD) activity and malonaldehyde (MDA) content in the serum were measured. Expression of advanced glycation end products (AGEs), receptor for AGEs (RAGE), nuclear factor-κB (NF-κB), interleukin (IL)-6, IL-1β and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay, real-time polymerase chain reaction or western blotting. AS-IV improved the general status of the aging rats induced by D-galactose, prevented the impairment of memory function, organ indexes, and the pathological damage of the hippocampus. From the prospective of oxidative stress, AS-IV increased sera SOD activity and decreased MDA content. Additionally, AS-IV also reduced the inflammatory response by reducing hippocampal IL-1β, TNF-α, and IL-6 expression. Importantly, AS-IV prevented D-galactose-induced expression of AGEs, RAGE and NF-κB in the hippocampus. AS-IV could prevent D-galactose-induced aging and memory impairment in rats, likely via regulation of inflammatory response, which was modulated by AGEs/RAGE/NF-κB axis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), a common neurodegenerative disease, is the main cause of dementia, with cognitive decline as the core symptom observed during diagnosis. Synaptic loss may be the main cause of early cognitive dysfunction in AD, but the detailed mechanism is still unclear. In this study, we investigated the role of abnormal miR-455–5p/CPEB1 pathway in AD mouse model. We found that miR-455–5p was upregulated, while its downstream target, cytoplasmic polyadenylation element-binding 1 (CPEB1), was downregulated in the hippocampus of APP/PS1 mice at the age of 9 m. Abnormal miR-455–5p/CPEB1 pathway mediated cognitive deficits in APP/PS1 mice through suppressing α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor expressions. And miR-455–5p suppression, CPEB1 overexpression or application of a peptide disrupting the miR-455–5p/CPEB1 interaction in CA1 of APP/PS1 mice rescued AD-like phenotypes in mice, including deficits in synaptic plasticity and memory. In conclusion, our results indicated that miRNA-455–5p/CPEB1 pathway mediated synaptic and memory deficits in Alzheimer's Disease through targeting on AMPARs, providing a potential therapeutic strategy for AD. • MiR-455–5p/CPEB1 pathway mediated synaptic and memory deficits in APP/PS1 mice. • MiR-455–5p suppression through antagomirs or CPEB1 overexpression rescued synaptic and memory deficits. • Application of peptides to disrupt interaction between miR-455–5p and CPEB1 rescued synaptic and memory deficiency. • CPEB1 decrease in APP/PS1 mice mediates Aβ-related synaptic failure through broadly suppressing AMPAR expressions. [ABSTRACT FROM AUTHOR]

• Animal data finds that a Western-style (WS) diet impairs hippocampal function (HF). • There is emerging data for a similar effect of WS-diet in humans. • We report the first systematic review and meta-analyses of these human data. • We find a small significant pooled-effect size, for the effect of a WS-diet on HF. • We explore why the human data are so heterogenous. Paralleling animal research, there is emerging evidence that a Western-style (WS) diet – high in saturated fat and added sugar – impairs human hippocampal functioning. However, the conditions under which this occurs are not fully understood and there have been published failures to detect such effects. To date, there has been no systematic review or meta-analysis of relevant human studies. We undertook a systematic database search and review. Twenty studies were identified, two experimental, with the remainder correlational. The latter were included in a meta-analyses on the impact of WS-diet and its macronutrient components on human hippocampal function. Effects of age and sex were also examined. A WS-diet adversely impacted human hippocampal volume and functioning, with a small-pooled effect size. No effects were found for individual macronutrients. There was a high-level of study heterogeneity, which was not fully explained by study/sample characteristics. This may arise via the wide range of assessment tools used to measure both dietary intake and hippocampal functioning. Overall, a WS-diet clearly impacts human hippocampal functioning as in animals. [ABSTRACT FROM AUTHOR]

The deep layers of the entorhinal cortex are important for spatial cognition, as well as memory storage, consolidation and retrieval. A long-standing hypothesis is that deep-layer neurons relay spatial and memory-related signals between the hippocampus and telencephalon. We review the implications of recent circuit-level analyses that suggest more complex roles. The organization of deep entorhinal layers is consistent with multi-stage processing by specialized cell populations; in this framework, hippocampal, neocortical, and subcortical inputs are integrated to generate representations for use by targets in the telencephalon and for feedback to the superficial entorhinal cortex and hippocampus. Addressing individual sublayers of the deep entorhinal cortex in future experiments and models will be important for establishing systems-level mechanisms for spatial cognition and episodic memory. The circuit organization of the deep layers of the entorhinal cortex suggests multi-stage processing of hippocampal, cortical, and superficial entorhinal inputs. Neurons in layer 5a (L5a) provide the main output from deep layers of the entorhinal cortex to the telencephalon, whereas neurons in L5b influence superficial entorhinal cortex. Hippocampal replay events and cortical up–down states preferentially engage neurons in L5b of entorhinal cortex. The deep layers of the entorhinal cortex are crucial for memory storage, consolidation, and retrieval, and neurons in L5a and 5b probably play different roles. Accounting for multistage processing by the deep entorhinal cortex may be important for establishing systems-level mechanisms of episodic memory and spatial cognition. [ABSTRACT FROM AUTHOR]

• Anti-inflammatory cytokines protect information processes in the brain. • Anti-inflammatory cytokines modulate synaptic plasticity. • Anti-inflammatory cytokines control local blood flow. • Anti-inflammatory cytokines modulate neurogenesis in the hippocampus. The role of anti-inflammatory cytokines in the mechanisms of learning and memory, modulation of synaptic plasticity in the mammalian brain has not received sufficient attention. These issues are discussed in this review, and among the many cytokines, attention is paid to the most studied in this respect IL-10, IL-4, IL-13 and TGF-β. The level of anti-inflammatory cytokines in the brain tends to increase during memory acquisition, but the significance of such an increase is unclear. We hypothesize that anti-inflammatory cytokines primarily protect and optimize the functioning of neuronal circuits involved in information processing. The increased local activity of neurons during memory acquisition activates many signaling molecules, and some of them can trigger unwanted processes (including neuroinflammation), but increased levels of anti-inflammatory cytokines prevent this triggering. Each of the anti-inflammatory cytokines plays a specific role in supporting information processing. For example, the role of IL-4 and IL-13 in recruiting T cells to the meninges during training in healthy animals has been most studied. It has also been shown that TGF-β is able to optimize late stage LTP in the hippocampus and support the consolidation of memory traces in behavioral studies. Cytokines have an effect on learning and memory through their influence on neuroplasticity, neurogenesis in the hippocampus and regulation of the neurovascular unit. Experiments have shown such an effect, and the data obtained create the prerequisites for new therapeutic approaches to the correction of cognitive impairments. [ABSTRACT FROM AUTHOR]

Identification of molecules and molecular pathways that can ameliorate aging-associated decline in cognitive function is crucial. Here we report that the protein levels of transcription factor EB (TFEB) were markedly reduced in both the cytosolic and nuclear fractions of the frontal cortex and hippocampus at 18-months of age relative to 6 months in the normal male wild-type mice. In the transgenic mice with ectopic expression of flag-TFEB in neurons, we observed that the levels of actin-normalized PGC1α and mtTFA were significantly increased in both the cortex and the hippocampus. Additionally, we confirmed increased mitochondria numbers in the flag-TFEB mice by transmission electron microscopy. Most importantly, TFEB expression in the 18-month-old transgenic mice mitigated markers of senescence including P16INK4a, γ-H2AX, and lamin B1, and improved memory skills implying that TFEB may exert an anti-aging effect by modulating neuronal senescence. Taken together these data strongly support that TFEB can be a useful therapeutic target for brain senescent cells to help overcome the age-related issues in cognition and possibly, achieve healthy aging. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disease. One of the main pathology markers of AD is the beta-amyloid plaques (βA1-42) created from residues of the badly processed amyloid precursor protein. The accumulation of these plaques can induce neuroinflammation and oxidative stress and impair antioxidant mechanisms, culminating in cognitive and memory deficits. New therapies are necessary to treat AD as the approved drugs do not treat the progress of the disease. Transcranial low-intensity pulsed ultrasound (LIPUS) affects brain metabolism and could be tested as a treatment for AD. This study was aimed at evaluating the LIPUS treatment in a model of AD induced by βA1-42 intracerebroventricularly (ICV) and its effects on learning memory, neurotrophins, neuroinflammation and oxidative status. βA1-42 was administered ICV 24 h before the start of a 5-wk LIPUS treatment. The treatment with LIPUS improved recognition memory, as well as increasing nerve growth factor β and brain-derived neurotrophic factor levels in the hippocampus and cortex. There was a decrease in protein damage in the hippocampus treated with LIPUS. Neuroinflammation and oxidative stress were not present in the AD model used. The results indicated that LIPUS is a novel and promising adjuvant strategy for treatment of the late stage of AD. [ABSTRACT FROM AUTHOR]

• Exactly how circadian rhythms modulate learning and memory is unclear • Focusing on oscillators in brain areas such as the hippocampus is key • A semi-autonomous oscillator involved in memory was recently discovered • We present a novel framework delineating entrainment of this oscillator • Past and future experiments related to this framework are discussed The master clock, suprachiasmatic nucleus, is believed to control peripheral circadian oscillators throughout the brain and body. However, recent data suggest there is a circadian clock involved in learning and memory, potentially housed in the hippocampus, which is capable of acting independently of the master clock. Curiously, the hippocampal clock appears to be influenced by the master clock and by hippocampal dependent learning, while under certain conditions it may also revert to its endogenous circadian rhythm. Here we propose a mechanism by which the hippocampal clock could locally determine the nature of its entrainment. We introduce a novel theoretical framework, inspired by but extending beyond the hippocampal memory clock, which provides a new perspective on how circadian clocks throughout the brain coordinate their rhythms. Importantly, a local clock for memory would suggest that hippocampal-dependent learning at the same time every day should improve memory, opening up a range of possibilities for non-invasive therapies to alleviate the detrimental effects of circadian rhythm disruption on human health. [ABSTRACT FROM AUTHOR]

Memory contextualization is vital for the subsequent retrieval of relevant memories in specific situations and is a critical dimension of social cognition. The inability to properly contextualize information has been described as characteristic of psychiatric disorders like autism spectrum disorders, schizophrenia, and post-traumatic stress disorder. The exposure to early-life adversities, such as nutritional deficiency, increases the risk to trigger alterations in different domains of cognition related to those observed in mental diseases. In this work, we explored the consequences of exposure to perinatal protein malnutrition on contextual memory in a mouse model and assessed whether these consequences are transmitted to the next generation. Female mice were fed with a normal or hypoproteic diet during pregnancy and lactation. To evaluate contextual memory, the object-context mismatch test was performed in both sexes of F1 offspring and in the subsequent F2 generation. We observed that contextual memory was altered in mice of both sexes that had been subjected to maternal protein malnutrition and that the deficit in contextual memory was transmitted to the next generation. The basis of this alteration seems to be a transcriptional dysregulation of genes involved in the excitatory and inhibitory balance and immediate-early genes within the medial prefrontal cortex (mPFC) of both generations. The expression of genes encoding enzymes that regulate H3K27me3 levels was altered in the mPFC and partially in sperm of F1 malnourished mice. These results support the hypothesis that early nutritional deficiency represents a risk factor for the emergence of symptoms associated with mental disorders. • Maternal protein malnutrition impairs contextual memory in mice. • Deficit in contextual memory is transmitted to the following generation. • Genes involved in E/I balance are dysregulated in mPFC of malnourished offspring. • Malnourished mice exhibit altered expression of H3K27me3 modifiers in mPFC and sperm. [ABSTRACT FROM AUTHOR]

• Exactly how CA2 contributes to hippocampal computation is unclear. • Recent findings implicate CA2 in a range of hippocampal-dependent memory processes. • Research that highlights CA2 function beyond social memory is reviewed. • The computational role of CA2's unique features are discussed. • Existing proposals for the role of CA2 are evaluated in light of experimental findings. Hippocampal region CA2 has received increased attention due to its importance in social recognition memory. While its specific function remains to be identified, there are indications that CA2 plays a major role in a variety of situations, widely extending beyond social memory. In this targeted review, we highlight lines of research which have begun to converge on a more fundamental role for CA2 in hippocampus-dependent memory processing. We discuss recent proposals that speak to the computations CA2 may perform within the hippocampal circuit. [ABSTRACT FROM AUTHOR]

[Display omitted] • Kindled animals show impairment in learning & memory. • Kindled animals show impairment in synaptic plasticity. • Electromagnetic field improves this impairment in learning & memory and synaptic plasticity. Kindling results in abnormal synaptic potentiation and significant impairment in learning and memory. Electromagnetic field (EMF) effects on learning and memory in kindled animals and its effects on hippocampal neural activity are largely unknown. In the current study, the effects of EMF on learning and memory, as well as hippocampal synaptic plasticity, in kindled rats were investigated. EMF (10 mT; 100 Hz) was applied to fully kindled animals one hour/day for a period of one week. The behavioral and electrophysiological studies were performed 24 h following the EMF application. The kindled rats showed spatial learning deficits during the training phase of the Morris water maze (MWM) test. Moreover, there were increments in escape latency and path length compared to the sham group. The kindled rats spent less time in the target-quadrant probe test, indicating spatial memory impairment. Applying EMF to the KEMF group (kindling + EMF) restored learning and memory, and decreased escape latency and path length significantly compared to the kindled group. EMF alone had no significant effects on the learning and memory parameters. Based on the open field (OF) test results, EMF alone in the EMF group, but not in the kindled or the KEMF groups, decreased the total traveled distance and increased the spent time in the peripheral zone, compared to the sham group. Based on electrophysiological results, applying EMF in the KEMF group returned the ability of synaptic potentiation to the hippocampal CA1 area and high-frequency stimulation induced long-term potentiation (LTP). Accordingly, EMF can be considered a potential therapy for seizure-induced deficits in learning and memory. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders have a pathophysiology that heavily involves neuroinflammation. In this study, we used lipopolysaccharide (LPS) to create a model of cognitive impairment by inducing systemic and neuroinflammation in experimental animals. LPS was injected intraperitoneally at a dose of 0.5 mg/kg during the last seven days of the study. Adalimumab (ADA), a TNF-α inhibitor, was injected at a dose of 10 mg/kg a total of 3 times throughout the study. On the last two days of the experiment, 50 mg/kg of curcumin was administered orally as a positive control group. Open field (OF) and elevated plus maze tests (EPM) were used to measure anxiety-like behaviors. The tail suspension test (TST) was used to measure depression-like behaviors, while the novel object recognition test (NOR) was used to measure learning and memory activities. Blood and hippocampal TNF α and nitric oxide (NO) levels, hippocampal BDNF, CREB, and ACh levels, and AChE activity were measured by ELISA. LPS increased anxiety and depression-like behaviors while decreasing the activity of the learning-memory system. LPS exerted this effect by causing systemic and neuroinflammation, cholinergic dysfunction, and impaired BDNF release. ADA controlled LPS-induced behavioral changes and improved biochemical markers. ADA prevented cognitive impairment induced by LPS by inhibiting inflammation and regulating the release of BDNF and the cholinergic pathway. • LPS caused anxiety and depression in mice and impaired learning. • LPS induced neuroinflammation and disrupted BDNF and cholinergic pathways. • ADA ameliorated LPS-induced behavioral changes. • ADA prevented inflammation and regulated BDNF release and the cholinergic pathway. [ABSTRACT FROM AUTHOR]

Polygala tenuifolia Wild is an ancient traditional Chinese medicine. Its main component, tenuifolin (TEN), has been proven to improve cognitive impairment caused by neurodegenerative diseases and ovariectomy. However, there was hardly any pharmacological research about TEN and its potential gender differences. Considering the reduction of TEN on learning and memory dysfunction in ovariectomized animals, therefore, we focused on the impact of TEN in different mice genders in the current study. Spontaneous alternation behavior (SAB), light-dark discrimination, and Morris water maze (MWM) tests were used to evaluate the mice's learning and memory abilities. The field excitatory postsynaptic potential (fEPSP) of the hippocampal CA1 region was recorded using an electrophysiological method, and the morphology of the dendritic structure was examined using Golgi staining. In the behavioral experiments, TEN improved the correct rate in female mice in the SAB test, the correct rate in the light-dark discrimination test, and the number of crossing platforms in the MWM test. Additionally, TEN reduced the latency of female mice rather than male mice in light-dark discrimination and MWM tests. Moreover, TEN could significantly increase the slope of fEPSP in hippocampal Schaffer-CA1 and enhance the total length and the number of intersections of dendrites in the hippocampal CA1 area in female mice but not in male mice. Collectively, the results of the current study showed that TEN improved learning and memory by regulating long-term potentiation (LTP) and dendritic structure of hippocampal CA1 area in female mice but not in males. These findings would help to explore the improvement mechanism of TEN on cognition and expand the knowledge of the potential therapeutic value of TEN in the treatment of cognitive impairment. • Tenuifolin enhanced learning and memory abilities with a more positive effect on female mice than on male mice. • Tenuifolin improved long-term potentiation and dendritic structure in female mice but not in male mice. • Tenuifolin showed noticeable gender differences in pharmacodynamics. [ABSTRACT FROM AUTHOR]

Recent findings show that effective integration of novel information in the brain requires coordinated processes of homo- and heterosynaptic plasticity. In this work, we hypothesize that activity-dependent remodeling of the peri-synaptic extracellular matrix (ECM) contributes to these processes. We show that clusters of the peri-synaptic ECM, recognized by CS56 antibody, emerge in response to sensory stimuli, showing temporal and spatial coincidence with dendritic spine plasticity. Using CS56 co-immunoprecipitation of synaptosomal proteins, we identify several molecules involved in Ca2+ signaling, vesicle cycling, and AMPA-receptor exocytosis, thus suggesting a role in long-term potentiation (LTP). Finally, we show that, in the CA1 hippocampal region, the attenuation of CS56 glycoepitopes, through the depletion of versican as one of its main carriers, impairs LTP and object location memory in mice. These findings show that activity-dependent remodeling of the peri-synaptic ECM regulates the induction and consolidation of LTP, contributing to hippocampal-dependent memory. [Display omitted] • Glia-derived chondroitin sulfate (CS) proteoglycans form aggregates of peri-synaptic matrix • Clusters of peri-synaptic matrix arise in an experience-dependent fashion • Versican core protein regulates the expression of a specific 6-sulfated CS glycoform • 6-sulfated CS contributes to spatially organized synaptic refinement Chelini et al. demonstrate that versican regulates the expression of a specific proteoglycan glycoform, contributing to long-term potentiation and hippocampal-dependent memory in mice. These findings bring attention to a potential mechanism contributing to the spatial arrangement of synaptic ensembles during the active phase of experience-dependent plasticity. [ABSTRACT FROM AUTHOR]