Neuroplasticity, the brain's capacity to reorganize itself by forming new neural connections, is central to modern neuroscience. Once believed to occur only during early development, research now shows that plasticity continues throughout the lifespan, supporting learning, memory, and recovery from injury or disease. Substantial progress has been made in understanding the mechanisms underlying neuroplasticity and their therapeutic applications. This overview article examines synaptic plasticity, structural remodeling, neurogenesis, and functional reorganization, highlighting both adaptive (beneficial) and maladaptive (harmful) processes across different life stages. Recent strategies to harness neuroplasticity, ranging from pharmacological agents and lifestyle interventions to cutting-edge technologies like brain-computer interfaces (BCIs) and targeted neuromodulation are evaluated in light of current empirical evidence. Contradictory findings in the literature are addressed, and methodological limitations that hamper widespread clinical adoption are discussed. The ethical and societal implications of deploying novel neuroplasticity-based interventions, including issues of equitable access, data privacy, and the blurred line between treatment and enhancement, are then explored in a structured manner. By integrating mechanistic insights, empirical data, and ethical considerations, the aim is to provide a comprehensive and balanced perspective for researchers, clinicians, and policymakers working to optimize brain health across diverse populations.

EFA6A is a guanine nucleotide exchange factor for ADP ribosylation factor 6 (Arf6), a small GTPase involved in membrane trafficking and actin cytoskeleton remodeling. While EFA6A-Arf6 signaling has been shown to regulate dendritic spine formation and maintenance in cultured neurons, its role in higher brain functions remains unclear in vivo. Here, we generated mice lacking two EFA6A splicing isoforms, EFA6A and EFA6As, to examine their role in regulating spine morphology and hippocampus-dependent learning and memory. The loss of EFA6A and EFA6As caused reduced dendritic spine density in developing CA1 pyramidal neurons, whereas dendritic spines aberrantly increased in adults. Furthermore, the mutant mice also showed impaired maintenance of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses in the hippocampus and memory retention in the passive avoidance test. These findings provide the first in vivo evidence that the EFA6A isoforms, EFA6A and EFA6As, collectively regulate spine formation bidirectionally in a developmental stage-dependent manner, which is likely to underlie hippocampal synaptic plasticity and memory formation.

Cortical paired associative stimulation (cPAS), repeated at spaced intervals and applied to the primary motor cortex (M1) and posterior parietal cortex (PPC), has a dose-dependent effect on corticomotor excitability in young adults. The present study investigated whether aging affects this additive (nonhomeostatic) metaplasticity by performing the same manipulation in a sample of older adults.

In the multi-dose cPAS condition, three consecutive sessions of the Hebbian-plasticity-induction cPAS protocol were administered with a 50-minute interval between sessions. In the single-dose control cPAS condition, one session of the Hebbian-plasticity-induction cPAS protocol was followed by two sessions of a control non-Hebbian cPAS protocol. We measured motor-evoked potentials (MEPs) before and after each cPAS session.

Compared to a single dose of cPAS, the multi-dose cPAS protocol prevented the reduction in MEP amplitude, resulting in relatively greater corticomotor excitability following the Hebbian procedures. We did not find evidence for an increase in MEP amplitude after the repeated, spaced Hebbian-plasticity-induction cPAS protocol from baseline levels, suggesting reduced neuroplasticity in older adults compared to young adults.

Repeated spaced paired-associative stimulation to the parietal-motor pathway maintains corticomotor excitability in older adults.

These findings provide insight into age-related differences in neuroplastic capacity in healthy humans.

Exposure to lead during early life, including in pregnancy, is toxic to neurodevelopment. Though public health initiatives have resulted in an overall reduction in lead exposure levels, lead remains a significant environmental hazard, requiring innovative efforts to mitigate the burden of early life lead. This study explored whether positive postnatal social experiences in the forms of positive caregiving and a rich cognitive home environment moderate the associations of prenatal lead on child neurodevelopmental outcomes including language skills, effortful control, and executive function skills. We leverage an analytic sample (N = 107) drawn from a prospective cohort of mother-infant dyads. Prenatal lead was measured from maternal urine, positive caregiving from observational methods, and cognitive home environment from a validated questionnaire. Results reveal a negative association of prenatal lead on child language when the cognitive home environment in infancy was poor (β=-0.32, p = 0.04) but not when the cognitive home environment in infancy was rich (β=0.20, p = 0.16). This buffering effect was not observed for the child outcomes of effortful control or executive function skills. Our results encourage future research into the provision of a rich cognitive home environment as a means of mitigating the detrimental effects of prenatal lead exposure on early child language skills.

Mitochondria, often known as the cell's powerhouses, are primarily responsible for generating energy through aerobic oxidative phosphorylation. However, their functions extend far beyond just energy production. Mitochondria play crucial roles in maintaining calcium balance, regulating apoptosis (programmed cell death), supporting cellular signaling, influencing cell metabolism, and synthesizing reactive oxygen species (ROS). Recent research has highlighted a strong link between bipolar disorder (BD) and mitochondrial dysfunction. Mitochondrial dysfunction contributes to oxidative stress, particularly through the generation of ROS, which are implicated in the pathophysiology of BD. Oxidative stress arises when there is an imbalance between the production of ROS and the cell's ability to neutralize them. In neurons, excessive ROS can damage various cellular components, including proteins in neuronal membranes and intracellular enzymes. Such damage may interfere with neurotransmitter reuptake and the function of critical enzymes, potentially affecting brain regions involved in mood regulation and emotional control, which are key aspects of BD. In this review, we will explore how various types of mitochondrial dysfunction contribute to the production of ROS. These include disruptions in energy metabolism, impaired ROS management, and defects in mitochondrial quality control mechanisms such as mitophagy (the process by which damaged mitochondria are selectively degraded). We will also examine how abnormalities in calcium signaling, which is crucial for synaptic plasticity, can lead to mitochondrial dysfunction. Additionally, we will discuss the specific mitochondrial dysfunctions observed in BD, highlighting how these defects may contribute to the disorder's pathophysiology. Finally, we will identify potential therapeutic targets to improve mitochondrial function, which could pave the way for new treatments to manage or mitigate symptoms of BD.

Homeostatic and Hebbian plasticity co-operate during the critical period, refining neuronal circuits; however, the interaction between these two forms of plasticity is still unclear, especially in adulthood. Here, we directly investigate this issue in adult humans using two consolidated paradigms to elicit each form of plasticity in the visual cortex: the long-term potentiation-like change of the visual evoked potential (VEP) induced by high-frequency stimulation (HFS) and the shift of ocular dominance induced by short-term monocular deprivation (MD). We tested homeostatic and Hebbian plasticity independently, then explored how they interacted by inducing them simultaneously in a group of adult healthy volunteers. We successfully induced both forms of plasticity: 60 min of MD induced a reliable change in ocular dominance and HFS reliably modulated the amplitude of the P1 component of the VEP. Importantly, we found that, across participants, homeostatic and Hebbian plasticity were negatively correlated, indicating related neural mechanisms, potentially linked to intracortical excitation/inhibition balance. On the other hand, we did not find an interaction when the two forms of plasticity were induced simultaneously. Our results indicate a largely preserved plastic potential in the visual cortex of the adult brain, for both short-term homeostatic and Hebbian plasticity. Crucially, we show for the first time a direct relationship between these two forms of plasticity in the adult human visual cortex, which could inform future research and treatment protocols for neurological diseases. KEY POINTS: Homeostatic and Hebbian plasticity co-operate during the critical period to refine neuronal circuits in the visual cortex. The interaction between these two forms of plasticity is still unknown, especially after the closure of the critical periods and in humans. We directly investigate the interplay between Hebbian and homeostatic visual plasticity in adult humans using non-invasive paradigms. We found a negative correlation between these forms of plasticity showing for the first time a direct relationship between Hebbian and homeostatic plasticity. Our results could inform future research and treatment protocols for neurological diseases.

Non-invasive brain stimulation (NIBS) methods such as paired associative stimulation (PAS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS) are used to modulate cortical excitability and reduce symptoms in a variety of psychiatric disorders. Recent studies have shown significant inter-individual variability in the physiological response to these techniques when they are applied over the hand representation of primary motor cortex (M1hand). The goal of the present study was to identify neurophysiological, neuroanatomical, and neurochemical baseline characteristics that may predict response to commonly used NIBS protocols using data from a previously published study (Therrien-Blanchet et al., 2023). To this end, PAS, anodal tDCS, and 20-Hz tACS were administered to healthy participants in a repeated measures design. Pre/Post differences in transcranial magnetic stimulation-induced input-output curves were used to quantify changes in corticospinal excitability. Primary predictors were late I-wave latency, cortical thickness (CT) of M1hand, and fractional anisotropy of the corticospinal tract (CSThand) originating from M1hand. Secondary exploratory analysis was performed with CT in areas outside motor cortex, diffusion MRI (dMRI) metrics of the CSThand, magnetic resonance spectroscopy measurements of GABA, glutamate, and n-acetyl aspartate of M1hand, baseline corticospinal excitability, and cranial circumference. Multiple regression analysis showed that none of the primary variables predicted intervention outcome for any of the NIBS protocols. Exploratory analysis revealed no significant correlation between predictor variables and PAS outcome. tDCS and tACS were significantly correlated with some baseline measures. These data suggest that modulation of cortical excitability following several NIBS protocols may not be easily predicted by baseline characteristics, underscoring the need for a better understanding of their mechanism of action. Significant exploratory associations need to be confirmed in larger samples and confirmatory designs.

Lumbar spinal stenosis (LSS) is a degenerative condition characterized by the narrowing of the spinal canal, resulting in chronic pain and impaired mobility. However, the molecular mechanisms underlying LSS remain unclear. In this study, we performed RNA sequencing (RNA-seq) to investigate differential gene expression in a rat LSS model and identify the key genes and pathways involved in its pathogenesis.

We used bioinformatics analysis to identify significant alterations in gene expression between the LSS-induced and sham groups.

Pearson's correlation analysis demonstrated strongly consistent intragroup expression (r > 0.9), with distinct gene expression between the LSS and sham groups. A total of 113 differentially expressed genes (DEGs) were identified, including upregulated genes such as Slc47a1 and Prg4 and downregulated genes such as Higd1c and Mln. Functional enrichment analysis revealed that these DEGs included those involved in key biological processes, including synaptic plasticity, extracellular matrix organization, and hormonal regulation. Gene ontology analysis highlighted critical molecular functions such as mRNA binding and integrin binding, as well as cellular components such as contractile fibers and the extracellular matrix, which were significantly affected by LSS.

Our findings provide novel insights into the molecular mechanisms underlying LSS and offer potential avenues for the development of targeted therapies aimed at mitigating disease progression and improving patient outcomes.

Prosapip1 is a brain-specific protein localized to the postsynaptic density, where it promotes dendritic spine maturation in primary hippocampal neurons. However, nothing is known about the role of Prosapip1 in vivo. To examine this, we utilized the Cre-loxP system to develop a Prosapip1 neuronal knockout mouse. We found that Prosapip1 controls the synaptic localization of its binding partner SPAR, along with PSD-95 and the GluN2B subunit of the NMDA receptor (NMDAR) in the dorsal hippocampus (dHP). We next sought to identify the potential contribution of Prosapip1 to the activity and function of the NMDAR and found that Prosapip1 plays an important role in NMDAR-mediated transmission and long-term potentiation (LTP) in the CA1 region of the dHP. As LTP is the cellular hallmark of learning and memory, we examined the consequences of neuronal knockout of Prosapip1 on dHP-dependent memory. We found that global or dHP-specific neuronal knockout of Prosapip1 caused a deficit in learning and memory whereas developmental, locomotor, and anxiety phenotypes were normal. Taken together, Prosapip1 in the dHP promotes the proper localization of synaptic proteins which, in turn, facilitates LTP driving recognition, social, and spatial learning and memory.

The phenomenon of neural plasticity pertains to the intrinsic capacity of neurons to undergo structural and functional reconfiguration through learning and experiential interaction with the environment. These changes could manifest themselves not only as a consequence of various life experiences but also following therapeutic interventions, including the application of noninvasive brain stimulation (NIBS) and psychotherapy. As standalone therapies, both NIBS and psychotherapy have demonstrated their efficacy in the amelioration of psychiatric disorders' symptoms, with a certain variability in terms of effect sizes and duration. Consequently, scholars suggested the convenience of integrating the two interventions into a multimodal treatment to boost and prolong the therapeutic outcomes. Such an approach is still in its infancy, and the physiological underpinnings substantiating the effectiveness and utility of combined interventions are still to be clarified. Therefore, this opinion paper aims to provide a theoretical framework consisting of compelling arguments as to why adding NIBS to psychotherapy can promote therapeutic change. Namely, we will discuss the physiological effects of the two interventions, thus providing a rationale to explain the potential advantages of a combined approach.

Exposure to air pollution is thought to cause millions of deaths globally each year. According to the Who 2018, approximately 7 million deaths annually are caused predominantly by noncommunicable diseases due to air pollution. Exposure to air particulate matter 2.5 (PM2.5) has been strongly associated with increased mortality and has significant effects on brain health. Air pollution, particularly ultrafine particulate matter, has emerged as a serious environmental concern with profound implications for human health. Studies in animal models have indicated that exposure to these pollutants during gestational development impacts prenatal and postnatal brain development. In particular, air pollution has been increasingly identified as a potential causative factor, as it affects neurogenesis in the brain's hippocampal region. The hippocampus is highly vulnerable to PM exposure, and any alteration in the structure or function of this region leads to various neurodevelopmental defects and neurodegenerative disorders via oxidative stress, microglial activation, neuronal death, and differential expression of genes. The neurogenesis process involves several steps, such as proliferation, differentiation, migration, synaptogenesis, and neuritogenesis. If any step of the neurogenesis process is hampered by environmental exposure or other factors, it can lead to neurodevelopmental defects, neurodegenerative disorders, and cognitive decline. One significant contributor to these alterations is air pollution, which ranks as the leading environmental risk factor worldwide. Some of the most common effects include oxidative stress, neuroinflammation, depressive behavior, altered cognitive processes, and microglial activation. This review explores how prenatal and postnatal PM exposure affects the hippocampal regions of the brain and the defects associated with exposure.

Conventional research has asserted that cognitive function, particularly, response inhibition, is closely related to the inferior frontal cortex (IFC), dorsolateral prefrontal cortex (DLPFC), or orbital frontal cortex (OFC), which belong to the prefrontal cortex (PFC). Different targets of anodal or cathodal transcranial direct current stimulation (a-tDCS or c-tDCS) would affect the experimental results, but the stimulation of the same brain target would produce inconsistent findings.

This study aimed to investigate the effects of a-tDCS and c-tDCS applied over the PFC for healthy populations on reactive and proactive control process compared with sham or no tDCS conditions, as assessed using the Stop-signal task (SST) and Go/NoGo (GNG) task performance.

This systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Search was conducted on Web of Science, Google Scholar, PubMed, Elsevier, Scopus, and Science Direct until March 2024. Studies that assessed the inhibitory control in SST or/and GNG tasks were included to achieve a homogenous sample.

Fourteen studies were included for meta-analyses, which were performed for two outcome measures, namely, stop-signal reaction time (SSRT) and commission error (CE) rate. A-tDCS and c-tDCS over the PFC had significant ergogenic effects on SST performance (mean difference = -17.03, 95% CI [-24.62, -9.43], p < 0.0001; mean difference = -15.19, 95% CI [-19.82, -10.55], p < 0.00001), and that of a-tDCS had a positive effect on GNG task performance (mean difference = -1.42, 95% CI [-2.71, -0.14], p = 0.03).

This review confirmed the engagement of PFC tDCS in reactive and proactive inhibitory processes. Future research should increase sample size and implement personalized stimulus protocols.

Brain state-dependent transcranial magnetic stimulation (TMS) holds promise for enhancing neuromodulatory effects by synchronizing stimulation with specific features of cortical oscillations derived from real-time electroencephalography (EEG). However, conventional approaches rely on open-loop systems with static stimulation parameters, assuming that pre-determined EEG features universally indicate high or low excitability states. This one-size-fits-all approach overlooks individual neurophysiological differences and the dynamic nature of brain states, potentially compromising therapeutic efficacy. We present a supervised machine learning framework that predicts individual motor excitability states from pre-stimulus EEG features. Our approach combines established biomarkers with a comprehensive set of spectral and connectivity measures, implementing multi-scale feature selection within a nested cross-validation scheme. Validation across multiple classifiers, feature sets, and experimental protocols in 50 healthy participants demonstrated a mean prediction accuracy of 71 ± 7%. Hierarchical clustering of top predictive EEG features revealed two distinct participant subgroups. The first subgroup, comprising approximately 50% of participants, showed predictive features predominantly in alpha and low-beta bands in sensorimotor regions of the stimulated hemisphere, aligning with traditional associations of motor excitability and the sensorimotor μ-rhythm. The second subgroup exhibited predictive features primarily in low and high gamma bands in parietal regions, suggesting that motor excitability is influenced by broader neural dynamics for these individuals. Our data-driven framework effectively identifies personalized motor excitability biomarkers, holding promise to optimize TMS interventions in clinical and research settings. Additionally, our approach provides a versatile platform for biomarker discovery and validation across diverse neuromodulation paradigms and brain signal classification tasks.

Calcium ions play a key role in the physiological processes of the central nervous system. The intracellular calcium signal, in nerve cells, is part of the neurotransmission mechanism. They are responsible for stabilizing membrane potential and controlling the excitability of neurons. Calcium ions are a universal second messenger that participates in depolarizing signal transduction and contributes to synaptic activity. These ions take an active part in the mechanisms related to memory and learning. As a result of depolarization of the plasma membrane or stimulation of receptors, there is an extracellular influx of calcium ions into the cytosol or mobilization of these cations inside the cell, which increases the concentration of these ions in neurons. The influx of calcium ions into neurons occurs via plasma membrane receptors and voltage-dependent ion channels. Calcium channels play a key role in the functioning of the nervous system, regulating, among others, neuronal depolarization and neurotransmitter release. Channelopathies are groups of diseases resulting from mutations in genes encoding ion channel subunits, observed including the pathophysiology of neurological diseases such as migraine. A disturbed ability of neurons to maintain an appropriate level of calcium ions is also observed in such neurodegenerative processes as Alzheimer's disease, Parkinson's disease, Huntington's disease, and epilepsy. This review focuses on the involvement of calcium ions in physiological and pathological processes of the central nervous system. We also consider the use of calcium ions as a target for pharmacotherapy in the future.

Neuroplasticity is the brain's ability to reorganize and modify its neuronal connections in response to environmental stimuli, experiences, learning, and disease processes. This encompasses a variety of mechanisms, including changes in synaptic strength and connectivity, the formation of new synapses, alterations in neuronal structure and function, and the generation of new neurons. Proper functioning of synapses, which facilitate neuron-to-neuron communication, is crucial for brain activity. Neuronal synapse homeostasis, which involves regulating and maintaining synaptic strength and function in the central nervous system (CNS), is vital for this process. Disruptions in synaptic balance, due to factors like inflammation, aging, or infection, can lead to impaired brain function. This review highlights the main aspects and mechanisms underlying synaptic homeostasis, particularly in the context of aging, infection, and inflammation.

Studies have demonstrated the potential of repetitive transcranial magnetic stimulation (rTMS) to decrease smoking cravings in individuals with tobacco use disorder (TUD). However, the neural features underlying the effects of rTMS treatment, especially the dynamic attributes of brain networks associated with the treatment, remain unclear.

Using dynamic functional connectivity analysis, this study first explored the differences in dynamic functional network features between 60 subjects with TUD and 64 nonsmoking healthy controls (HCs). Then, the left dorsolateral prefrontal cortex (DLPFC) was targeted for a five-day course of rTMS treatment in the 60 subjects with TUD (active rTMS in 42 subjects and sham treatment in 18 subjects). We explored the effect of rTMS on the dynamic network features associated with rTMS by comparing the actively treated group and the sham group.

Compared to nonsmokers, TUD subjects exhibited an increased integration coefficient between the frontoparietal network (FPN) and the basal ganglia network (BGN) and a reduced integration coefficient between the medial frontal network (MFN) and the FPN. Analysis of variance revealed that rTMS treatment reduced the integration coefficient between the FPN and BGN and improved the recruitment coefficient of the FPN.

This study involved a limited sample of young male smokers, and the findings may not generalize to older smokers or female smokers with an extensive history of smoking.

rTMS treatment of the left DLPFC exhibited significant effectiveness in restructuring the neural circuits associated with TUD while significantly mitigating smoking cravings.

We investigate Quantum Electrodynamics (QED) of water coupled with sound and light, namely Quantum Brain Dynamics (QBD) of water, phonons and photons. We provide phonon degrees of freedom as additional quanta in the framework of QBD in this paper. We begin with the Lagrangian density QED with non-relativistic charged bosons, photons and phonons, and derive time-evolution equations of coherent fields and Kadanoff-Baym (KB) equations for incoherent particles. We next show an acoustic super-radiance solution in our model. We also introduce a kinetic entropy current in KB equations in 1st order approximation in the gradient expansion and show the H-theorem for self-energy in Hartree-Fock approximation. We finally derive conserved number density of charged bosons and conserved energy density in spatially homogeneous system.

The neuroscience of meditation is providing insight into meditation's beneficial effects on well-being and informing understanding of consciousness. However, further research is needed to explicate mechanisms linking brain activity and meditation. Non-invasive brain stimulation (NIBS) presents a promising approach for causally investigating neural mechanisms of meditation. Prior NIBS-meditation research has predominantly targeted frontal and parietal cortices suggesting that it might be possible to boost the behavioral and neural effects of meditation with NIBS. Moreover, NIBS has revealed distinct neural signatures in long-term meditators. Nonetheless, methodological variations in NIBS-meditation research contributes to challenges for definitive interpretation of previous results. Future NIBS studies should further investigate core substrates of meditation, including specific brain networks and oscillations, and causal neural mechanisms of advanced meditation. Overall, NIBS-meditation research holds promise for enhancing meditation-based interventions in support of well-being and resilience in both non-clinical and clinical populations, and for uncovering the brain-mind mechanisms of meditation and consciousness.

Acute pain is a transient sensation that typically serves as part of the body's defense mechanism. However, in certain patients, acute pain can evolve into chronic pain, which persists for months or even longer. Neuroplasticity refers to the capacity for variation and adaptive alterations in the morphology and functionality of neurons and synapses, and it plays a significant role in the transmission and modulation of pain. In this paper, we explore the molecular mechanisms and signaling pathways underlying neuroplasticity during the transition of pain. We also examine the effects of neurotransmitters, inflammatory mediators, and central sensitization on neuroplasticity, as well as the potential of neuroplasticity as a therapeutic strategy for preventing chronic pain. The aims of this article is to clarify the role of neuroplasticity in the transformation from acute pain to chronic pain, with the hope of providing a novel theoretical basis for unraveling the pathogenesis of chronic pain and offering more effective strategies and approaches for its diagnosis and treatment.

This paper introduces a compact end-effector ankle rehabilitation robot (CEARR) system for addressing ankle range of motion (ROM) rehabilitation. The CEARR features a bilaterally symmetrical rehabilitation structure, with each side possessing three degrees of freedom (DOF) driven by three independently designed actuators. The working intervals of each actuator are separated by a series connection, ensuring they operate without interference to accommodate the dorsiflexion/plantarflexion (DO/PL), inversion/eversion (IN/EV), and adduction/abduction (AD/AB) DOF requirements for comprehensive ankle rehabilitation. In addition, we integrated an actuator and foldable brackets to accommodate patients in varied postures. We decoded the motor intention based on the surface electromyography (sEMG) and torque signals generated by the subjects' ankle joints in voluntary rehabilitation. Besides, we designed a real-time voluntary-triggered control (VTC) strategy to enhance the rehabilitation effect, in which the root mean square (RMS) of sEMG was utilized to trigger and adjust the CEARR rehabilitation velocity support. We verified the consistency of voluntary movement with CEARR rehabilitation support output for four healthy subjects on a nonlinear sEMG signal with anR 2 metric of approximately 0.67. We tested the consistency of triggering velocity trends with a linear torque signal for one healthy individual with anR 2 metric of approximately 0.99.

Synaptic dysfunction is highly correlated with cognitive impairments in Alzheimer's disease (AD), the most common dementia syndrome in the elderly. Long-term potentiation (LTP) and long-term depression (LTD) are two primary forms of synaptic plasticity with opposite direction of synaptic efficiency change. Both LTD and LTD are considered to mediate the cellular process of learning and memory. Substantial studies demonstrate AD-associated deficiency of both LTP and LTD. Meanwhile, the molecular signaling mechanisms underlying impairment of synaptic plasticity, particularly LTD, are poorly understood. By taking advantage of the novel transgenic mouse models recently developed in our lab, here we aimed to investigate the roles of AMP-activated protein kinase (AMPK), a central molecular senor that plays a critical role in maintaining cellular energy homeostasis, in regulation of LTD phenotypes in AD. We found that brain-specific suppression of the AMPKα1 isoform (but not AMPKα2 isoform) was able to alleviate mGluR-LTD deficits in APP/PS1 AD mouse model. Moreover, suppression of either AMPKα isoform failed to alleviate AD-related NMDAR-dependent LTD deficits. Taken together with our recent studies on roles of AMPK signaling in AD pathophysiology, the data indicate isoform-specific roles of AMPK in mediating AD-associated synaptic and cognitive impairments.

Synaptic plasticity is a key cellular model for learning, memory and chronic pain. Most previous studies were carried out in rats and mice, and less is known about synaptic plasticity in non-human primates. In the present study, we used integrative experimental approaches to study long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of adult tree shrews. We found that glutamate is the major excitatory transmitter and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid (AMPA) receptors mediate postsynaptic responses. LTP in tree shrews was greater than that in adult mice and lasted for at least 5 h. N-methyl-d-aspartic acid (NMDA) receptors, Ca2+ influx and adenylyl cyclase 1 (AC1) contributed to tree shrew LTP. Our results suggest that LTP is a major form of synaptic plasticity in the ACC of primate-like animals. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Oxytocin (OXT) is an "affiliative" hormone or neurohormone or neuropeptide consists of nine amino acids, synthesized in magnocellular neurons of paraventricular (PVN) and supraoptic nuclei (SON) of hypothalamus. OXT receptors are widely distributed in various region of brain and OXT has been shown to regulate various social and nonsocial behavior. Hippocampus is the main region which regulates the learning and memory. Hippocampus particularly regulates the acquisition of new memories and retention of acquired memories. OXT has been shown to regulate the synaptic plasticity, neurogenesis, and consolidation of memories. Further, findings from both preclinical and clinical studies have suggested that the OXT treatment improves performance in memory related task. Various trials have suggested the positive impact of intranasal OXT in the dementia patients. However, these studies are limited in number. In the present study authors have highlighted the role of OXT in the formation and retrieval of memories. Further, the study demonstrated the outcome of OXT treatment in various memory and related disorders.

In major depressive disorder (MDD), exploration of biomarkers will be helpful in diagnosing the disorder as well as in choosing a treatment and predicting the treatment response. Currently, tRNA-derived small ribonucleic acids (tsRNAs) have been established as promising non-invasive biomarker candidates that may enable a more reliable diagnosis or monitoring of various diseases. Herein, we aimed to explore tsRNA expression together with functional activities in MDD development.

Serum samples were obtained from patients with MDD and healthy controls, and small RNA sequencing (RNA-Seq) was used to profile tsRNA expression. Dysregulated tsRNAs in MDD were validated by quantitative real-time polymerase chain reaction (qRT-PCR). The diagnostic utility of specific tsRNAs and the expression of these tsRNAs after antidepressant treatment were analysed.

In total, 38 tsRNAs were significantly differentially expressed in MDD samples relative to healthy individuals (34 up-regulated and 4 down-regulated). qRT-PCR was used to validate the expression of six tsRNAs that were up-regulated in MDD (tiRNA-1:20-chrM.Ser-GCT, tiRNA-1:33-Gly-GCC-1, tRF-1:22-chrM.Ser-GCT, tRF-1:31-Ala-AGC-4-M6, tRF-1:31-Pro-TGG-2 and tRF-1:32-chrM.Gln-TTG). Interestingly, serum tiRNA-Gly-GCC-001 levels exhibited an area under the ROC curve of 0.844. Moreover, tiRNA-Gly-GCC-001 is predicted to suppress brain-derived neurotrophic factor (BDNF) expression. Furthermore, significant tiRNA-Gly-GCC-001 down-regulation was evident following an 8-week treatment course and served as a promising baseline predictor of patient response to antidepressant therapy.

Our current work reports for the first time that tiRNA-Gly-GCC-001 is a promising MDD biomarker candidate that can predict patient responses to antidepressant therapy.

Alzheimer Disease (AD) is a highly polygenic disease that presents with relatively earlier onset (≤70yo; EOAD) in about 5% of cases. Around 90% of these EOAD cases remain unexplained by pathogenic mutations. Using data from EOAD cases and controls, we performed a genome-wide association study (GWAS) and trans-ancestry meta-analysis on non-Hispanic Whites (NHW, NCase=6,282, NControl=13,386), African Americans (AA NCase=782, NControl=3,663) and East Asians (NCase=375, NControl=838 CO). We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. By integrating gene-based analysis, eQTL, pQTL and functional annotations, we nominate four novel genes that are involved in microglia activation, glutamate production, and signaling pathways. These results indicate that EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.

We aimed to summarise and critically appraise the available evidence for the effect of age on responsiveness to non-invasive brain stimulation (NBS) paradigms delivered to the primary motor cortex.

Four databases (Medline, Embase, PsycINFO and Scopus) were searched from inception to February 7, 2023. Studies investigating age group comparisons and associations between age and neuroplasticity induction from NBS paradigms were included. Only studies delivering neuroplasticity paradigms to the primary motor cortex and responses measured via motor-evoked potentials (MEPs) in healthy adults were considered.

39 studies, encompassing 40 experiments and eight NBS paradigms were included: paired associative stimulation (PAS; n = 12), repetitive transcranial magnetic stimulation (rTMS; n = 2), intermittent theta burst stimulation (iTBS; n = 8), continuous theta burst stimulation (cTBS; n = 7), transcranial direct and alternating current stimulation ((tDCS; n = 7; tACS; n = 2)), quadripulse stimulation (QPS; n = 1) and i-wave periodic transcranial magnetic stimulation (iTMS; n = 1). Pooled findings from PAS paradigms suggested older adults have reduced post-paradigm responses, although there was considerable heterogeneity. Mixed results were observed across all other NBS paradigms and post-paradigm timepoints.

Whilst age-dependent reduction in corticospinal excitability is possible, there is extensive inter- and intra-individual variability both within and between studies, making it difficult to draw meaningful conclusions from pooled analyses.

The hippocampus is a neuron-rich specialised brain structure that plays a central role in the regulation of emotions, learning and memory, cognition, spatial navigation, and motivational processes. In human fetal development, hippocampal neurogenesis is principally complete by mid-gestation, with subsequent maturation comprising dendritogenesis and synaptogenesis in the third trimester of pregnancy and infancy. Dendritogenesis and synaptogenesis underpin connectivity. Hippocampal development is exquisitely sensitive to perturbations during pregnancy and at birth. Clinical investigations demonstrate that preterm birth, fetal growth restriction (FGR), and acute hypoxic-ischaemic encephalopathy (HIE) are common perinatal complications that alter hippocampal development. In turn, deficits in hippocampal development and structure mediate a range of neurodevelopmental disorders, including cognitive and learning problems, autism, and Attention-Deficit/Hyperactivity Disorder (ADHD). In this review, we summarise the developmental profile of the hippocampus during fetal and neonatal life and examine the hippocampal deficits observed following common human pregnancy complications. IMPACT: The review provides a comprehensive summary of the developmental profile of the hippocampus in normal fetal and neonatal life. We address a significant knowledge gap in paediatric research by providing a comprehensive summary of the relationship between pregnancy complications and subsequent hippocampal damage, shedding new light on this critical aspect of early neurodevelopment.

Neurological complications of the COVID-19 infection may be caused in part by local neurochemical and structural abnormalities that could not be detected during routine medical examinations. We examined within subject neurometabolic and structural brain alterations from pre-to post-COVID-19 in the hippocampal region of three elderly individuals (aged 63-68 years) who had a COVID-19 infection with mild symptoms. Patients were participating in an interventional study in which they were closely monitored at the time they were diagnosed with COVID-19. Patients 1 and 2 just completed 18-20 resistance training sessions prior to their diagnosis. Patient 3 was assigned to a non-training condition in the same study.

Whole brain magnetic resonance imaging (MRI) images and proton magnetic resonance spectroscopy (1H-MRS) of the left hippocampus were collected before and after infection. Structural and spectroscopic imaging measures post-COVID-19 were contrasted to the pre-COVID-19 measures and were compared with values for Minimal Detectable Change at 95% (MDC95) and 90% (MDC90) confidence from a group of six elderly (aged 60-79 years) without COVID-19 that participated in the same study.

After SARS-COV-2 infection, we observed a reduction of glutamate-glutamine (Glx) in Patients 1 and 2 (≥ 42.0%) and elevation of myo-inositol (mIns) and N-acetyl-aspartate (NAA) in Patient 3 (≥ 36.4%); all > MDC90. MRI findings showed increased (Patients 1 and 2) or unchanged (Patient 3) hippocampal volume.

Overall, findings from this exploratory study suggest that mild COVID-19 infection could be associated with development of local neuroinflammation and reduced glutamate levels in the hippocampus. Our 1H-MRS findings may have clinical value for explaining chronic neurological and psychological complaints in COVID-19 long-haulers.

This study aims to evaluate the neuroprotective effect of caffeic acid (CAF) against cadmium chloride (CdCl2) in rats via its effect on memory index as well as on altered enzymatic activity in the brain of CdCl2-induced neurotoxicity.

The experimental rats were divided into seven groups (n=6 rats per group) of healthy rats (group 1), CdCl2 -induced (CD) (3 mg/kg BW) rats (group 2), CD rats + Vitamin C (group 3), CD rats + CAF (10 and 20 mg/kg BW respectively) (group 4 & 5), and healthy rat + CAF (10 and 20 mg/kg BW respectively) (group 6 & 7). Thereafter, CdCl2 and CAF were administered orally to the experimental rats in group 2 to group 5 on daily basis for 14 days. Then, the Y-maze test was performed on the experimental rats to ascertain their memory index.

CdCl2 administration significantly altered cognitive function, the activity of cholinesterase, monoamine oxidase, arginase, purinergic enzymes, nitric oxide (NOx), and antioxidant status of Cd rats (untreated) when compared with healthy rats. Thereafter, CD rats treated with vitamin C and CAF (10 and 20 mg/kg BW) respectively exhibited an improved cognitive function, and the observed altered activity of cholinesterase, monoamine oxidase, arginase, purinergic were restored when compared with untreated CD rats. Also, the level of brain NOx and antioxidant status were significantly (p<0.05) enhanced when compared with untreated CD rats. In the same vein, CAF administration offers neuro-protective effect in healthy rats vis-à-vis improved cognitive function, reduction in the activity of some enzymes linked to the progression of cognitive dysfunction, and improved antioxidant status when compared to healthy rats devoid of CAF.

This study demonstrated the neuroprotective effect of CAF against CdCl2 exposure and in healthy rats.

Studies report that rapidly repeated sensory stimulation can evoke LTP-like improvement of neural response in the sensory cortex. Whether this neural response potentiation is similar to the classic LTP induced by presynaptic electrical stimulation remains unclear. This study examined the effects of repeated high-frequency (9 Hz) versus low-frequency (1 Hz) visual stimulation on visually-evoked field potentials (VEPs) and the membrane protein content of AMPA / NMDA receptors in the primary visual cortex (V1) of cats. The results showed that repeated high-frequency visual stimulation (HFS) caused a long-term improvement in peak-to-peak amplitude of V1-cortical VEPs in response to visual stimuli at HFS-stimulated orientation (SO: 90°) and non-stimulated orientation (NSO: 180°), but the effect exhibited variations depending on stimulus orientation: the amplitude increase of VEPs in response to visual stimuli at SO was larger, reached a maximum earlier and lasted longer than at NSO. By contrast, repeated low-frequency visual stimulation (LFS) had not significantly affected the amplitude of V1-cortical VEPs in response to visual stimuli at both SO and NSO. Furthermore, the membrane protein content of the key subunit GluA1 of AMPA receptors and main subunit NR1 of AMPA receptors in V1 cortex was significantly increased after HFS but not LFS when compared with that of control cats. Taken together, these results indicate that HFS can induce LTP-like improvement of VEPs and an increase in membrane protein of AMPA and NMDA receptors in the V1 cortex of cats, which is similar to but less specific to stimulus orientation than the classic LTP.

To evaluate available evidence examining safety and efficacy of non-invasive brain stimulation (NIBS) on upper extremity outcomes in children with cerebral palsy (CP).

We electronically searched 12 sources up to May 2023 using JBI and Cochrane guidelines. Two reviewers selected articles with predetermined eligibility criteria, conducted data extraction, and assessed risk of bias using the Cochrane Risk of Bias criteria.

Nineteen studies were included: eight using repetitive transcranial magnetic stimulation (rTMS) and 11 using transcranial direct current stimulation (tDCS). Moderate certainty evidence supports the safety of rTMS and tDCS for children with CP. Very low to moderate certainty evidence suggests that rTMS and tDCS result in little to no difference in upper extremity outcomes.

Evidence indicates that NIBS is a safe and feasible intervention to target upper extremity outcomes in children with CP, although it also indicates little to no significant impact on upper extremity outcomes. These findings are discussed in relation to the heterogeneous participants' characteristics and stimulation parameters. Larger studies of high methodological quality are required to inform future research and protocols for NIBS.

This study aimed to compare the physiological performance and physical fitness based on the academic achievement levels of secondary school students and to explore the effect of gender on the relationship between physiological performance, physical fitness, and academic achievement. In this cross-sectional study, 304 children aged 13-14 years were recruited. To assess physical fitness, students performed a 20 m sprint test, a pro-agility test, a one-mile endurance run/walk test, and a countermovement jump test. At the end of the one-mile endurance run/walk test, the estimated VO2peak value of the participants was calculated. The physiological performance of the students was determined by measuring their resting heart rate and blood pressure. Students were grouped into three categories based on their academic achievement levels. The assessment of academic achievement considered their scores from the previous academic year. The scores were divided into three levels: poor (average score of 69 points or less), average (scores ranging from 70 to 84 points), and good (scores of 85 points or higher). The study revealed a notable disparity among students' VO2Max measurements based on their academic achievement (F = 8.938, p < 0.001, η2 = 0.056). However, we observed that the group with poor academic achievement displayed lower diastolic blood pressure values than the groups with average and good performances. Finally, no significant gender differences were evident in the relationship between academic achievement and any of the physical and physiological parameters.

Non-invasive brain stimulation (NIBS) is a complex and multifaceted approach to modulating brain activity and holds the potential for broad accessibility. This work discusses the mechanisms of the four distinct approaches to modulating brain activity non-invasively: electrical currents, magnetic fields, light, and ultrasound. We examine the dual stochastic and deterministic nature of brain activity and its implications for NIBS, highlighting the challenges posed by inter-individual variability, nebulous dose-response relationships, potential biases and neuroanatomical heterogeneity. Looking forward, we propose five areas of opportunity for future research: closed-loop stimulation, consistent stimulation of the intended target region, reducing bias, multimodal approaches, and strategies to address low sample sizes.

Ventricular arrhythmias in cardiac channelopathies are linked to autonomic triggers, which are sub-optimally targeted in current management strategies. Improved molecular understanding of cardiac channelopathies and cellular autonomic signalling could refine autonomic therapies to target the specific signalling pathways relevant to the specific aetiologies as well as the central nervous system centres involved in the cardiac autonomic regulation. This review summarizes key anatomical and physiological aspects of the cardiac autonomic nervous system and its impact on ventricular arrhythmias in primary inherited arrhythmia syndromes. Proarrhythmogenic autonomic effects and potential therapeutic targets in defined conditions including the Brugada syndrome, early repolarization syndrome, long QT syndrome, and catecholaminergic polymorphic ventricular tachycardia will be examined. Pharmacological and interventional neuromodulation options for these cardiac channelopathies are discussed. Promising new targets for cardiac neuromodulation include inhibitory and excitatory G-protein coupled receptors, neuropeptides, chemorepellents/attractants as well as the vagal and sympathetic nuclei in the central nervous system. Novel therapeutic strategies utilizing invasive and non-invasive deep brain/brain stem stimulation as well as the rapidly growing field of chemo-, opto-, or sonogenetics allowing cell-specific targeting to reduce ventricular arrhythmias are presented.

Metabolic syndrome (MetS) is a common disorder associated with disturbed neurotransmitter homeostasis. Memantine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, was first used in Alzheimer's disease. Allopregnanolone (Allo), a potent positive allosteric modulator of the Gamma-Amino-Butyric Acid (GABA)-A receptors, decreases in neurodegenerative diseases. The study investigated the impact of Memantine versus Allo administration on the animal model of MetS to clarify whether the mechanism of abnormalities is related more to excitatory or inhibitory neurotransmitter dysfunction.

Fifty-six male rats were allocated into 7 groups: 4 control groups, 1 MetS group, and 2 treated MetS groups. They underwent assessment of cognition-related behavior by open field and forced swimming tests, electroencephalogram (EEG) recording, serum markers confirming the establishment of MetS model and hippocampal Glial Fibrillary Acidic Protein (GFAP) and Brain-Derived Neurotrophic Factor (BDNF).

Allo improved anxiety-like behavior and decreased grooming frequency compared to Memantine. Both drugs increased GFAP and BDNF expression, improving synaptic plasticity and cognition-related behaviors. The therapeutic effect of Allo was more beneficial regarding lipid profile and anxiety. We reported progressive slowing of EEG waves in the MetS group with Memantine and Allo treatment with increased relative theta and decreased relative delta rhythms.

Both Allo and Memantine boosted the outcome parameters in the animal model of MetS. Allo markedly improved the anxiety-like behavior in the form of significantly decreased grooming frequency compared to the Memantine-treated groups. Both drugs were associated with increased hippocampal GFAP and BDNF expression, indicating an improvement in synaptic plasticity and so, cognition-related behaviors.

Repetitive transcranial magnetic stimulation (rTMS) exerts neuroprotective effects early in cerebral ischemia/reperfusion (I/R) injury. Intermittent theta-brust stimulation (iTBS), a more time-efficient modality of rTMS, improves the efficiency without at least decreasing the efficacy of the therapy. iTBS elevates cortical excitability, and in recent years it has become increasingly common to apply iTBS to patients in the early post-IS period. However, little is known about the neuroprotective mechanisms of iTBS. Endoplasmic reticulum stress (ERS), and ferroptosis have been shown to be involved in the development of I/R injury. We aimed to investigate the potential regulatory mechanisms by which iTBS attenuates neurological injury after I/R in rats.

Rats were randomly divided into three groups: sham-operated group, MCAO/R group, and MCAO/R + iTBS group, and were stimulated with iTBS 36 h after undergoing middle cerebral artery occlusion (MCAO) or sham-operated. The expression of ERS, ferroptosis, and apoptosis-related markers was subsequently detected by western blot assays. We also investigated the mechanism by which iTBS attenuates nerve injury after ischemic reperfusion in rats by using the modified Neurological Severity Score (mNSS) and the balance beam test to measure nerve function.

iTBS performed early in I/R injury attenuated the levels of ERS, ferroptosis, and apoptosis, and improved neurological function, including mNSS and balance beam experiments. It is suggested that this mode of stimulation reduces the cost per treatment by several times without compromising the efficacy of the treatment and could be a practical and less costly intervention.

More than half of methamphetamine (METH) users present with cognitive impairment, making it difficult for them to reintegrate into society. However, the mechanisms of METH-induced cognitive impairment remain unclear. METH causes neuronal hyperactivation in the nucleus accumbens (NAc) by aberrantly releasing dopamine, which triggers dependence. In this study, to clarify the involvement of hyperactivation of NAc in METH-induced cognitive impairment, mice were locally microinjected with METH into NAc (mice with METH (NAc)) and investigated their cognitive phenotype. Mice with METH (NAc) exhibited cognitive dysfunction in behavioral analyses and decreased long-term potentiation in the hippocampus, with NAc activation confirmed by expression of FosB, a neuronal activity marker. In the hippocampus of mice with METH (NAc), activated microglia, but not astroglia, and upregulated microglia-related genes, Il1b and C1qa were observed. Finally, administration of minocycline, a tetracycline antibiotic with suppressive effect on microglial activation, to mice with METH (NAc) ameliorated cognitive impairment and synaptic dysfunction by suppressing the increased expression of Il1b and C1qa in the hippocampus. In conclusion, activation of NAc by injection of METH into NAc elicited cognitive impairment by facilitating immune activation in mice. This study suggests that immunological intervention could be a therapeutic strategy for addiction-related cognitive disturbances.

This perspective review aims to explore the potential neurobiological mechanisms involved in the application of transcranial Direct Current Stimulation (tDCS) for Down syndrome (DS), the leading cause of genetically-based intellectual disability. The neural mechanisms underlying tDCS interventions in genetic disorders, typically characterized by cognitive deficits, are grounded in the concept of brain plasticity. We initially present the neurobiological and functional effects elicited by tDCS applications in enhancing neuroplasticity and in regulating the excitatory/inhibitory balance, both associated with cognitive improvement in the general population. The review begins with evidence on tDCS applications in five neurogenetic disorders, including Rett, Prader-Willi, Phelan-McDermid, and Neurofibromatosis 1 syndromes, as well as DS. Available evidence supports tDCS as a potential intervention tool and underscores the importance of advancing neurobiological research into the mechanisms of tDCS action in these conditions. We then discuss the potential of tDCS as a promising non-invasive strategy to mitigate deficits in plasticity and promote fine-tuning of the excitatory/inhibitory balance in DS, exploring implications for cognitive treatment perspectives in this population.

The present study aimed to investigate the effects of a short period of normobaric hypoxic exposure on spatial learning and memory, and brain-derived neurotrophic factor (BDNF) levels in the rat hippocampus. Hypoxic conditions were set at 12.5% O2. We compared all variables between normoxic trials (Norm), after 24 h (Hypo-24 h), and after 72 h of hypoxic exposure (Hypo-72 h). Spatial learning and memory were evaluated by using a water-finding task in an open field. Time to find water drinking fountains was significantly extended in Hypo 24 h (36.2 ± 21.9 s) compared to those in Norm (17.9 ± 12.8 s; P < 0.05), whereas no statistical differences between Norm and Hypo-72 h (22.7 ± 12.3 s). Moreover, hippocampal BDNF level in Hypo-24 h was significantly lower compared to Norm (189.4 ± 28.4 vs. 224.9 ± 47.7 ng/g wet tissue, P < 0.05), whereas no statistically differences in those between Norm and Hypo-72 h (228.1 ± 39.8 ng/g wet tissue). No significant differences in the changes in corticosterone and adrenocorticotropic hormone levels were observed across the three conditions. When data from Hypo-24 h and Hypo-72 h of hypoxia were pooled, there was a marginal negative relationship between the time to find drinking fountains and BDNF (P < 0.1), and was a significant negative relationship between the locomotor activities and BDNF (P < 0.05). These results suggest that acute hypoxic exposure (24 h) may impair spatial learning and memory; however, it recovered after 72 h of hypoxic exposure. These changes in spatial learning and memory may be associated with changes in the hippocampal BDNF levels in rats.

Major depressive disorder affects over 300 million people globally, with approximately 30% experiencing treatment-resistant depression (TRD). Given that impaired neuroplasticity underlies depression, the present study focused on neuroplasticity in the dorsolateral prefrontal cortex (DLPFC). Here, we aimed to investigate the differences in neuroplasticity between 60 individuals with TRD and 30 age- and sex-matched healthy controls (HCs). To induce neuroplasticity, participants underwent a paired associative stimulation (PAS) paradigm involving peripheral median nerve stimulation and transcranial magnetic stimulation (TMS) targeting the left DLPFC. Neuroplasticity was assessed by using measurements combining TMS with EEG before and after PAS. Both groups exhibited significant increases in the early component of TMS-evoked potentials (TEP) after PAS (P < 0.05, paired t-tests with the bootstrapping method). However, the HC group demonstrated a greater increase in TEPs than the TRD group (P = 0.045, paired t-tests). Additionally, event-related spectral perturbation analysis highlighted that the gamma power significantly increased after PAS in the HC group, whereas it was decreased in the TRD group (P < 0.05, paired t-tests with the bootstrapping method). This gamma power modulation revealed a significant group difference (P = 0.006, paired t-tests), indicating an inverse relationship for gamma power modulation. Our findings underscore the impaired neuroplasticity of the DLPFC in individuals with TRD.

In recent years, primary familial brain calcification (PFBC), a rare neurological disease characterized by a wide spectrum of cognitive disorders, has been associated to mutations in the sodium (Na)-Phosphate (Pi) co-transporter SLC20A2. However, the functional roles of the Na-Pi co-transporters in the brain remain still largely elusive. Here we show that Slc20a1 (PiT-1) and Slc20a2 (PiT-2) are the most abundant Na-Pi co-transporters expressed in the brain and are involved in the control of hippocampal-dependent learning and memory. We reveal that Slc20a1 and Slc20a2 are differentially distributed in the hippocampus and associated with independent gene clusters, suggesting that they influence cognition by different mechanisms. Accordingly, using a combination of molecular, electrophysiological and behavioral analyses, we show that while PiT-2 favors hippocampal neuronal branching and survival, PiT-1 promotes synaptic plasticity. The latter relies on a likely Otoferlin-dependent regulation of synaptic vesicle trafficking, which impacts the GABAergic system. These results provide the first demonstration that Na-Pi co-transporters play key albeit distinct roles in the hippocampus pertaining to the control of neuronal plasticity and cognition. These findings could provide the foundation for the development of novel effective therapies for PFBC and cognitive disorders.