Adolescent brain development is characterized by significant anatomical and physiological alterations, but little is known whether and how these alterations impact the neural network. Here we investigated the development of functional networks by measuring synaptic plasticity and neural synchrony of local filed potentials (LFPs), and further explored the underlying mechanisms. LFPs in the hippocampus were recorded in young (21 ~ 25 days), adolescent (1.5 months) and adult (3 months) rats. Long term potentiation (LTP) and neural synchrony were analyzed. The results showed that the LTP was the lowest in adolescent rats. During development, the theta coupling strength was increased progressively but there was no significant change of gamma coupling between young rats and adolescent rats. The density of dendrite spines was decreased progressively during development. The lowest levels of NR2A, NR2B and PSD95 were detected in adolescent rats. Importantly, it was found that the expression levels of autophagy markers were the highest during adolescent compared to that in other developmental stages. Moreover, there were more co-localization of autophagosome and PSD95 in adolescent rats. It suggests that autophagy is possibly involved in synaptic elimination during adolescence, and further impacts synaptic plasticity and neural synchrony.

Deficits in learning and memory are some of the most commonly reported symptoms following a traumatic brain injury (TBI). We will examine whether the neural basis of these deficits stems from alterations to bidirectional synaptic plasticity within the hippocampus. Although the CA1 subregion of the hippocampus has been a focus of TBI research, the dentate gyrus should also be given attention as it exhibits a unique ability for adult neurogenesis, a process highly susceptible to TBI-induced damage. This review examines our current understanding of how TBI results in deficits in synaptic plasticity, as well as how TBI-induced changes in endocannabinoid (eCB) systems may drive these changes. Through the synthesis and amalgamation of existing data, we propose a possible mechanism for eCB-mediated recovery in synaptic plasticity deficits. This hypothesis is based on the plausible roles of CB1 receptors in regulating inhibitory tone, influencing astrocytes and microglia, and modulating glutamate release. Dysregulation of the eCBs may be responsible for deficits in synaptic plasticity and learning following TBI. Taken together, the existing evidence indicates eCBs may contribute to TBI manifestation, pathogenesis, and recovery, but it also suggests there may be a therapeutic role for the eCB system in TBI.

The small GTPase Ras is an intracellular signaling hub required for long-term potentiation (LTP) in the hippocampus and for memory formation. Genetic alterations in Ras signaling (i.e., RASopathies) are linked to cognitive disorders in humans. However, it remains unclear how Ras controls synaptic plasticity, and whether different Ras isoforms play overlapping or distinct roles in neurons. Using genetically modified mice, we show here that H-Ras (the most abundant isoform in the brain) does not promote LTP, but instead long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). Mechanistically, H-Ras is activated locally in spines during mGluR-LTD via c-Src, and is required to trigger Erk activation and de novo protein synthesis. Furthermore, H-Ras deletion impairs object recognition as well as social and spatial memory. Conversely, K-Ras is the isoform specifically required for LTP. This functional specialization correlates with a differential synaptic distribution of the two isoforms H-Ras and K-Ras, which may have important implications for RASopathies and cognitive function.

Precise control of intracellular calcium ([Formula: see text]) concentration at the synaptic neuron terminal can unravel the mechanism behind computation, learning, and memory formation inside the brain. Recently, the discovery of [Formula: see text]-permeable channelrhodopsins (CapChRs) has opened the opportunity to effectively control the intracellular [Formula: see text] concentration using optogenetics. Here, we present a new theoretical model for precise optogenetic control with newly discovered CapChR2 at postsynaptic neuron. A detailed theoretical analysis of coincident stimulation of presynaptic terminal, postsynaptic spine and optogenetic activation of CapChR2-expressing postsynaptic spine shows different ways to control postsynaptic intracellular [Formula: see text] concentration. Irradiance-dependent [Formula: see text] flow is an additional advantage of this novel method. The minimum threshold of light irradiance and optimal ranges of time lag among different stimulations and stimulation frequencies have also been determined. It is shown that synaptic efficacy occurs at 20 µW/mm2 at coincident electrical stimulation of presynaptic terminal and postsynaptic spine with optogenetic activation of CapChR2-expressed postsynaptic spine. The analysis provides a new means of direct optogenetic control of [Formula: see text]-based synaptic plasticity, better understanding of learning and memory processes, and opens prospects for targeted therapeutic interventions to modulate synaptic function and address various neurological disorders.

The review explores the complex interplay between brain structures and their associated functions, presenting a diversity of hierarchical models that enhances our understanding of these relationships. Central to this approach are structure-function flow diagrams, which offer a visual representation of how specific neuroanatomical structures are linked to their functional roles. These diagrams are instrumental in mapping the intricate connections between different brain regions, providing a clearer understanding of how functions emerge from the underlying neural architecture. The study details innovative attempts to develop new functional hierarchies that integrate structural and functional data. These efforts leverage recent advancements in neuroimaging techniques such as fMRI, EEG, MEG, and PET, as well as computational models that simulate neural dynamics. By combining these approaches, the study seeks to create a more refined and dynamic hierarchy that can accommodate the brain's complexity, including its capacity for plasticity and adaptation. A significant focus is placed on the overlap of structures and functions within the brain. The manuscript acknowledges that many brain regions are multifunctional, contributing to different cognitive and behavioral processes depending on the context. This overlap highlights the need for a flexible, non-linear hierarchy that can capture the brain's intricate functional landscape. Moreover, the study examines the interdependence of these functions, emphasizing how the loss or impairment of one function can impact others. Another crucial aspect discussed is the brain's ability to compensate for functional deficits following neurological diseases or injuries. The investigation explores how the brain reorganizes itself, often through the recruitment of alternative neural pathways or the enhancement of existing ones, to maintain functionality despite structural damage. This compensatory mechanism underscores the brain's remarkable plasticity, demonstrating its ability to adapt and reconfigure itself in response to injury, thereby ensuring the continuation of essential functions. In conclusion, the study presents a system of brain functions that integrates structural, functional, and dynamic perspectives. It offers a robust framework for understanding how the brain's complex network of structures supports a wide range of cognitive and behavioral functions, with significant implications for both basic neuroscience and clinical applications.

We probed the dependence of metabotropic glutamate receptor dependent long-term depression (mGluR-LTD) on L-type voltage gated calcium channels (LTCCs). In prior work, we found that in a rat model of early life seizures (ELS), exaggerated mGluR-LTD was partly mediated by LTCCs and protein phosphatase 2A (PP2A). Here, we further investigated the interactive role of LTCCs, PP2A, and protein kinase A (PKA) in this same model. PP2Ac is known to bind CaV1.2 and modulate its function; displacement of PP2A (C subunit, or PP2Ac) as well as PKA phosphorylation of CaV1.2 at serine 1928, result in enhanced CaV1.2 function. We found that ELS enhanced LTCC activity. We further found that pharmacological displacement of PP2Ac (but not PP2B/calcineurin) from CaV1.2 enhanced mGluR-LTD in controls. This was occluded by blockade of PP2A or ELS. The LTCC-dihydropyridine agonist BayK 8644 enhanced mGluR-LTD in controls, which was also occluded by ELS. Up-regulation of both intracellular Ca2+ and PKA activity were implicated in ELS enhancement of mGluR-LTD, as LTD was normalized in ELS by depletion of internal calcium stores or blockade of PKA. These results support a dynamic model of mGluR-LTD regulation by LTCCs through PP2Ac binding and phosphorylation by PKA. This regulation is chronically lost after ELS. Together with our prior work, these studies tie hyperactive LTCCs to the chronic ELS behavioral phenotype that includes abnormal working memory, fear conditioning and socialization.

Fear, whether innate or learned, is an essential emotion required for survival. The learning, and subsequent memory, of fearful events enhances our ability to recognise and respond to threats, aiding adaptation to new, ever-changing environments. Considerable research has leveraged associative learning protocols such as contextual or auditory forms of fear conditioning in rodents, to understand fear learning, memory consolidation and extinction phases of memory. Such assays have led to detailed characterisation of the underlying neurocircuitry and neurobiology supporting fear learning processes. Given fear processing is conserved across rodents and humans, fear conditioning experiments provide translational insights into fundamental memory processes and fear-related pathologies. This review examines associative learning protocols used to measure fear learning, memory and extinction, before providing an overview on the underlying complex neurocircuitry including the amygdala, hippocampus and medial prefrontal cortex. This is followed by an in-depth commentary on the neurobiology, particularly synaptic plasticity mechanisms, which regulate fear learning, memory and extinction. Next, we consider how fear conditioning assays in rodents can inform our understanding of disrupted fear memory in human disorders such as post-traumatic stress disorder (PTSD), anxiety and psychiatric disorders including schizophrenia. Lastly, we critically evaluate fear conditioning protocols, highlighting some of the experimental and theoretical limitations and the considerations required when conducting such assays, alongside recent methodological advancements in the field. Overall, rodent-based fear conditioning assays remain central to making progress in uncovering fundamental memory phenomena and understanding the aetiological mechanisms that underpin fear associated disorders, alongside the development of effective therapeutic strategies.

Learning and memory are thought to require hippocampal long-term potentiation (LTP), a form of synaptic plasticity that is persistently impaired after cerebral ischemia and that requires movement of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) to excitatory synapses. We show here that oxygen/glucose-deprivation (OGD) in cultures hippocampal neurons causes a long-lasting impairment of CaMKII movement. Notably, CaMKII inhibition at 30 min after onset of OGD prevented the impairment in CaMKII movement. Thus, CaMKII mediates both, LTP mechanisms and their ischemia-induced impairment. These findings provide a mechanism by which ischemic conditions can impair LTP and explain how CaMKII inhibition after cerebral ischemia can prevent these LTP impairments.

Repetitive brain stimulation is hypothesized to bidirectionally modulate excitability, with low-frequency trains decreasing and high-frequency (>5 Hz) trains increasing activity. Most insights on the neuroplastic effects of repetitive stimulation protocols stem from non-invasive human studies (TMS/EEG) or data from rodent slice physiology. Here, we developed a rodent experimental preparation enabling simultaneous imaging of cellular activity during stimulation in vivo to understand the mechanisms by which brain stimulation modulates excitability of prefrontal cortex.

Repetitive trains of intracortical stimulation were applied to the medial prefrontal cortex using current parameters mapped to human rTMS electric-field estimates. Calcium imaging of glutamatergic (CamKII) and GABAergic (mDLX) neurons was performed before, during, and after stimulation in awake rodents (n=9 females). Protocols included low-frequency (1 Hz, 1000 pulses) and high-frequency (10 Hz, 3000 pulses), with sham stimulation as a control.

Glutamatergic neurons were differentially modulated by stimulation frequency, with 10 Hz increasing and 1 Hz decreasing activity. Post-stimulation, 1 Hz suppressed both glutamatergic and GABAergic activity, whereas 10 Hz selectively suppressed GABAergic neurons.

These findings provide direct evidence that clinical brain stimulation protocols induce long-term modulation of cortical excitability, with low-frequency stimulation broadly suppressing activity and high-frequency stimulation preferentially inhibiting GABAergic neurons after stimulation.

Autism spectrum disorder, or autism, is a neurodevelopmental disorder of the developing child's brain with a genetic causality. It can be diagnosed at about three years after birth when it begins to present itself via a range of neuropsychiatric symptoms. Nitric oxide is a crucial small molecule of life synthesized within cells of our body systems, including cells of our brain. Peroxynitrite is the product of reaction between superoxide anion and nitric oxide. It normally isomerizes into harmless nitrates or nitrites. However, when excessive superoxide anion is present, the cellular concentration of peroxynitrite can increase to a toxic level. Autism has been suggested to cause oxidative damage to brain cells. Until now, it is impossible to sample tissue from a live brain. Instead, stem cells can be derived (from an autism patient's somatic cells) which can then be differentiated and chemically directed to grow into miniature 3-dimensional tissue masses resembling specific brain regions (e.g., the cortex) called brain organoids. This review discusses utilizing nitric oxide and peroxynitrite as biomarkers and comparing their relative concentrations in stem cells and stem cell derived brain organoids of healthy and autistic individuals to develop a bioanalytical process for early diagnosis of autism.

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.

Synaptic dysfunction is a critical pathological feature in the early phase of Alzheimer's disease (AD) that precedes typical hallmarks of AD, including beta-amyloid (Aβ) plaques and neurofibrillary tangles. However, the underlying mechanism of synaptic dysfunction remains incompletely defined. Apolipoprotein E (APOE) has been shown to play a key role in the pathogenesis of AD, and the ε4 allele of APOE remains the strongest genetic risk factor for sporadic AD. It is widely recognized that APOE4 accelerates the development of Aβ and tau pathology in AD. Recent studies have indicated that APOE affects synaptic function through a variety of pathways. Here, we summarize the mechanism of modulating synapses by various APOE isoforms and demonstrate the therapeutic potential by targeting APOE4 for AD treatment.

Slow-acting biogenic amines, such as dopamine, are known to modulate fast neurotransmitters e.g. glutamate. In the striatum, dopamine (DA) interacts with glutamate, influencing neural excitability and promoting synaptic plasticity. The exact mechanism of such interaction is not fully understood. This study investigates, in detail, how dopamine overactivity in dopamine transporter knockout (DAT-/-) rats, alters the homeostasis of the striatal glutamate synapse from a molecular, behavioural and functional point of view.

The expression, localisation, retention and electrophysiological properties of N-methyl-D-aspartate (NMDA) receptors as well as dendritic spine density and morphology were investigated in the striatum of DAT-/- rats, at baseline and after treatment with the non-competitive NMDA receptor antagonist memantine (30 mg kg-1).

Dopamine overactivity dramatically reorganises the striatal glutamate synapse, redistributing NMDA receptors in the synapse as typified by reduced synaptic availability and reduced expression of NMDA scaffolding proteins, as well as by increased GluN2B-containing NMDA receptors in the extra synapse. Such changes are accompanied by reduced spine density, suggesting dopamine-induced structural rearrangements. These results converge into a compromised plasticity, as shown by the impaired ability to promote long-term depression (LTD) in the striatum of DAT-/-rats. Notably, memantine counteracts hyperlocomotion, reverses spine alterations and abolishes the extrasynaptic movements of NMDA receptors in the striatum of DAT-/- rats, thus restoring functional LTD.

A hyperdopaminergic condition seems to alter striatal homeostasis by increasing extrasynaptic NMDA receptors. These findings may be relevant to manipulate disorders characterised by elevated dopaminergic activity.

Brain information processing complexity is conventionally recognized as derived from neuronal activity, with neurons and their dynamic signalling responsible for the transfer and processing of information. However, the brain also contains other non-neuronal cells, glial cells, which exceed the number of neurons and are involved in the processes related with information coding by neural networks and underlying brain functions. Decisive advances in the characterization of the molecular and physiological properties of glial cells shed light on their active roles in neurotransmission and neuronal physiopathology. This expanded relationship between neurons and glia challenges traditional neurobiology by highlighting their reciprocal influence, where it is difficult to determine whether neuronal or glial processes initiate and drive the interactions. This interplay creates a dilemma, where the causal hierarchy between these two cell types remains unresolved. A philosophical tool, the 'Theory of Complexity' of Edgard Morin can help to better explain and study the complexity of neuron-glia interactions. Morin's proposal on complexity is useful to transform brain knowledge, in order to review the brain molecular functions in antireductionist pattern. In this manuscript, we will discuss how to use the 'retroactive loop' principle from Morin's 'Theory of Complexity' at the brain molecular level, proposing a new philosophical-experimental grid that can help neuroscientists for a better understanding of the glia-neuron interactions in the brain.

Selenium (Se) is an essential trace element of the utmost importance to human health. Its deficiency induces various disorders. Se species can be absorbed by organisms and metabolized to hydrogen selenide for the biosynthesis of selenoproteins, selenonucleic acids, or selenosugars. Se in mammals mainly acts as selenoproteins to exert their biological functions. The brain ranks highest in the specific hierarchy of organs to maintain the level of Se and the expression of selenoproteins under the circumstances of Se deficiency. Dyshomeostasis of Se and dysregulation of selenoproteins result in encephalopathy such as Alzheimer's disease, Parkinson's disease, depression, amyotrophic lateral sclerosis, and multiple sclerosis. This review provides a summary and discussion of Se metabolism, selenoprotein function, and their roles in modulating brain diseases based on the most currently published literature. It focuses on how Se is utilized and transported to the brain, how selenoproteins are biosynthesized and function physiologically in the brain, and how selenoproteins are involved in neurodegenerative diseases. At the end of this review, the perspectives and problems are outlined regarding Se and selenoproteins in the regulation of encephalopathy.

Chimera states and bump states are collective synchronization phenomena observed independently (in different parameter regions) in networks of coupled nonlinear oscillators. And while chimera states are characterized by coexistence of coherent and incoherent domains, bump states consist of alternating active and inactive domains. The idea of multistable plasticity in the network connections originates from brain dynamics where the strength of the synapses (axons) connecting the network nodes (neurons) may change dynamically in time; when reaching the steady state the network connections may be found in one of many possible values depending on various factors, such as local connectivity, influence of neighboring cells etc. The sign of the link weights is also a significant factor in the network dynamics: positive weights are characterized as excitatory connections and negative ones as inhibitory. In the present study we consider the simplest case of bistable plasticity, where the link dynamics has only two fixed points. During the system/network integration, the link weights change and as a consequence the network organizes in excitatory or inhibitory domains characterized by different synaptic strengths. We specifically explore the influence of bistable plasticity on collective synchronization states and we numerically demonstrate that the dynamics of the linking may, under special conditions, give rise to co-existence of bump-like and chimera-like states simultaneously in the network. In the case of bump and chimera co-existence, confinement effects appear: the different domains stay localized and do not travel around the network. Memory effects are also reported in the sense that the final spatial arrangement of the coupling strengths reflects some of the local properties of the initial link distribution. For the quantification of the system's spatial and temporal features, the global and local entropy functions are employed as measures of the network organization, while the average firing rates account for the network evolution and dynamics. In particular, the spatial minima of the local entropy designate the transition points between domains of different synaptic weights in the hybrid states, while the number of minima corresponds to the number of different domains. In addition, the entropy deviations signify the presence of chimera-like or bump-like states in the network.

In university students with depressive symptoms, inhibitory control dysfunctions strongly contribute to functional impairments, yet they are not adequately addressed in current therapies. This study aims to investigate the intervention effect of an 8-week Taekwondo exercise program on inhibitory control in individuals with depressive symptoms.

A total of 41 university students with depressive symptoms were randomly divided into a Taekwondo group and a control group. The Taekwondo group participated in an 8-week intervention. Behavioral and ERP measures were collected before and after the intervention during a response inhibition task.

1.The 8-week Taekwondo exercise intervention significantly improved depressive symptoms in the exercise group (P < 0.05), while depressive symptoms in the control group worsened, although the difference was not statistically significant;2.The results from the behavioral task showed a statistically significant difference in accuracy between the Taekwondo group and the control group in the Go condition during the post-test stage (P < 0.05). In the Nogo condition, there was also a significant difference in accuracy between the two groups (P < 0.05). Notably, only the Taekwondo group exhibited a significant improvement in Nogo condition accuracy from pre-test to post-test (P < 0.001);3.The event-related potential (ERP) results revealed a significant time × group interaction effect for N2 amplitude, F(1, 39) = 4.821, P = 0.034, ƞp2=0.110. Additionally, there was a significant condition × electrode interaction effect, F(3, 117) = 18.368, P < 0.001, ƞp2= 0.320. For N2 latency, the time × group interaction effect was significant, F(1, 39) = 13.028, P < 0.001, ƞp2=0.250, and a significant time × condition × electrode interaction effect was also observed, F(3, 117) = 3.199, P = 0.026, ƞp2 = 0.076.

Regular moderate-intensity Taekwondo exercise can effectively improve response inhibition in university students with depressive symptoms, along with improvements in depressive symptoms. The changes in N2 amplitude and latency at the Fz, Cz, and Pz electrode sites under task conditions may represent the cognitive neural processing mechanism through which Taekwondo enhances response inhibition in students with depressive symptoms.

Neocortical circuits use synaptic and intrinsic forms of homeostatic plasticity to stabilize key features of network activity, but whether these different homeostatic mechanisms act redundantly, or can be independently recruited to stabilize different network features, is unknown. Here we used pharmacological and genetic perturbations both in vitro and in vivo to determine whether synaptic scaling and intrinsic homeostatic plasticity (IHP) are arranged and recruited in a hierarchical or modular manner within L2/3 pyramidal neurons in rodent V1. Surprisingly, although the expression of synaptic scaling and IHP was dependent on overlapping signaling pathways, they could be independently recruited by manipulating spiking activity or NMDAR signaling, respectively. Further, we found that changes in visual experience that affect NMDAR activation but not mean firing selectively trigger IHP, without recruiting synaptic scaling. These findings support a modular model in which synaptic and intrinsic homeostatic plasticity respond to and stabilize distinct aspects of network activity.

Long-term plasticity at pyramidal cell to basket cell (PC → BC) synapses is important for the functioning of cortical microcircuits. It is well known that at neocortical PC → PC synapses, dendritic calcium (Ca2+) dynamics signal coincident pre-and postsynaptic spiking which in turn triggers long-term potentiation (LTP). However, the link between dendritic Ca2+ dynamics and long-term plasticity at PC → BC synapses of primary visual cortex (V1) is not as well known. Here, we explored if PC → BC synaptic plasticity in developing V1 is sensitive to postsynaptic spiking. Two-photon (2P) Ca2+ imaging revealed that action potentials (APs) in dendrites of V1 layer-5 (L5) BCs back-propagated decrementally but actively to the location of PC → BC putative synaptic contacts. Pairing excitatory inputs with postsynaptic APs elicited dendritic Ca2+ supralinearities for pre-before-postsynaptic but not post-before-presynaptic temporal ordering, suggesting that APs could impact synaptic plasticity. In agreement, extracellular stimulation as well as high-throughput 2P optogenetic mapping of plasticity both revealed that pre-before-postsynaptic but not post-before-presynaptic pairing resulted in anti-Hebbian long-term depression (LTD). Our results demonstrate that V1 BC dendritic Ca2+ nonlinearities and synaptic plasticity at PC → BC connections are both sensitive to somatic spiking.

Neurodegenerative diseases such as Alzheimer's and Parkinson's diseases are among the leading causes of physical and cognitive disability across the globe. Fifty million people worldwide suffer these diseases, and that number is expected to rise as the population ages. Ictus is another pathology that also courses with neurodegeneration and is a leading cause of mortality and long-term disability in developed countries. Schizophrenia is not as common as other mental disorders, affecting approximately 24 million people worldwide. All these disorders have in common that still there is not an effective pharmacological treatment to cure them. The N-methyl-D-aspartate (NMDA) receptor (NMDAR) has attracted attention as a potential therapeutic target due to its important role in learning and memory and also due to its implication in excitotoxicity processes. Some drugs targeting NMDARs are already being used to treat symptoms of disorders affecting the central nervous system (CNS). Here, we aim to review the implications of NMDAR in these CNS pathologies, its role as a potential therapeutic target, and the future perspectives for developing new treatments focused on these receptors.

Friedreich ataxia (FRDA) is an autosomal recessive disorder caused by GAA expansions in the FXN gene, which codes for the protein frataxin (FXN). These mutations reduce FXN expression, leading to mitochondrial dysfunction and multisystemic disease. Accumulating evidence suggests that neuronal dysfunction, rather than neuronal death, may drive the neurological phenotypes of FRDA, but the mechanisms underlying such neurological phenotypes remain unclear. To investigate the neural circuit basis of this dysfunction, we employed field recordings to measure Purkinje cell (PC) function and synaptic properties along with western blotting and immunohistochemistry to determine their density and structure in two established FRDA mouse models, the shRNA-frataxin (FRDAkd) and the frataxin knock in-knockout (KIKO) mice. Western blotting demonstrated subtle changes in mitochondrial proteins and only a modest reduction in the density of calbindin positive cells PCs in the cerebellar cortex of the FRDAkd mice, with no change in the density of PCs in the KIKO mice. Though PC density differed slightly in the two models, field recordings of parallel fiber-PC synapses in the molecular layer demonstrated concordant hypo-excitability of basal synaptic transmission and impairments of long-term plasticity using induction protocols associated with both potentiation and depression of synaptic strength. These results indicate that synaptic instability might be a common feature in FRDA mouse models.

Over the past decade, research has shown that the primary motor cortex (M1), the brain's main output for movement, also responds to rewards. These reward signals may shape motor output in its final stages, influencing movement invigoration and motor learning. In this Perspective, we highlight the functional roles of M1 reward signals and propose how they could guide advances in neurotechnologies for movement restoration, specifically brain-computer interfaces and non-invasive brain stimulation. Understanding M1 reward signals may open new avenues for enhancing motor control and rehabilitation.

Parkinson's disease (PD), an age-associated neurodegenerative motor disorder, is associated with dementia and cognitive decline. However, the precise molecular insight into PD-induced cognitive decline is not fully understood. Here, we have investigated the possible alterations in the expression of glutamate receptor and its trafficking/scaffolding/regulatory proteins underlying the memory formation and neuroprotective effects of a specialized Bacopa monnieri extract, CDRI-08 (BME) in the hippocampus of the rotenone-induced PD mouse model. Our Western blotting and qRT-PCR data reveal that the PD-induced recognition memory decline is associated with significant upregulation of the AMPA receptor subunit GluR1 and downregulation of GluR2 subunit genes in the hippocampus of rotenone-affected mice as compared to the vehicle control. Further, expressions of the trafficking proteins are significantly upregulated in the hippocampus of rotenone-affected mice compared to the vehicle control. Our results also reveal that the above alterations in the hippocampus are associated with similar expression patterns of total CREB, pCREB, and BDNF. BME (CDRI-08, 200 mg/kg BW) reverses the expression of AMPA receptor subunits, their trafficking proteins differentially, and the transcriptional modulatory proteins depending on whether the BME treatment was given before or after the rotenone treatment. Our data suggest that expression of the above genes is significantly reversed in the BME pre-treated mice subjected to rotenone treatment towards their levels in the control mice compared to its treatment after rotenone administration. Our results provide the possible molecular basis underlying the rotenone-induced recognition memory decline, conditions mimicking the PD symptoms in mouse model and neuroprotective action of bacoside A and bacoside B (58%)-enriched Bacopa monnieri extract (BME) in the hippocampus.

High-frequency stimulation (HFS)-induced long-term potentiation (LTP) is generally regarded as a homosynaptic Hebbian-type LTP, where synaptic changes are thought to occur at the synapses that project from the stimulation site and terminate onto the neurons at the recording site. In this study, we first investigated HFS-induced LTP on urethane-anesthetized rats and found that cortical HFS enhances neural responses at the recording site through the strengthening of local connectivity with nearby neurons at the stimulation site rather than through synaptic strengthening at the recording site. This enhanced local connectivity at the stimulation site leads to increased output propagation, resulting in signal potentiation at the recording site. Additionally, we discovered that HFS can also nonspecifically strengthen distant afferent synapses at the HFS site, thereby expanding its impact beyond local neural connections. This form of plasticity exhibits a neo-Hebbian characteristic as it exclusively manifests in the presence of cholecystokinin release, induced by HFS. The cortical HFS-induced local LTP was further supported by a behavioral task, providing additional evidence. Our results unveil a previously overlooked mechanism underlying cortical plasticity: synaptic plasticity is more likely to occur around the soma site of strongly activated cortical neurons rather than solely at their projection terminals.

Alzheimer's disease is a neurodegenerative disease resulting from deficits in synaptic transmission and homeostasis. The Alzheimer's disease brain tends to be hyperexcitable and hypersynchronized, thereby causing neurodegeneration and ultimately disrupting the operational abilities in daily life, leaving patients incapacitated. Repetitive transcranial magnetic stimulation is a cost-effective, neuro-modulatory technique used for multiple neurological conditions. Over the past two decades, it has been widely used to predict cognitive decline; identify pathophysiological markers; promote neuroplasticity; and assess brain excitability, plasticity, and connectivity. It has also been applied to patients with dementia, because it can yield facilitatory effects on cognition and promote brain recovery after a neurological insult. However, its therapeutic effectiveness at the molecular and synaptic levels has not been elucidated because of a limited number of studies. This study aimed to characterize the neurobiological changes following repetitive transcranial magnetic stimulation treatment, evaluate its effects on synaptic plasticity, and identify the associated mechanisms. This review essentially focuses on changes in the pathology, amyloidogenesis, and clearance pathways, given that amyloid deposition is a major hypothesis in the pathogenesis of Alzheimer's disease. Apoptotic mechanisms associated with repetitive transcranial magnetic stimulation procedures and different pathways mediating gene transcription, which are closely related to the neural regeneration process, are also highlighted. Finally, we discuss the outcomes of animal studies in which neuroplasticity is modulated and assessed at the structural and functional levels by using repetitive transcranial magnetic stimulation, with the aim to highlight future directions for better clinical translations.

Understanding how neuronal circuits stabilize their activity is a fundamental yet poorly understood aspect of neuroscience. Here, we show that hippocampal network properties, such as firing rate distribution and dimensionality, are actively regulated, despite perturbations and single-cell drift. Continuous inhibition of N-methyl-D-aspartate receptors (NMDARs) ex vivo lowers the excitation/inhibition ratio and network firing rates while preserving resilience to perturbations. This establishes a new network firing rate set point via NMDAR-eEF2K signaling pathway. NMDARs' capacity to modulate and stabilize network firing is mediated by excitatory synapses and the intrinsic excitability of parvalbumin-positive neurons, respectively. In behaving mice, continuous NMDAR blockade in CA1 reduces network firing without altering single-neuron drift or triggering a compensatory response. These findings expand NMDAR function beyond their canonical role in synaptic plasticity and raise the possibility that some NMDAR-dependent behavioral effects are mediated by their unique regulation of population activity set points.

Neuropeptide-S (NPS) has been demonstrated to mitigate learning and memory deficits in experimental models of Parkinson's Disease (PD). Despite this, the precise mechanisms through which NPS exerts its influence on cognitive functions remain to be fully unknown. This study aims to elucidate the effects of central administration of NPS on learning and memory deficits associated with an experimental rat hemiparkinsonian model, examining both electrophysiological and molecular parameters. The hemiparkinsonian model was established via stereotactic injection of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle. Central NPS (1 nmol, icv) was administered into the lateral ventricle via a cannula for seven consecutive days following the 6-OHDA lesion. The Morris water maze and object recognition tests were used to evaluate the rat's learning and memory abilities. Long-term potentiation (LTP) recordings were conducted to assess hippocampal synaptic plasticity. Immunohistochemistry was employed to determine the expression levels of phosphorylated CaMKII (pCaMKII), GluR1, and GluR2 in the hippocampus. The 6-OHDA-induced decline in cognitive performance was significantly (p < 0.05) improved in rats that received central NPS. In 6-OHDA-lesioned rats, NPS treatment significantly (p < 0.05) enhanced the amplitude of LTP at the dentate gyrus/perforant path synapses. Furthermore, NPS significantly (p < 0.05) increased the number of pCaMKII and GluR1 immunoreactive cells in the hippocampus, which had been diminished due to 6-OHDA, except for GluR2 levels. These findings provide insight into the mechanisms by which central NPS administration enhances cognitive functions in an experimental model of PD, highlighting its potential therapeutic benefits for addressing cognitive deficits in PD.

In response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in animal models and human patients. However, whether mechanisms of homeostatic plasticity are engaged in sensory neurons of the peripheral nervous system (PNS) is unknown. Here, we show that sustained depolarization (induced by 24-h incubation in 30 mM KCl) induces compensatory changes that decrease the excitability of mouse and human sensory neurons without directly opposing membrane depolarization. Voltage-clamp recordings show that sustained depolarization produces no significant alteration in voltage-gated potassium currents, but a robust reduction in voltage-gated sodium currents, likely contributing to the overall decrease in neuronal excitability. The compensatory decrease in neuronal excitability and reduction in voltage-gated sodium currents reversed completely following a 24-h recovery period in a normal medium. Similar adaptive changes were not observed in response to 24 h of sustained action potential firing induced by optogenetic stimulation at 1 Hz, indicating the need for prolonged depolarization to drive engagement of this adaptive mechanism in sensory neurons. Our findings show that mouse and human sensory neurons are capable of engaging adaptive mechanisms to regulate intrinsic excitability in response to sustained depolarization in a manner similar to that described in neurons in the central nervous system.

Neuronal gene expression in the brain dynamically responds to synaptic activity. The interplay among synaptic activity, gene expression, and synaptic plasticity has crucial implications for understanding the pathophysiology of diseases such as Alzheimer's disease and epilepsy. These diseases are marked by synaptic dysfunction that affects the expression patterns of neuroprotective genes that are incompletely understood. In our study, we developed a cellular model of synaptic activity using human cholinergic neurons derived from SH-SY5Y cell differentiation. Depolarization induction modulates the expression of neurotrophic genes and synaptic markers, indicating a potential role in synaptic plasticity regulation. This hypothesis is further supported by the induction kinetics of various long non-coding RNAs, including primate-specific ones. Our experimental model showcases the utility of SH-SY5Y cells in elucidating the molecular mechanisms underlying synaptic plasticity in human cellular systems.

A central question in neuroscience is how synaptic plasticity shapes the feature selectivity of neurons in behaving animals1. Hippocampal CA1 pyramidal neurons display one of the most striking forms of feature selectivity by forming spatially and contextually selective receptive fields called place fields, which serve as a model for studying the synaptic basis of learning and memory. Various forms of synaptic plasticity have been proposed as cellular substrates for the emergence of place fields. However, despite decades of work, our understanding of how synaptic plasticity underlies place-field formation and memory encoding remains limited, largely due to a shortage of tools and technical challenges associated with the visualization of synaptic plasticity at the single-neuron resolution in awake behaving animals. To address this, we developed an all-optical approach to monitor the spatiotemporal tuning and synaptic weight changes of dendritic spines before and after the induction of a place field in single CA1 pyramidal neurons during spatial navigation. We identified a temporally asymmetric synaptic plasticity kernel resulting from bidirectional modifications of synaptic weights around the induction of a place field. Our work identified compartment-specific differences in the magnitude and temporal expression of synaptic plasticity between basal dendrites and oblique dendrites. Our results provide experimental evidence linking synaptic plasticity to the rapid emergence of spatial selectivity in hippocampal neurons, a critical prerequisite for episodic memory.

A decline in hippocampal function has long been associated with the progression of cognitive impairments in patients with Alzheimer's disease (AD). The disruption of hippocampal synaptic plasticity [primarily the reduction of long-term potentiation LTP] by excess production of soluble beta-amyloid (Aβ) has long been accepted as the mechanism by which AD pathology impairs memory, at least during the early stages of AD pathogenesis. However, the premise that hippocampal LTP underpins the formation of associative, long-term memories has been challenged. Here, we consider evidence that this canonical view of LTP needs to be refined. Similarly, the view that the hippocampus simply supports memory ignores the wealth of data showing that the hippocampus is functionally heterogeneous along its septo-temporal axis. The ventral (but not the dorsal) hippocampus plays a major role in modulating emotional reactions to conflict. Here, we suggest that hippocampal LTP is not involved in forming long-term associative memories, but instead contributes to the disambiguation of overlapping memories in situations of conflict and associative interference. This conceptualisation of hippocampal synaptic plasticity may help explain how early-stage AD pathology may impact both memory and anxiety.

Endosomes are crucial sites for intracellular material sorting and transportation. Endosomal transport is a critical process involved in the selective uptake, processing, and intracellular transport of substances. The equilibrium between endocytosis and circulation mediated by the endosome-centered transport pathway plays a significant role in cell homeostasis, signal transduction, and immune response. In recent years, there have been hints linking endosomal transport abnormalities to neurodegenerative diseases, including Alzheimer's disease. Nonetheless, the related mechanisms remain unclear. Here, we provide an overview of endosomal-centered transport pathways and highlight potential physiological processes regulated by these pathways, with a particular focus on the correlation of endosomal trafficking disorders with common pathological features of neurodegenerative diseases. Additionally, we summarize potential therapeutic agents targeting endosomal trafficking for the treatment of neurodegenerative diseases.

In recent years, evidence supporting non-ionotropic signalling by the NMDA receptor (niNMDAR) has emerged, including roles in long-term depression (LTD). Here, we investigated whether niNMDAR-pannexin-1 (Panx1) contributes to LTD at the CA3-CA1 hippocampal synapse. Using whole-cell, patch clamp electrophysiology in rat hippocampal slices, we show that a low-frequency stimulation (3 Hz) of the Schaffer collaterals produces LTD that is blocked by continuous but not transient application of the NMDAR competitive antagonist, MK-801. After transient MK-801, LTD involved pannexin-1 and sarcoma (Src) kinase. We show that pannexin-1 is not permeable to Ca2+, but probably releases ATP to induce LTD via P2X4 purinergic receptors because LTD after transient MK-801 application was prevented by 5-BDBD. Thus, we conclude that niNMDAR activation of Panx1 can link glutamatergic and purinergic pathways to produce LTD following low frequency synaptic stimulation when NMDARs are transiently inhibited. KEY POINTS: Differential effect of short-term D-APV and MK-801 application on long-term depression (LTD) suggests that the NMDA receptor (niNMDAR) contributes to later phases of synaptic depression. niNMDAR LTD involved sarcoma (Src) kinase and pannexin-1 (Panx1), which is a pathway previously identified to be active during excitotoxicity. Panx1 was not calcium permeable but may contribute to late phase LTD via ATP release. Panx1 blockers prevent LTD, and this was rescued with exogenous ATP application. Inhibition of LTD with 5-BDBD suggests the downstream involvement of postsynaptic P2X4 receptors.

Alzheimer's disease (AD), the most common form of dementia among the elderly, affects numerous individuals worldwide. Despite advances in understanding the molecular underpinnings of AD pathology, effective treatments to prevent or cure the disease remain elusive. AD is characterized not only by pathological hallmarks such as amyloid plaques and neurofibrillary tangles but also by impairments in synaptic physiology, circuit activity and cognitive function. Synaptic homeostatic plasticity plays a vital role in maintaining the stability of synaptic and neural functions amid genetic and environmental disturbances. A key component of this regulation is presynaptic homeostatic potentiation, where increased presynaptic neurotransmitter release compensates for reduced postsynaptic glutamate receptor functionality, thereby stabilizing neuronal excitability. The role of presynaptic homeostatic plasticity in synapse stabilization in AD, however, remains unclear. Moreover, recent advances in transcriptomics have illuminated the complex roles of glial cells in regulating synaptic function in ageing brains and in the progression of neurodegenerative diseases. Yet, the impact of AD-related abnormalities in glial signalling on synaptic homeostatic plasticity has not been fully delineated. This review discusses recent findings on how glial dysregulation in AD affects presynaptic homeostatic plasticity. There is increasing evidence that disrupted glial signalling, particularly through aberrant histone acetylation and transcriptomic changes in glia, compromises this plasticity in AD. Notably, the sphingosine signalling pathway has been identified as being protective in stabilizing synaptic physiology through epigenetic and homeostatic mechanisms, presenting potential therapeutic targets for treating neurodegenerative disorders.

Impulsivity is a broad construct that often refers to one of several distinct behaviors and can be measured with self-report questionnaires and behavioral paradigms. Several psychiatric conditions are characterized by one or more forms of impulsive behavior, most notably the impulsive/hyperactive subtype of attention-deficit/hyperactivity disorder (ADHD), mood disorders, and substance use disorders. Monoaminergic neurotransmitters are known to mediate impulsive behaviors and are implicated in various psychiatric conditions. However, growing evidence suggests that glutamate, the major excitatory neurotransmitter of the mammalian brain, regulates important functions that become dysregulated in conditions like ADHD. The purpose of the current review is to discuss clinical and preclinical evidence linking glutamate to separate aspects of impulsivity, specifically motor impulsivity, impulsive choice, and affective impulsivity. Hyperactive glutamatergic activity in the corticostriatal and the cerebro-cerebellar pathways are major determinants of motor impulsivity. Conversely, hypoactive glutamatergic activity in frontal cortical areas and hippocampus and hyperactive glutamatergic activity in anterior cingulate cortex and nucleus accumbens mediate impulsive choice. Affective impulsivity is controlled by similar glutamatergic dysfunction observed for motor impulsivity, except a hyperactive limbic system is also involved. Loss of glutamate homeostasis in prefrontal and nucleus accumbens may contribute to motor impulsivity/affective impulsivity and impulsive choice, respectively. These results are important as they can lead to novel treatments for those with a condition characterized by increased impulsivity that are resistant to conventional treatments.

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.

The ability to coactivate (or "superpose") multiple conceptual representations is a fundamental function that we constantly rely upon; this is crucial in complex cognitive tasks requiring multi-item working memory, such as mental arithmetic, abstract reasoning, and language comprehension. As such, an artificial system aspiring to implement any of these aspects of general intelligence should be able to support this operation. I argue here that standard, feed-forward deep neural networks (DNNs) are unable to implement this function, whereas an alternative, fully brain-constrained class of neural architectures spontaneously exhibits it. On the basis of novel simulations, this proof-of-concept article shows that deep, brain-like networks trained with biologically realistic Hebbian learning mechanisms display the spontaneous emergence of internal circuits (cell assemblies) having features that make them natural candidates for supporting superposition. Building on previous computational modelling results, I also argue that, and offer an explanation as to why, in contrast, modern DNNs trained with gradient descent are generally unable to co-activate their internal representations. While deep brain-constrained neural architectures spontaneously develop the ability to support superposition as a result of (1) neurophysiologically accurate learning and (2) cortically realistic between-area connections, backpropagation-trained DNNs appear to be unsuited to implement this basic cognitive operation, arguably necessary for abstract thinking and general intelligence. The implications of this observation are briefly discussed in the larger context of existing and future artificial intelligence systems and neuro-realistic computational models.

Emotional arousal is caused by the activity of two parallel ascending systems targeting mostly the subcortical limbic regions and the prefrontal cortex. The aversive, negative arousal system is initiated by the activity of the mesolimbic cholinergic system and the hedonic, appetitive, arousal is initiated by the activity of the mesolimbic dopaminergic system. Both ascending projections have a diffused nature and arise from the rostral, tegmental part of the brain reticular activating system. The mesolimbic cholinergic system originates in the laterodorsal tegmental nucleus and the mesolimbic dopaminergic system in the ventral tegmental area. Cholinergic and dopaminergic arousal systems have converging input to the medial prefrontal cortex. The arousal system can modulate cortical EEG with alpha rhythms, which enhance synaptic strength as shown by an increase in long-term potentiation (LTP), whereas delta frequencies are associated with decreased arousal and a decrease in synaptic strength as shown by an increase in long-term depotentiation (LTD). It is postulated that the medial prefrontal cortex is an adaptable node with decision making capability and may control the switch between positive and negative affect and is responsible for modifying or changing emotional state and its expression.

Neuroplasticity refers to functional and structural changes in brain regions in response to healthy and pathological activity. Activity dependent plasticity induced by epileptic activity can involve healthy brain regions into the epileptogenic network by perturbing their excitation/inhibition balance. In this article, we present a new neural mass model, which accounts for neuroplasticity, for investigating the possible mechanisms underlying the epileptogenic network expansion. Our multiple-timescale model is inspired by physiological calcium-mediated synaptic plasticity and pathological extrasynaptic N-methyl-D-aspartate (NMDA) dependent plasticity dynamics. The model highlights that synaptic plasticity at excitatory connections and structural changes in the inhibitory system can transform a healthy region into a secondary epileptic focus under recurrent seizures and interictal activity occurring in the primary focus. Our results suggest that the latent period of this transformation can provide a window of opportunity to prevent the expansion of epileptogenic networks, formation of an epileptic focus, or other comorbidities associated with epileptic activity.

The brain has the powerful ability to transform experiences into anatomic maps and continuously integrate massive amounts of information to form new memories. The manner in which the brain performs these processes has been investigated extensively for decades. Emerging reports suggest that dendritic spines are the structural basis of information storage. The complex orchestration of functional and structural dynamics of dendritic spines is associated with learning and memory. Owing to advancements in techniques, more precise observations and manipulation enable the investigation of dendritic spines and provide clues to the challenging question of how memories reside in dendritic spines. In this review, we summarize the remarkable progress made in revealing the role of dendritic spines in fear memory and the techniques used in this field.

A wide number of natural molecules demonstrated neuroprotective effects on synaptic plasticity defects induced by amyloid-β (Aβ) in ex vivo and in vivo Alzheimer's disease (AD) models, suggesting a possible use in the treatment of this neurodegenerative disorder. However, several compounds, administered parenterally and orally, are unable to reach the brain due to the presence of the blood-brain barrier (BBB) which prevents the passage of external substances, such as proteins, peptides, or phytocompounds, representing a limit to the development of treatment for neurodegenerative diseases, such as AD. The combination of nano vesicular systems, as colloidal systems, and nose to brain (NtB) delivery depicts a new nanotechnological strategy to overtake this limit and to develop new treatment approaches for brain diseases, including the use of natural molecules in combination therapy for AD. Herein, we will provide an updated overview, examining the literature of the last 20 years and using specific keywords that provide evidence on natural products with the ability to restore synaptic plasticity alterations in AD models, and the possible application using safe and non-invasive strategies focusing on nano vesicular systems for NtB delivery.

Experimental studies show improvement in physical performance following acute application of transcranial direct current stimulation (tDCS). This study examined the neuromuscular and neural responses to a single training session (Part 1) and following a 3 wk resistance training program (Part 2) performed with the knee extensors, preceded by tDCS over the primary motor cortex. Twenty-four participants (age, 30 ± 7 yr; stature, 172 ± 8 cm; mass, 72 ± 15 kg) were randomly allocated to perform either resistance training with anodal tDCS (a-tDCS) or a placebo tDCS (Sham). Resistance training consisted of 3 × 10 isometric contractions of 3 s at 75% maximal voluntary contraction (MVC). Measures of neuromuscular function (MVC, voluntary activation, and potentiated twitch force), corticospinal excitability, along with short and long cortical inhibition were assessed. Acute tDCS did not affect neuromuscular and neural responses to a single training session (all P ≥ 0.10). Conversely, after the 3 wk training program, MVC increased in both groups (P < 0.01) with a greater increase observed for a-tDCS vs. Sham (∼6%, P = 0.04). Additionally, increased voluntary activation (∼2%, P = 0.04) and corticospinal excitability (∼22%, P = 0.04), accompanied by a shorter silent period (-13%, P = 0.04) were found after a-tDCS vs. Sham. The potentiated twitch force and measures of short and long cortical inhibition did not change after the training program (all P ≥ 0.29). Pretraining administration of tDCS only resulted in greater neuromuscular adaptations following 3 wk of resistance training. These results provide new evidence that tDCS facilitates adaptations to resistance training in healthy individuals.NEW & NOTEWORTHY The initial increase in maximal strength during resistance training is attributed to neural adaptations. Acute administration of transcranial direct current stimulation (tDCS) has been shown to improve motor function and neural adaptations in healthy and clinical populations. This study measured the neuromuscular and neural response to acute (single training session) and short-term (3 wk) resistance training with tDCS. Greater neuromuscular and neural adaptations were only found following 3 wk of resistance training.

The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer's disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirements. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB1R, astrocyte activity, and glutamate released by astrocytes. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses.

Neurostimulation protocols are increasingly used as therapeutic interventions, including for brain injury. In addition to the direct activation of neurons, these stimulation protocols are also likely to have downstream effects on those neurons' synaptic outputs. It is well known that alterations in the strength of synaptic connections (long-term potentiation, LTP; long-term depression, LTD) are sensitive to the frequency of stimulation used for induction; however, little is known about the contribution of the temporal pattern of stimulation to the downstream synaptic plasticity that may be induced by neurostimulation in the injured brain. We explored interactions of the temporal pattern and frequency of neurostimulation in the normal cerebral cortex and after mild traumatic brain injury (mTBI), to inform therapies to strengthen or weaken neural circuits in injured brains, as well as to better understand the role of these factors in normal brain plasticity. Whole-cell (WC) patch-clamp recordings of evoked postsynaptic potentials in individual neurons, as well as field potential (FP) recordings, were made from layer 2/3 of visual cortex in response to stimulation of layer 4, in acute slices from control (naive), sham operated, and mTBI rats. We compared synaptic plasticity induced by different stimulation protocols, each consisting of a specific frequency (1 Hz, 10 Hz, or 100 Hz), continuity (continuous or discontinuous), and temporal pattern (perfectly regular, slightly irregular, or highly irregular). At the individual neuron level, dramatic differences in plasticity outcome occurred when the highly irregular stimulation protocol was used at 1 Hz or 10 Hz, producing an overall LTD in controls and shams, but a robust overall LTP after mTBI. Consistent with the individual neuron results, the plasticity outcomes for simultaneous FP recordings were similar, indicative of our results generalizing to a larger scale synaptic network than can be sampled by individual WC recordings alone. In addition to the differences in plasticity outcome between control (naive or sham) and injured brains, the dynamics of the changes in synaptic responses that developed during stimulation were predictive of the final plasticity outcome. Our results demonstrate that the temporal pattern of stimulation plays a role in the polarity and magnitude of synaptic plasticity induced in the cerebral cortex while highlighting differences between normal and injured brain responses. Moreover, these results may be useful for optimization of neurostimulation therapies to treat mTBI and other brain disorders, in addition to providing new insights into downstream plasticity signaling mechanisms in the normal brain.