Long-term Potentiation Research Articles

Role of brain-derived neurotrophic factor in dysfunction of short-term to long-term memory transformation after surgery and anaesthesia in older mice.

Memory decline is one of the main manifestations in perioperative neurocognitive disorder. Short-term memory (STM) to long-term memory (LTM) transformation is one aspect of memory consolidation. Early-phase long-term potentiation (E-LTP) to late-phase long-term potentiation (L-LTP) is the molecular correlate of STM to LTM transformation. We examined whether the STM to LTM transformation was impaired after anaesthesia and surgery in older mice. Optogenetics and chemogenetics were used to confirm the role of Vglut1+ glutamatergic neurones in the STM to LTM transformation in older mice. Synaptosomes were isolated to analyse expression of brain-derived neurotrophic factor (BDNF). Golgi-Cox staining and hippocampal field potential recordings were also used to measure synaptic plasticity. We found that the STM to LTM and E-LTP to L-LTP transformations were impaired after anaesthesia and surgery in older mice, and Vglut1+ excitatory neurone activity in the hippocampal CA1 region was reduced. BDNF expression decreased in the postsynaptic fraction, especially in Vglut1+ neurones, whereas cell-type specific overexpression of BDNF in Vglut1+ neurones reversed postoperative STM to LTM transformation dysfunction in older mice. Reduced BDNF expression was involved in anaesthesia and surgery-induced impairment of the STM to LTM transition involving glutamatergic neurones in the hippocampal CA1 region of older mice. This provides a potential target that might be helpful for understanding and developing treatments for postoperative neurocognitive dysfunction.

Bidirectional synapse based on anti-resonance modulation of a photonic microring

A synaptic device is fundamental for memory and learning functions of neural networks. In this work, we demonstrated a GST (Ge2Sb2Te5)-based microring synapse with nonvolatile reconfigurable characteristics. The device shows bidirectional weight modulation during unidirectional crystallization or amorphization of GST, simulating long-term depression (LTD) and long-term potentiation (LTP). In addition, we adopted an anti-resonance pump scheme to reduce the fluctuations in pump energy coupled into the device to less than 12%. This scheme significantly enhances the programming precision of the microring synapse, achieving 24 resolvable states over 15 cycles. This work holds promise for laying the foundation for novel, to the best of our knowledge, photonic computing architectures and provides possibilities for the implementation of vision and adaptive optical neural networks that rely on bidirectional plasticity.

Reconfigurable Organic Electrochemical Transistors with High Dynamic Ranges for Fully Integrated Physical Reservoir Computing

AbstractReconfigurable organic electrochemical transistors (r‐OECTs) are considered a promising platform for fully integrated physical reservoir computing (RC) owing to their dual switching modes, which are suitable for both the reservoir and readout layers. However, their restricted dynamic ranges (DR) have constrained their nonlinearity, high‐dimensional mapping capacity, and the reconfigurability of neural networks for optimal physical RC. In this study, r‐OECTs with a modified PEDOT:PSS channel and solid electrolyte is designed and fabricated, achieving dual‐modal essential synaptic functions (nonvolatile and volatile) through ethylene glycol (EG) content adjustment. The r‐OECTs with the EG of 680 and 1000 µL exhibit exceptional DR of 1.12 × 10⁵ in nonvolatile mode and 1.20 × 103 volatile mode, respectively, representing a significant improvement over previously reported OECTs. The nonvolatile mode exhibits long‐term memory with robust and gradual long‐term potentiation (LTP) and long‐term depression (LTD), while the volatile mode demonstrates short‐term memory for extracting reservoir states. The r‐OECTs, functioning in two modes as the reservoir and readout layers with high DRs, enable accurate classification of human activities such as jogging (J), brushing teeth (B), and folding clothes (F) with an accuracy of 84.38% in a fully integrated physical RC system.

Inhibition of hippocampal interleukin-6 receptor-evoked signalling normalises long-term potentiation in dystrophin-deficient mdx mice.

Duchenne muscular dystrophy (DMD), an X-linked neuromuscular disorder, characterised by progressive immobility, chronic inflammation and premature death, is caused by the loss of the mechano-transducing signalling molecule, dystrophin. In non-contracting cells, such as neurons, dystrophin is likely to have a functional role in synaptic plasticity, anchoring post-synaptic receptors. Dystrophin-expressing hippocampal neurons are key to cognitive functions such as emotions, learning and the consolidation of memories. In the context of disease-induced chronic inflammation, we have explored the role of the pleiotropic cytokine, interleukin (IL)-6 in hippocampal dysfunction using immunofluorescence, electrophysiology and metabolic measurements in dystrophic mdx mice. Hippocampal long-term potentiation (LTP) of the Schaffer collateral-CA1 projections was suppressed in mdx slices. Given the importance of mitochondria-generated ATP in synaptic plasticity, reduced maximal respiration in the CA1 region may impact upon this process. Consistent with a role for IL-6 in this observation, early LTP was suppressed in dystrophin-expressing wildtype slices exposed to IL-6. In dystrophic mdx mice, exposure to IL-6 suppressed mitochondrial-mediated basal metabolism in CA1, CA3 and DG hippocampal regions. Furthermore, blocking IL-6-mediated signalling by administering neutralising monoclonal IL-6 receptor antibodies intrathecally, normalised LTP in mdx mice. The impact of dystrophin loss from the hippocampus was associated with modified cellular bioenergetics, which underpin energy-driven processes such as the induction of LTP. The additional challenge of pathophysiological levels of IL-6 resulted in altered cellular bioenergetics, which may be key to cognitive deficits associated with the loss of dystrophin.

Female mice exhibit similar long-term plasticity and microglial properties between the dorsal and ventral hippocampal poles

The hippocampus is a heterogenous structure that exhibits functional segregation along its longitudinal axis. We recently showed that in male mice, microglia, the brain’s resident immune cells, differ between the dorsal (DH) and ventral (VH) hippocampus, impacting long-term potentiation (LTP) mainly through the CX3CL1-CX3CR1 signaling. Here, we assessed the specific features of the hippocampal poles in female mice, demonstrating a similar LTP amplitude in VH and DH in both control and Cx3cr1 knock-out mice. In addition, the expression levels of Cx3cr1 and Cx3cl1 mRNA do not differ between the two poles in control mice. These data support the critical role of the CX3CL1-CX3CR1 signaling in setting the physiological amount of plasticity, equally between poles in females. Although BDNF is higher in DH compared to VH, the expression levels of inflammatory markers involved in plasticity and of phagocytosis markers in microglia are comparable between the two poles. In accordance, microglia soma and arborization area/perimeter, and microglial ultrastructure are similar across regions, with the exception of microglial density, cells arborization solidity and circularity that are higher in DH. Understanding the molecular processes underlying microglial sex differences and their potential implications for plasticity in specific brain regions is of major importance in physiological and pathological conditions.

Repeated social defeat in male mice induced unique RNA profiles in projection neurons from the amygdala to the hippocampus

Chronic stress increases the incidence of psychiatric disorders including anxiety, depression, and posttraumatic stress disorder. Repeated Social Defeat (RSD) in mice recapitulates several key physiological, immune, and behavioral changes evident after chronic stress in humans. For instance, neurons in the prefrontal cortex, amygdala, and hippocampus are involved in the interpretation of and response to fear and threatful stimuli after RSD. Therefore, the purpose of this study was to determine how stress influenced the RNA profile of hippocampal neurons and neurons that project into the hippocampus from threat appraisal centers. Here, RSD increased anxiety-like behavior in the elevated plus maze and reduced hippocampal-dependent novel object location memory in male mice. Next, pan-neuronal (Baf53b-Cre) RiboTag mice were generated to capture ribosomal bound mRNA (i.e., active translation) activated by RSD in the hippocampus. RNAseq revealed that there were 1,694 differentially expressed genes (DEGs) in hippocampal neurons after RSD. These DEGs were associated with an increase in oxidative stress, synaptic long-term potentiation, and neuroinflammatory signaling. To further examine region-specific neural circuitry associated with fear and anxiety, a retrograde-adeno-associated-virus (AAV2rg) expressing Cre-recombinase was injected into the hippocampus of male RiboTag mice. This induced expression of a hemagglutinin epitope in neurons that project into the hippocampus. These AAV2rg-RiboTag mice were subjected to RSD and ribosomal-bound mRNA was collected from the amygdala for RNA-sequencing. RSD induced 677 DEGs from amygdala projections. Amygdala neurons that project into the hippocampus had RNA profiles associated with increased synaptogenesis, interleukin-1 signaling, nitric oxide, and reactive oxygen species production. Using a similar approach, there were 1,132 DEGs in neurons that project from the prefrontal cortex. These prefrontal cortex neurons had RNA profiles associated with increased synaptogenesis, integrin signaling, and dopamine feedback signaling after RSD. Collectively, there were unique RNA profiles of stress-influenced projection neurons and these profiles were associated with hippocampal-dependent behavioral and cognitive deficits.

Abstract TP113: Cerebellar Intermittent Theta Burst Stimulation in Post-Stroke Gait Impairment: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Persistent gait impairments affect nearly half of stroke survivors six months post-stroke, despite standard rehabilitation. Intermittent theta burst stimulation (iTBS), a specialized form of repetitive transcranial magnetic stimulation (TMS), has shown promise in enhancing neural circuit activity and promoting long-term potentiation. While traditionally targeting the primary motor cortex, recent studies suggest that cerebellar iTBS may further improve gait and balance by modulating cerebello-cortical pathways. Aim: This meta-analysis aims to evaluate the efficacy of cerebellar iTBS in improving gait and balance in stroke patients. Methods: We conducted a systematic search in PubMed, Embase, and the Cochrane Library until August 2024, following the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Included studies were peer-reviewed randomized controlled trials (RCTs) that assessed the effects of cerebellar iTBS on balance, assessed using the Berg Balance Scale; gait, measured through 3D gait analysis and the Timed Up and Go (TUG) test; and activities of daily living, assessed via the Barthel Index, in post-stroke patients with persistent gait and balance impairments. Meta-analyses were performed using a random-effects model. Results: Seven RCTs involving a total of 230 post-stroke patients (iTBS group, n=115) were included in this meta-analysis. The analysis revealed a significant improvement in balance (standardized mean difference [SMD] = 1.20, 95% confidence interval [CI] 0.12 to 2.29, p = 0.03). However, the TUG test did not demonstrate a significant change (SMD = 0.04, 95% CI: -0.37–0.46, p = 0.83), potentially reflecting variability in baseline gait performance. The 3D gait analysis showed a favorable but non-significant trend towards step length improvement (SMD = 0.71, 95% CI: -0.82–2.23, p = 0.37). Notably, a significant enhancement was observed in activities of daily living (SMD = 1.24, 95% CI: 0.49–1.98, p = 0.001). Conclusions: This meta-analysis suggests that cerebellar iTBS significantly enhances activities of daily living in post-stroke patients, with a potential but less consistent impact on balance and gait. These findings highlight the promise of cerebellar iTBS as an adjunctive therapy in stroke rehabilitation, though further high-quality RCTs are needed to clarify its specific therapeutic benefits.

Cholecystokinin facilitates the formation of long-term heterosynaptic plasticity in the distal subiculum

It has been well established that Cornu Ammonis-(CA1) and subiculum (SUB) serve as the major output components of the entorhinal-hippocampal circuitry. Nevertheless, how the neuromodulators regulate the neurocircuitry in hippocampal formation has remained elusive. Cholecystokinin (CCK), is the most abundant neuropeptide in the central nervous system, which broadly regulates the animal’s physiological status at multiple levels, including neuroplasticity and its behavioral consequences. Here, we uncover that exogenous CCK potentiates the excitatory synaptic transmission in the CA1-SUB projections via CCK-B receptor. Dual-color light theta burst stimulation elicits heterosynaptic long-term potentiation in distal SUB region. Light activation of medial entorhinal cortex (MEC) derived CCK-positive neurons triggers the CCK release in the SUB. Neuronal activities of SUB-projecting MECCCK neurons are necessary for conveying and processing of navigation-related information. In conclusion, our findings prove a crucial role of CCK in regulating neurobiological functions in the SUB region.

Platelets tune fear memory in mice.

Several lines of evidence have shown that platelet-derived factors are key molecules in brain-body communication in pathological conditions. Here, we identify platelets as key actors in the modulation of fear behaviors in mice through the control of inhibitory neurotransmission and plasticity in the hippocampus. Interfering with platelet number or activation reduces hippocampal serotonin (5-HT) and modulates fear learning and memory in mice, and this effect is reversed by serotonin replacement by serotonin precursor (5-HTP)/benserazide. In addition, we unravel that natural killer (NK) cells participate in this mechanism, regulating interleukin-13 (IL-13) levels in the gut, with effects on serotonin production by enterochromaffin cells and uptake by platelets. Both NK cells and platelet depletion reduce the activation of hippocampal inhibitory neurons and increase the long-term potentiation of synaptic transmission. Understanding the role of platelets in the modulation of neuro-immune interactions offers additional tools for the definition of the molecular and cellular elements involved in the growing field of brain-body communication.

Amplification of the therapeutic potential of AMPA receptor potentiators from the nootropic era to today.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors (AMPA receptors or AMPARs) are involved in fast excitatory neurotransmission and as such control multiple important physiological processes. AMPARs also are involved in the dynamics of synaptic plasticity in the nervous system where they impact neuroplastic responses such as long-term facilitation and long-term potentiation that regulate biological functions ranging from breathing to cognition. AMPARs also regulate neurotrophic factors that are strategically involved in neural plastic changes in the nervous system. As with other major ionotropic receptors, modulation of AMPARs can have prominent effects on biological systems that can include marked tolerability issues. AMPAR potentiators (AMPAkines) are positive allosteric modulators of AMPARs which have clear therapeutic potential. Medicinal chemistry combined with new pharmacological findings have defined AMPAkines with favorable oral bioavailability and pharmacological safety parameters that enable clinical advancement of their therapeutic utility. AMPAkines are being investigated in patients with diverse neurological and psychiatric disorders including spinal cord injury (breathing and bladder function), cognition, attention-deficit-hyperactivity disorder, and major depressive disorder. The present discussion of this class of compounds focuses on their general value as therapeutics through their impact on synaptic plasticity.

Synaptic vulnerability to amyloid-β and tau pathologies differentially disrupts emotional and memory neural circuits.

Alzheimer's disease (AD) is characterized by memory loss and neuropsychiatric symptoms associated with cerebral amyloid-β (Aβ) and tau pathologies, but whether and how these factors differentially disrupt neural circuits remains unclear. Here, we investigated the vulnerability of memory and emotional circuits to Aβ and tau pathologies in mice expressing mutant human amyloid precursor protein (APP), Tau or both APP/Tau in excitatory neurons. APP/Tau mice develop age- and sex-dependent Aβ and phosphorylated tau pathologies, the latter exacerbated at early stages, in vulnerable brain regions. Early memory deficits were associated with hippocampal tau pathology in Tau and APP/Tau mice, whereas anxiety and fear appeared linked to intracellular Aβ in the basolateral amygdala (BLA) of APP and APP/Tau mice. Transcriptome hippocampal profiling revealed gene changes affecting myelination and RNA processing in Tau mice, and inflammation and synaptic-related pathways in APP/Tau mice at 6 months. At 9 months, we detected common and region-specific changes in astrocytic, microglia and 63 AD-associated genes in the hippocampus and BLA of APP/Tau mice. Spatial learning deficits were associated with synaptic tau accumulation and synapse disruption in the hippocampus of Tau and APP/Tau mice, whereas emotional disturbances were linked to Aβ pathology but not synaptic tau in the BLA. Interestingly, Aβ and tau exhibited synergistic detrimental effects in long-term potentiation (LTP) in the hippocampus but they counteract with each other to mitigate LTP impairments in the amygdala. These findings indicate that Aβ and tau pathologies cause region-specific effects and synergize to induce synaptic dysfunction and immune responses, contributing to the differing vulnerability of memory and emotional neural circuits in AD.

Inactivation of CaV1 and CaV2 channels.

Voltage-gated Ca2+ channels (VGCCs) are highly expressed throughout numerous biological systems and play critical roles in synaptic transmission, cardiac excitation, and muscle contraction. To perform these various functions, VGCCs are highly regulated. Inactivation comprises a critical mechanism controlling the entry of Ca2+ through these channels and constitutes an important means to regulate cellular excitability, shape action potentials, control intracellular Ca2+ levels, and contribute to long-term potentiation and depression. For CaV1 and CaV2 channel families, inactivation proceeds via two distinct processes. Voltage-dependent inactivation (VDI) reduces Ca2+ entry through the channel in response to sustained or repetitive depolarization, while Ca2+-dependent inactivation (CDI) occurs in response to elevations in intracellular Ca2+ levels. These processes are critical for physiological function and undergo exquisite fine-tuning through multiple mechanisms. Here, we review known determinants and modulatory features of these two critical forms of channel regulation and their role in normal physiology and pathophysiology.

Study Protocol for 'PsilOCD: A Pharmacological Challenge Study Evaluating the Effects of the 5-HT2A Agonist Psilocybin on the Neurocognitive and Clinical Correlates of Compulsivity'.

Obsessive-compulsive disorder (OCD) is a complex condition marked by persistent distressing thoughts and repetitive behaviours. Despite its prevalence, the mechanisms behind OCD remain elusive, and current treatments are limited. This protocol outlines an investigative study for individuals with OCD, exploring the potential of psilocybin to improve key components of cognition implicated in the disorder. The PsilOCD study strives to assess the effects of low-moderate psilocybin treatment (10 mg) alongside non-interventional therapy on several facets of OCD. The main focus points of PsilOCD are cognitive flexibility, measured with cognitive tests, and neuroplasticity, assessed through electroencephalography (EEG). 20 blinded participants with OCD will complete two dosing sessions, separated by four weeks, where they will receive 1 mg of psilocybin on the first and 10 mg on the second. The first dose serves as an active placebo, and the latter is a low-moderate dose that induces relatively mild-moderate emotional and perceptual effects.Participants will be supported by trained psychedelic therapists, who will sit with them during each dosing session and provide virtual preparation and integration sessions over the 12-week study period. Therapeutic support will be the same for both the 1 mg and 10 mg sessions. PsilOCD's primary outcomes include scores in the intradimensional-extradimensional (ID-ED) shift task, which is an established measure of cognitive flexibility, and neuroplasticity as quantified by a visual long-term potentiation (vLTP) task. This task is delivered as part of an EEG paradigm and measures acute quantified changes in neuroplasticity in the brain's visual system. The ID-ED task will be conducted twice, two days after each dosing session, and the EEG recordings will also be taken twice, immediately after each session. Secondary outcome assessments will include OCD and affective symptom severity, as well as an array of patient-reported outcome measures (PROMs), in the form of questionnaires designed to assess well-being, dissociable and well-established mood-related (affective) measures, and participants' subjective experience of the psilocybin experience. This study's results are expected to offer critical insights into the neural mechanisms underlying the effects of psilocybin-assisted therapy in treating OCD, and whether these correlate with changes in the cognitive features of the condition. As a secondary aim, it will ascertain whether a low, tolerable dose is a feasible and efficacious clinical treatment, and will provide crucial data to guide the design of a potential follow-up randomised control trial (RCT).

Active Compounds and Potential Actions of Anti-aging Remedy in Mild Cognitive Impairment Based on Network Pharmacology

Mild cognitive impairment (MCI) may occurs during the aging process and often progress to dementia. This study investigates an anti-aging remedy (AAR) from Thai traditional medicine, which is known for promoting lifespan, by exploring its interactions with biological systems using network pharmacology. Natural compounds related to AAR were retrieved from databases (NPASS, Duke’s, and literatures) and assessed for bioactivity based on pharmacokinetic properties and other criteria. Protein targets linked to MCI were identified using SwissTargetPrediction and DisGeNET databases, and the network was constructed with Cytoscape software and its plugins (MCODE, BinGo, JEPETTO). A total of 178 bioactive compounds and 105 MCI-related protein targets were identified. The top 10 protein targets in the AAR network include GRB2, SRC, TP53, MAPK1, ESR1, PRKCA, STAT3, PIK3R1, FYN, and AKT1, which play important roles in cell processes associated with aging-related cognitive dysfunction. KEGG pathway analysis revealed 37 significant pathways, such as neuroactive ligand-receptor interaction, long-term potentiation, long-term depression and neurotrophin signaling pathways, providing insights into the molecular mechanisms involved in biological processes in cognitive impairment. Gene ontology (GO) analysis identified five modules related to cellular functions potentially contributing to MCI, including metabolic process, and multicellular organismal process. This study enhances the understanding of AAR's protective effects on cognitive function and could inform improvements in the quality and efficacy of AAR treatments for age-related cognitive decline.

Varenicline Attenuates Memory Impairment in Amyloid-Beta-Induced Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by cognitive decline. Despite extensive research, therapeutic options remain limited. Varenicline, an α4β2 nicotinic acetylcholine receptor agonist, shows promise in enhancing cognitive function. This study aimed to evaluate varenicline's effect on memory and hippocampal activity in rat model of AD. Forty-eight adult male Wistar rats were randomly assigned to control, sham, AD, and varenicline (0.1, 1, and 3mg/kg/po for 14 days) groups. AD was induced by intracerebroventricular (i.c.v.) injection of 4µl amyloid-beta (Aβ)1-42 (1µg/µl). Spatial learning and memory, hippocampal synaptic function, and CA1 electrophysiological activity were evaluated using appropriate methods. Barnes maze and T-maze behavioral tests revealed that varenicline, particularly at 1mg/kg, significantly improved spatial memory compared to the AD group. Western blot analysis showed varenicline's ability to upregulate synaptic proteins PSD-95, synaptophysin, and GAP-43 in the hippocampus, with the most significant effects observed at 1mg/kg. Electrophysiological recordings demonstrated that varenicline at 1mg/kg enhanced hippocampal long-term potentiation (LTP), indicating improved synaptic plasticity. Single-unit recordings showed an increase in spike count with varenicline administration. These findings suggest that varenicline, particularly at 1mg/kg, ameliorates memory deficits in AD rats possibly through modulation of synaptic proteins and enhancement of hippocampal LTP and electrical activity. Further investigations are warranted to elucidate varenicline's precise mechanisms of action in alleviating AD-induced cognitive deficits and its potential as a therapeutic intervention for AD-related cognitive impairment.

Tau oligomers impair memory and synaptic plasticity through the cellular prion protein

Deposition of abnormally phosphorylated tau aggregates is a central event leading to neuronal dysfunction and death in Alzheimer’s disease (AD) and other tauopathies. Among tau aggregates, oligomers (TauOs) are considered the most toxic. AD brains show significant increase in TauOs compared to healthy controls, their concentration correlating with the severity of cognitive deficits and disease progression. In vitro and in vivo neuronal TauO exposure leads to synaptic and cognitive dysfunction, but their mechanisms of action are unclear. Evidence suggests that the cellular prion protein (PrPC) may act as a mediator of TauO neurotoxicity, as previously proposed for β-amyloid and α-synuclein oligomers. To investigate whether PrPC mediates TauO detrimental activities, we compared their effects on memory and synaptic plasticity in wild type (WT) and PrPC knockout (Prnp0/0) mice. Intracerebroventricular injection of TauOs significantly impaired recognition memory in WT but not in Prnp0/0 mice. Similarly, TauOs inhibited long-term potentiation in acute hippocampal slices from WT but not Prnp0/0 mice. Surface plasmon resonance indicated a high-affinity binding between TauOs and PrPC with a KD of 20–50 nM. Immunofluorescence analysis of naïve and PrPC-overexpressing HEK293 cells exposed to TauOs showed a PrPC dose-dependent association of TauOs with cells over time, and their co-localization with PrPC on the plasma membrane and in intracellular compartments, suggesting PrPC-may play a role in TauO internalization. These findings support the concept that PrPC mediates the detrimental activities of TauOs through a direct interaction, suggesting that targeting this interaction might be a promising therapeutic strategy for AD and other tauopathies.

The neural basis of the insight memory advantage.

Creative problem solving and memory are inherently intertwined: memory accesses existing knowledge while creativity enhances it. Recent studies show that insights often accompanying creative solutions enhance long-term memory. This insight memory advantage (IMA) is explained by the 'insight as prediction error (PE)' hypothesis which states that insights arise from PEs updating predictive solution models and thereby enhancing memory. Neurally, the hippocampus initially detects PEs and then, together with the medial prefrontal cortex (mPFC), integrates and updates these expectations facilitating efficient memory encoding and retrieval. Dopamine (DA) mediates reward PEs and long-term potentiation (LTP) in the hippocampus, while noradrenaline (NE) enhances arousal and attention impacting the amygdala, the salience network, and hippocampal plasticity. These neurobiological mechanisms likely underpin IMA and have significant implications for educational practices and problem-solving strategies.

Visual activity enhances neuronal excitability in thalamic relay neurons.

Amblyopia, a highly prevalent loss of visual acuity, is classically thought to result from cortical plasticity. The dorsal lateral geniculate nucleus (dLGN) has long been held to act as a passive relay for visual information, but recent findings suggest a largely underestimated functional plasticity in the dLGN. However, the cellular mechanisms supporting this plasticity have not yet been explored. We show here that monocular deprivation (MD), an experimental model of amblyopia, reduces the intrinsic excitability of dLGN cells. Furthermore, dLGN neurons exhibit long-term potentiation of their intrinsic excitability (LTP-IE) when suprathreshold afferent retinal inputs are stimulated at 40 hertz or when spikes are induced with current injection. LTP-IE is observed after eye opening, requires calcium influx, is expressed through the down-regulation of Kv1 channels, and is altered following MD. In conclusion, our study provides the first evidence for intrinsic plasticity in dLGN neurons induced by natural stimuli.

Early functional and structural hippocampal impairment in a bilateral common carotid artery stenosis mouse model.

Subcortical ischemic vascular dementia (SIVD) is a common subtype of vascular dementia. Currently, the bilateral common carotid artery stenosis (BCAS) mouse model is the most suitable SIVD rodent model. In this study, we investigated the functional and structural impairments in the hippocampus 1 month after BCAS. We used behavioral tests, laser speckle flowmetry, long-term potentiation, histochemical staining, molecular experiments, and voxel-based morphometry to evaluate the hippocampal impairments. Behavioral studies revealed that BCAS mice exhibited worse performance. Laser speckle flowmetry detected an obvious decrease in cerebral blood flow. The synaptic plasticity of the perforant path-dentate gyrus pathway was inhibited. Decreased fractional anisotropy and increased mean diffusivity were detected in the hippocampus via diffusion tensor imaging data. A reduction in gray matter volume, which was most prominent in the hippocampus and its surrounding areas, was detected via voxel-based morphometry analysis. Impairments in cell morphology and myelin integrity were validated using histochemical staining and molecular biology techniques. In addition, the numbers of GFAP+ astrocytes and Iba1+ microglia increased in the hippocampus. Overall, our study demonstrates early functional and structural impairments in the hippocampus contributing to learning and memory deficits after 1 month of BCAS, indicating that the hippocampus is vulnerable to chronic cerebral ischemia.

DYRK1A Up-Regulation Specifically Impairs a Presynaptic Form of Long-Term Potentiation

Chromosome 21 DYRK1A kinase is associated with a variety of neuronal diseases including Down syndrome. However, the functional impact of this kinase at the synapse level remains unclear. We studied a mouse model that incorporated YAC 152F7 (570 kb), encoding six chromosome 21 genes including DYRK1A. The 152F7 mice displayed learning difficulties but their N-methyl-D-aspartate (NMDA)-dependent synaptic long-term potentiation is indistinguishable from non-transgenic animals. We have demonstrated that a presynaptic form of NMDA-independent long-term potentiation (LTP) at the hippocampal mossy fiber was impaired in the 152F7 animals. To obtain insights into the molecular mechanisms involved in such synaptic changes, we analyzed the Dyrk1a interactions with chromatin remodelers. We found that the number of DYRK1A-EP300 and DYRK1A-CREBPP increased in 152F7 mice. Moreover, we observed a transcriptional decrease in genes encoding presynaptic proteins involved in glutamate vesicle exocytosis, namely Rims1, Munc13-1, Syn2 and Rab3A.To refine our findings, we used a mouse BAC 189N3 (152 kb) line that only triplicates the gene Dyrk1a. Again, we found that this NMDA-independent form of LTP is impaired in this mouse line. Altogether, our results demonstrate that Dyrk1a up-regulation is sufficient to specifically inhibit the NMDA-independent form of LTP and suggest that this inhibition is linked to chromatin changes that deregulate genes encoding proteins involved in glutamate synaptic release.