Physical activity promotes brain development through serotonin during early childhood.

Early childhood serves as a critical period for neural development and skill acquisition when children are extremely susceptible to the external environment and experience. As a crucial experiential stimulus, physical activity is believed to produce a series of positive effects on brain development, such as cognitive function, social-emotional abilities, and psychological well-being. The World Health Organization recommends that children engage in sufficient daily physical activity, which has already been strongly advocated in the practice of preschool education. However, the mechanisms by which physical activity promotes brain development are still unclear. The role of neurotransmitters, especially serotonin, in promoting brain development through physical activity has received increasing attention. Physical activity has been shown to stimulate the secretion of serotonin by increasing the bioavailability of free tryptophan and enriching the diversity of gut microbiota. Due to its important role in modulating neuronal proliferation, differentiation, synaptic morphogenesis, and synaptic transmission, serotonin can regulate children's explicit cognitive and social interaction behavior in the early stages of life. Therefore, we hypothesized that serotonin emerges as a pivotal transmitter that mediates the relationship between physical activity and brain development during early childhood. Further systematic reviews and meta-analyses are needed to specifically explore whether the type, intensity, dosage, duration, and degree of voluntariness of PA may affect the role of serotonin in the relationship between physical activity and brain function. This review not only helps us understand the impact of exercise on development but also provides a solid theoretical basis for increasing physical activity during early childhood.

Non-Hebbian plasticity transforms transient experiences into lasting memories.

The dominant models of learning and memory, such as Hebbian plasticity, propose that experiences are transformed into memories through input-specific synaptic plasticity at the time of learning. However, synaptic plasticity is neither strictly input-specific nor restricted to the time of its induction. The impact of such forms of non-Hebbian plasticity on memory has been difficult to test, and hence poorly understood. Here, we demonstrate that synaptic manipulations can deviate from the Hebbian model of learning, yet produce a lasting memory. First, we established a weak associative conditioning protocol in mice, where optogenetic stimulation of sensory thalamic input to the amygdala was paired with a footshock, but no detectable memory was formed. However, when the same input was potentiated minutes before or after, or even 24 hr later, the associative experience was converted into a lasting memory. Importantly, potentiating an independent input to the amygdala minutes but not 24 hr after the pairing produced a lasting memory. Thus, our findings suggest that the process of transformation of a transient experience into a memory is neither restricted to the time of the experience nor to the synapses triggered by it; instead, it can be influenced by past and future events.

Cortical plasticity is associated with blood-brain barrier modulation.

Brain microvessels possess the unique properties of a blood-brain barrier (BBB), tightly regulating the passage of molecules from the blood to the brain neuropil and vice versa. In models of brain injury, BBB dysfunction and the associated leakage of serum albumin to the neuropil have been shown to induce pathological plasticity, neuronal hyper-excitability, and seizures. The effect of neuronal activity on BBB function and whether it plays a role in plasticity in the healthy brain remain unclear. Here we show that neuronal activity induces modulation of microvascular permeability in the healthy brain and that it has a role in local network reorganization. Combining simultaneous electrophysiological recording and vascular imaging with transcriptomic analysis in rats, and functional and BBB-mapping MRI in human subjects, we show that prolonged stimulation of the limb induces a focal increase in BBB permeability in the corresponding somatosensory cortex that is associated with long-term synaptic plasticity. We further show that the increased microvascular permeability depends on neuronal activity and involves caveolae-mediated transcytosis and transforming growth factor ß signaling. Our results reveal a role of BBB modulation in cortical plasticity in the healthy brain, highlighting the importance of neurovascular interactions for sensory experience and learning.

Social play behavior is driven by glycine-dependent mechanisms.

Social play is pervasive in juvenile mammals, yet it is poorly understood in terms of its underlying brain mechanisms. Specifically, we do not know why young animals are most playful and why most adults cease to social play. Here, we analyze the synaptic mechanisms underlying social play. We found that blocking the rat periaqueductal gray (PAG) interfered with social play. Furthermore, an age-related decrease of neural firing in the PAG is associated with a decrease in synaptic release of glycine. Most importantly, modulation of glycine concentration-apparently acting on the glycinergic binding site of the N-methyl-D-aspartate (NMDA) receptor-not only strongly modulates social play but can also reverse the age-related decline in social play. In conclusion, we demonstrate that social play critically depends on the neurotransmitter glycine within the PAG.

Purkinje cell models: past, present and future.

The investigation of the dynamics of Purkinje cell (PC) activity is crucial to unravel the role of the cerebellum in motor control, learning and cognitive processes. Within the cerebellar cortex (CC), these neurons receive all the incoming sensory and motor information, transform it and generate the entire cerebellar output. The relatively homogenous and repetitive structure of the CC, common to all vertebrate species, suggests a single computation mechanism shared across all PCs. While PC models have been developed since the 70's, a comprehensive review of contemporary models is currently lacking. Here, we provide an overview of PC models, ranging from the ones focused on single cell intracellular PC dynamics, through complex models which include synaptic and extrasynaptic inputs. We review how PC models can reproduce physiological activity of the neuron, including firing patterns, current and multistable dynamics, plateau potentials, calcium signaling, intrinsic and synaptic plasticity and input/output computations. We consider models focusing both on somatic and on dendritic computations. Our review provides a critical performance analysis of PC models with respect to known physiological data. We expect our synthesis to be useful in guiding future development of computational models that capture real-life PC dynamics in the context of cerebellar computations.

Gadd45A-mediated autophagy regulation and its impact on Alzheimer's disease pathogenesis: Deciphering the molecular Nexus.

BACKGROUND: The growth arrest and DNA damage-inducible 45 (Gadd45) gene has been implicated in various central nervous system (CNS) functions, both normal and pathological, including aging, memory, and neurodegenerative diseases. In this study, we examined whether Gadd45A deletion triggers pathways associated with neurodegenerative diseases including Alzheimer's disease (AD). METHODS: Utilizing transcriptome data from AD-associated hippocampus samples, we identified Gadd45A as a pivotal regulator of autophagy. Comprehensive analyses, including Gene Ontology enrichment and protein-protein interaction network assessments, highlighted Cdkn1A as a significant downstream target of Gadd45A. Experimental validation confirmed Gadd45A's role in modulating Cdkn1A expression and autophagy levels in hippocampal cells. We also examined the effects of autophagy on hippocampal functions and proinflammatory cytokine secretion. Additionally, a murine model was employed to validate the importance of Gadd45A in neuroinflammation and AD pathology. RESULTS: Our study identified 20 autophagy regulatory factors associated with AD, with Gadd45A emerging as a critical regulator. Experimental findings demonstrated that Gadd45A influences hippocampal cell fate by reducing Cdkn1A expression and suppressing autophagic activity. Comparisons between wild-type (WT) and Gadd45A knockout (Gadd45A-/-) mice revealed that Gadd45A-/- mice exhibited significant cognitive impairments, including deficits in working and spatial memory, increased Tau hyperphosphorylation, and elevated levels of kinases involved in Tau phosphorylation in the hippocampus. Additionally, Gadd45A-/- mice showed significant increases in pro-inflammatory cytokines and decreases autophagy markers in the brain. Neurotrophin levels and dendritic spine length were also reduced in Gadd45A-/- mice, likely contributing to the observed cognitive deficits. CONCLUSIONS: These findings support the direct involvement of the Gadd45A gene in AD pathogenesis, and enhancing the expression of Gadd45A may represent a promising therapeutic strategy for the treatment of AD.

Histamine in the neocortex: Towards integrating multiscale effectors.

Histamine is a modulatory neurotransmitter, which has received relatively less attention in the central nervous system than other neurotransmitters. The functional role of histamine in the neocortex, the brain region that controls higher-order cognitive functions such as attention, learning and memory, remains largely unknown. This article focuses on the emerging roles and mechanisms of histamine release in the neocortex. We describe gaps in current knowledge and propose the application of interdisciplinary tools to dissect the detailed multiscale functional logic of histaminergic action in the neocortex ranging from sub-cellular, cellular, dendritic and synaptic levels to microcircuits and mesoscale effects.

Hippocampal Warburg effect Mediates Hydrogen Sulfide-Ameliorated Diabetes-Associated Cognitive Dysfunction: Involving Promotion of Hippocampal Synaptic Plasticity.

Our previous studies have reported that hydrogen sulfide (H2S) has ability to improve diabetes-associated cognitive dysfunction (DACD), but the exact mechanisms remain unknown. Recent research reveals that Warburg effect is associated with synaptic plasticity which plays a key role in cognition promotion. Herein, the present study was aimed to demonstrate whether hippocampal Warburg effect contributes to H2S-ameliorated DACD and further explore its potential mechanism. We found that H2S promoted the hippocampal Warburg effect and inhibited the OxPhos in the hippocampus of STZ-induced diabetic rats. It also improved the hippocampal synaptic plasticity in STZ-induced diabetic rats, as evidenced by the change of microstructures and the expression of different key-enzymes. Furthermore, inhibited hippocampal Warburg effect induced by DCA markedly abolished the improvement of H2S on synaptic plasticity in the hippocampus of STZ-induced diabetic rats. DCA blocked H2S-attenuated the cognitive dysfunction in STZ-induced diabetic rats, according to the Y-maze, Novel Objective Recognition, and Morris Water Maze tests. Collectively, these findings indicated that the hippocampal Warburg effect mediates H2S-ameliorated DACD by improving hippocampal synaptic plasticity.

Increased spontaneous activity and progressive suppression of adult neurogenesis in the hippocampus of rat offspring after maternal exposure to imidacloprid.

Imidacloprid (IMI) is a widely used neonicotinoid insecticide that poses risks for developmental neurotoxicity in mammals. The present study investigated the effects of maternal exposure to IMI on behaviors and adult neurogenesis in the hippocampal dentate gyrus (DG) of rat offspring. Dams were exposed to IMI via diet (83, 250, or 750 ppm in diet) from gestational day 6 until day 21 post-delivery on weaning, and offspring were maintained until adulthood on postnatal day 77. In the neurogenic niche, 750-ppm IMI decreased numbers of late-stage neural progenitor cells (NPCs) and post-mitotic immature granule cells by suppressing NPC proliferation and ERK1/2-FOS-mediated synaptic plasticity of granule cells on weaning. Suppressed reelin signaling might be responsible for the observed reductions of neurogenesis and synaptic plasticity. In adulthood, IMI at ≥ 250 ppm decreased neural stem cells by suppressing their proliferation and increasing apoptosis, and mature granule cells were reduced due to suppressed NPC differentiation. Behavioral tests revealed increased spontaneous activity in adulthood at 750 ppm. IMI decreased hippocampal acetylcholinesterase activity and Chrnb2 transcript levels in the DG on weaning and in adulthood. IMI increased numbers of astrocytes and M1-type microglia in the DG hilus, and upregulated neuroinflammation and oxidative stress-related genes on weaning. In adulthood, IMI increased malondialdehyde level and number of M1-type microglia, and downregulated neuroinflammation and oxidative stress-related genes. These results suggest that IMI persistently affected cholinergic signaling, induced neuroinflammation and oxidative stress during exposure, and increased sensitivity to oxidative stress after exposure in the hippocampus, causing hyperactivity and progressive suppression of neurogenesis in adulthood. The no-observed-adverse-effect level of IMI for offspring behaviors and hippocampal neurogenesis was determined to be 83 ppm (5.5-14.1 mg/kg body weight/day).

The effects of different types of social interactions on the electrophysiology of neurons in the nucleus accumbens in rodents.

BORLAND, J.M., The effects of different types of social interactions on the electrophysiology of neurons in the nucleus accumbens in rodents, NEUROSCI BIOBEH REV 21(1) XXX-XXX, 2024.-Sociality shapes an organisms' life. The nucleus accumbens is a critical brain region for mental health. In the following review, the effects of different types of social interactions on the physiology of neurons in the nucleus accumbens is synthesized. More specifically, the effects of sex behavior, aggression, social defeat, pair-bonding, play behavior, affiliative interactions, parental behaviors, the isolation from social interactions and maternal separation on measures of excitatory synaptic transmission, intracellular signaling and factors of transcription and translation in neurons in the nucleus accumbens in rodent models are reviewed. Similarities and differences in effects depending on the type of social interaction is then discussed. This review improves the understanding of the molecular and synaptic mechanisms of sociality.

BDNF-TrkB signaling orchestrates the buildup process of local sleep.

Sleep debt accumulates during wakefulness, leading to increased slow wave activity (SWA) during sleep, an encephalographic marker for sleep need. The use-dependent demands of prior wakefulness increase sleep SWA locally. However, the circuitry and molecular identity of this "local sleep" remain unclear. Using pharmacology and optogenetic perturbations together with transcriptomics, we find that cortical brain-derived neurotrophic factor (BDNF) regulates SWA via the activation of tyrosine kinase B (TrkB) receptor and cAMP-response element-binding protein (CREB). We map BDNF/TrkB-induced sleep SWA to layer 5 (L5) pyramidal neurons of the cortex, independent of neuronal firing per se. Using mathematical modeling, we here propose a model of how BDNF's effects on synaptic strength can increase SWA in ways not achieved through increased firing alone. Proteomic analysis further reveals that TrkB activation enriches ubiquitin and proteasome subunits. Together, our study reveals that local SWA control is mediated by BDNF-TrkB-CREB signaling in L5 excitatory cortical neurons.

Region-Related Differences in Short-Term Synaptic Plasticity and Synaptotagmin-7 in the Male and Female Hippocampus of a Rat Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is an intellectual developmental disorder characterized, inter alia, by deficits in the short-term processing of neural information, such as sensory processing and working memory. The primary cause of FXS is the loss of fragile X messenger ribonucleoprotein (FMRP), which is profoundly involved in synaptic function and plasticity. Short-term synaptic plasticity (STSP) may play important roles in functions that are affected by FXS. Recent evidence points to the crucial involvement of the presynaptic calcium sensor synaptotagmin-7 (Syt-7) in STSP. However, how the loss of FMRP affects STSP and Syt-7 have been insufficiently studied. Furthermore, males and females are affected differently by FXS, but the underlying mechanisms remain elusive. The aim of the present study was to investigate possible changes in STSP and the expression of Syt-7 in the dorsal (DH) and ventral (VH) hippocampus of adult males and females in a Fmr1-knockout (KO) rat model of FXS. We found that the paired-pulse ratio (PPR) and frequency facilitation/depression (FF/D), two forms of STSP, as well as the expression of Syt-7, are normal in adult KO males, but the PPR is increased in the ventral hippocampus of KO females (6.4 ± 3.7 vs. 18.3 ± 4.2 at 25 ms in wild type (WT) and KO, respectively). Furthermore, we found no gender-related differences, but did find robust region-dependent difference in the STSP (e.g., the PPR at 50 ms: 50.0 ± 5.5 vs. 17.6 ± 2.9 in DH and VH of WT male rats; 53.1 ± 3.6 vs. 19.3 ± 4.6 in DH and VH of WT female rats; 48.1 ± 2.3 vs. 19.1 ± 3.3 in DH and VH of KO male rats; and 51.2 ± 3.3 vs. 24.7 ± 4.3 in DH and VH of KO female rats). AMPA receptors are similarly expressed in the two hippocampal segments of the two genotypes and in both genders. Also, basal excitatory synaptic transmission is higher in males compared to females. Interestingly, we found more than a twofold higher level of Syt-7, not synaptotagmin-1, in the dorsal compared to the ventral hippocampus in the males of both genotypes (0.43 ± 0.1 vs. 0.16 ± 0.02 in DH and VH of WT male rats, and 0.6 ± 0.13 vs. 0.23 ± 0.04 in DH and VH of KO male rats) and in the WT females (0.97 ± 0.23 vs. 0.31 ± 0.09 in DH and VH). These results point to the susceptibility of the female ventral hippocampus to FMRP loss. Importantly, the different levels of Syt-7, which parallel the higher score of the dorsal vs. ventral hippocampus on synaptic facilitation, suggest that Syt-7 may play a pivotal role in defining the striking differences in STSP along the long axis of the hippocampus.

Mitigating the Functional Deficit after Neurotoxic Motoneuronal Loss by an Inhibitor of Mitochondrial Fission.

Amyotrophic lateral sclerosis (ALS) is an extremely complex neurodegenerative disease involving different cell types, but motoneuronal loss represents its main pathological feature. Moreover, compensatory plastic changes taking place in parallel to neurodegeneration are likely to affect the timing of ALS onset and progression and, interestingly, they might represent a promising target for disease-modifying treatments. Therefore, a simplified animal model mimicking motoneuronal loss without the other pathological aspects of ALS has been established by means of intramuscular injection of cholera toxin-B saporin (CTB-Sap), which is a targeted neurotoxin able to kill motoneurons by retrograde suicide transport. Previous studies employing the mouse CTB-Sap model have proven that spontaneous motor recovery is possible after a subtotal removal of a spinal motoneuronal pool. Although these kinds of plastic changes are not enough to counteract the functional effects of the progressive motoneuron degeneration, it would nevertheless represent a promising target for treatments aiming to postpone ALS onset and/or delay disease progression. Herein, the mouse CTB-Sap model has been used to test the efficacy of mitochondrial division inhibitor 1 (Mdivi-1) as a tool to counteract the CTB-Sap toxicity and/or to promote neuroplasticity. The homeostasis of mitochondrial fission/fusion dynamics is indeed important for cell integrity, and it could be affected during neurodegeneration. Lesioned mice were treated with Mdivi-1 and then examined by a series of behavioral test and histological analyses. The results have shown that the drug may be capable of reducing functional deficits after the lesion and promoting synaptic plasticity and neuroprotection, thus representing a putative translational approach for motoneuron disorders.

Exploring the Effect of Arsenic-Containing Hydrocarbon on the Bidirectional Synaptic Plasticity of the Dorsal Hippocampus.

Arsenic-containing hydrocarbons (AsHCs) are common in marine organisms. However, there is little research on their effects on the central nervous system's advanced activities, such as cognition. Bidirectional synaptic plasticity dynamically regulates cognition through the balance of long-term potentiation (LTP) and long-term depression (LTD). However, the effects of AsHCs on bidirectional synaptic plasticity and the underlying molecular mechanisms remain unexplored. This study provides the first evidence that 15 µg As L-1 AsHC 360 enhances bidirectional synaptic plasticity, occurring during the maintenance phase rather than the baseline phase. Further calcium gradient experiments hypothesize that AsHC 360 may enhance bidirectional synaptic plasticity by affecting calcium ion levels. The enhancement of bidirectional synaptic plasticity by 15 µg As L-1 AsHC 360 holds significant implications in improving cognitive function, treating neuro-psychiatric disorders, promoting neural recovery, and enhancing brain adaptability.

Novel Leptin-Based Therapeutic Strategies to Limit Synaptic Dysfunction in Alzheimer's Disease.

Accumulation of hyper-phosphorylated tau and amyloid beta (Aß) are key pathological hallmarks of Alzheimer's disease (AD). Increasing evidence indicates that in the early pre-clinical stages of AD, phosphorylation and build-up of tau drives impairments in hippocampal excitatory synaptic function, which ultimately leads to cognitive deficits. Consequently, limiting tau-related synaptic abnormalities may have beneficial effects in AD. There is now significant evidence that the hippocampus is an important brain target for the endocrine hormone leptin and that leptin has pro-cognitive properties, as activation of synaptic leptin receptors markedly influences higher cognitive processes including learning and memory. Clinical studies have identified a link between the circulating leptin levels and the risk of AD, such that AD risk is elevated when leptin levels fall outwith the physiological range. This has fuelled interest in targeting the leptin system therapeutically. Accumulating evidence supports this possibility, as numerous studies have shown that leptin has protective effects in a variety of models of AD. Recent findings have demonstrated that leptin has beneficial effects in the preclinical stages of AD, as leptin prevents the early synaptic impairments driven by tau protein and amyloid ß. Here we review recent findings that implicate the leptin system as a potential novel therapeutic target in AD.

The Effects of Sevoflurane and Aß Interaction on CA1 Dendritic Spine Dynamics and MEGF10-Related Astrocytic Synapse Engulfment.

General anesthetics may accelerate the neuropathological changes related to Alzheimer's disease (AD), of which amyloid beta (Aß)-induced toxicity is one of the main causes. However, the interaction of general anesthetics with different Aß-isoforms remains unclear. In this study, we investigated the effects of sevoflurane (0.4 and 1.2 maximal alveolar concentration (MAC)) on four Aß species-induced changes on dendritic spine density (DSD) in hippocampal brain slices of Thy1-eGFP mice and multiple epidermal growth factor-like domains 10 (MEGF10)-related astrocyte-mediated synaptic engulfment in hippocampal brain slices of C57BL/6 mice. We found that both sevoflurane and Aß downregulated CA1-dendritic spines. Moreover, compared with either sevoflurane or Aß alone, pre-treatment with Aß isoforms followed by sevoflurane application in general further enhanced spine loss. This enhancement was related to MEGF10-related astrocyte-dependent synaptic engulfment, only in AßpE3 + 1.2 MAC sevoflurane and 3NTyrAß + 1.2 MAC sevoflurane condition. In addition, removal of sevoflurane alleviated spine loss in Aß + sevoflurane. In summary, these results suggest that both synapses and astrocytes are sensitive targets for sevoflurane; in the presence of 3NTyrAß, 1.2 MAC sevoflurane alleviated astrocyte-mediated synaptic engulfment and exerted a lasting effect on dendritic spine remodeling.

Hypersensitivity of the nicotinic acetylcholine receptor subunit (CHRNA2L9'S/L9'S) in female adolescent mice produces deficits in nicotine-induced facilitation of hippocampal-dependent learning and memory.

Adolescence is characterized by a critical period of maturation and growth, during which regions of the brain are vulnerable to long-lasting cognitive disturbances. Adolescent exposure to nicotine can lead to deleterious neurological and psychological outcomes. Moreover, the nicotinic acetylcholine receptor (nAChR) has been shown to play a functionally distinct role in the development of the adolescent brain. CHRNA2 encodes for the α2 subunit of nicotinic acetylcholine receptors associated with CA1 oriens lacunosum moleculare GABAergic interneurons and is associated with learning and memory. Previously, we found that adolescent male hypersensitive CHRNA2L9'S/L9' mice had impairments in learning and memory during a pre-exposure-dependent contextual fear conditioning task that could be rescued by low-dose nicotine exposure. In this study, we assessed learning and memory in female adolescent hypersensitive CHRNA2L9'S/L9' mice exposed to saline or a subthreshold dose of nicotine using a hippocampus-dependent task of pre-exposure-dependent contextual fear conditioning. We found that nicotine-treated wild-type female mice had significantly greater improvements in learning and memory than both saline-treated wild-type mice and nicotine-treated CHRNA2L9'S/L9' female mice. Thus, hyperexcitability of CHRNA2 in female adolescent mice ablated the nicotine-mediated potentiation of learning and memory seen in wild-types. Our results indicate that nicotine exposure during adolescence mediates sexually dimorphic patterns of learning and memory, with wild-type female adolescents being more susceptible to the effects of sub-threshold nicotine exposure. To understand the mechanism underlying sexually dimorphic behavior between hyperexcitable CHRNA2 mice, it is critical that further research be conducted.

Want to learn? think again!

One of the best ways to improve new learning and increase memory strength is by reprocessing the recently acquired information, for example, by thinking of it again. Synaptic plasticity, the process by which neurons change the strength of their connections with each other, is fundamental for learning and memory formation. Yet, at present, it is unclear how reprocessing information drives synaptic plasticity to support memory improvement. A new study suggests that reprocessing enhances memory formation by recruiting more synapses to represent the new memory, thus increasing its strength.

Disorder of neuroplasticity aggravates cognitive impairment via neuroinflammation associated with intestinal flora dysbiosis in chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) impairs cognitive function, yet its effects on brain structure and underlying mechanisms remain elusive. This study aims to explore the mechanisms behind cognitive impairment. METHODS: CHF models in rats were induced by ligation of the left anterior descending coronary artery. Cardiac function was analyzed by cardiac ultrasound and hemodynamics. ELISA, immunofluorescence, Western blot, Golgi staining and transmission electron microscopy were performed on hippocampal tissues. The alterations of intestinal flora under the morbid state were investigated via 16S rRNA sequencing. The connection between neuroinflammation and synapses is confirmed by a co-culture system of BV2 microglia and HT22 cells in vitro. Results: CHF rats exhibited deteriorated cognitive behaviors. CHF induced neuronal structural disruption, loss of Nissl bodies, and synaptic damage, exhibiting alterations in multiple parameters. CHF rats showed increased hippocampal levels of inflammatory cytokines and activated microglia and astrocytes. Furthermore, the study highlights dysregulated PDE4-dependent cAMP signaling and intestinal flora dysbiosis, closely associated with neuroinflammation, and altered synaptic proteins. In vitro, microglial neuroinflammation impaired synaptic plasticity via PDE4-dependent cAMP signaling. CONCLUSIONS: Neuroinflammation worsens CHF-related cognitive impairment through neuroplasticity disorder, tied to intestinal flora dysbiosis. PDE4 emerges as a potential therapeutic target. These findings provide insightful perspectives on the heart-gut-brain axis.

Synaptic plasticity in human thalamocortical assembloids.

Synaptic plasticities, such as long-term potentiation (LTP) and depression (LTD), tune synaptic efficacy and are essential for learning and memory. Current studies of synaptic plasticity in humans are limited by a lack of adequate human models. Here, we modeled the thalamocortical system by fusing human induced pluripotent stem cell-derived thalamic and cortical organoids. Single-nucleus RNA sequencing revealed that >80% of cells in thalamic organoids were glutamatergic neurons. When fused to form thalamocortical assembloids, thalamic and cortical organoids formed reciprocal long-range axonal projections and reciprocal synapses detectable by light and electron microscopy, respectively. Using whole-cell patch-clamp electrophysiology and two-photon imaging, we characterized glutamatergic synaptic transmission. Thalamocortical and corticothalamic synapses displayed short-term plasticity analogous to that in animal models. LTP and LTD were reliably induced at both synapses; however, their mechanisms differed from those previously described in rodents. Thus, thalamocortical assembloids provide a model system for exploring synaptic plasticity in human circuits.