Structural Plasticity Research Articles

Principles of amyloplast replication in the ovule integuments of Arabidopsis thaliana.

Plastids in vascular plants have various differentiated forms, among which amyloplasts are crucial for starch storage and plant productivity. Despite the vast knowledge of the binary-fission mode of chloroplast division, our understanding of the replication of non-photosynthetic plastids, including amyloplasts, remains limited. Recent studies have suggested the involvement of stromules (stroma-filled tubules) in plastid replication when the division apparatus is faulty. However, details of the underlying mechanism(s) and their relevance to normal processes have yet to be elucidated. Here, we developed a live analysis system for studying amyloplast replication using Arabidopsis (Arabidopsis thaliana) ovule integuments. We showed the full sequence of amyloplast development and demonstrated that wild-type amyloplasts adopt three modes of replication, binary fission, multiple fission, and stromule-mediated fission, via multi-way placement of the FtsZ ring. The minE mutant, with severely inhibited chloroplast division, showed marked heterogeneity in amyloplast size, caused by size-dependent but wild-type modes of plastid fission. The dynamic properties of stromules distinguish the wild-type and minE phenotypes. In minE cells, extended stromules from giant amyloplasts acquired stability, allowing FtsZ ring assembly and constriction, as well as the growth of starch grains therein. Despite hyper-stromule formation, amyloplasts did not proliferate in the ftsZ null mutant. These data clarify the differences between amyloplast and chloroplast replication and demonstrate that the structural plasticity of amyloplasts underlies the multiplicity of their replication processes. Furthermore, this study shows that stromules can generate daughter plastids via the assembly of the FtsZ ring.

Effect of microstructural features on the fatigue behavior of the valve mechanism cam rolling contact

This study introduces a methodology that incorporates gradient structural features and crystal plasticity for assessing contact fatigue in engine valve cams. It explored the influence of grain characteristics and structural gradients on fatigue failure through the lens of Plastic Strain Energy Density (PSED). Findings indicate that variability in crystal orientation significantly impacts PSED and subsequent crack initiation. Additionally, shot peening induces a gradient in grain size, promoting orderly deformation, stress alleviation, and improved fatigue resistance. The study suggests that an optimal fatigue resistance in cam contacts is achievable with a gradient layer comprising 75% volume fraction, which strikes a balance between cost and technical feasibility.

Sex- and cycle-dependent changes in spine density and size in hippocampal CA2 neurons

Sex hormones affect structural and functional plasticity in the rodent hippocampus. However, hormone levels not only differ between males and females, but also fluctuate across the female estrous cycle. While sex- and cycle-dependent differences in dendritic spine density and morphology have been found in the rodent CA1 region, but not in the CA3 or the dentate gyrus, comparable structural data on CA2, i.e. the hippocampal region involved in social recognition memory, is so far lacking. In this study, we, therefore, used wildtype male and female mice in diestrus or proestrus to analyze spines on dendritic segments from identified CA2 neurons. In basal stratum oriens, we found no differences in spine density, but a significant shift towards larger spine head areas in male mice compared to females. Conversely, in apical stratum radiatum diestrus females had a significantly higher spine density, and females in either cycle stage had a significant shift towards larger spine head areas as compared to males, with diestrus females showing the larger shift. Our results provide further evidence for the sexual dimorphism of hippocampal area CA2, and underscore the importance of considering not only the sex, but also the stage of the estrous cycle when interpreting morphological data.

Higher surface folding of the human premotor cortex is associated with better long-term learning capability

The capacity to learn enabled the human species to adapt to various challenging environmental conditions and pass important achievements on to the next generation. A growing body of research suggests links between neocortical folding properties and numerous aspects of human behavior, but their impact on enhanced human learning capacity remains unexplored. Here we leverage three training cohorts to demonstrate that higher levels of premotor cortical folding reliably predict individual long-term learning gains in a challenging new motor task, above and beyond initial performance differences. Individual folding-related predisposition to motor learning was found to be independent of cortical thickness and intracortical microstructure, but dependent on larger cortical surface area in premotor regions. We further show that learning-relevant features of cortical folding occurred in close spatial proximity to practice-induced structural brain plasticity. Our results suggest a link between neocortical surface folding and human behavioral adaptability.

Integrating cryo-OrbiSIMS with computational modelling and metadynamics simulations enhances RNA structure prediction at atomic resolution

The 3D architecture of RNAs governs their molecular interactions, chemical reactions, and biological functions. However, a large number of RNAs and their protein complexes remain poorly understood due to the limitations of conventional structural biology techniques in deciphering their complex structures and dynamic interactions. To address this limitation, we have benchmarked an integrated approach that combines cryogenic OrbiSIMS, a state-of-the-art solid-state mass spectrometry technique, with computational methods for modelling RNA structures at atomic resolution with enhanced precision. Furthermore, using 7SK RNP as a test case, we have successfully determined the full 3D structure of a native RNA in its apo, native and disease-remodelled states, which offers insights into the structural interactions and plasticity of the 7SK complex within these states. Overall, our study establishes cryo-OrbiSIMS as a valuable tool in the field of RNA structural biology as it enables the study of challenging, native RNA systems.

The mutated cytoplasmic fragile X messenger ribonucleoprotein 1 (FMR1)-interacting protein 2 (CYFIP2 S968F) regulates cocaine-induced reward behaviour and plasticity in the nucleus accumbens.

Cytoplasmic fragile X messenger ribonucleoprotein 1 (FMR1)-interacting protein 2 (CYFIP2), as a component of the Wiskott-Aldrich syndrome protein family verprolin-homologous protein (WAVE) regulatory complex, is involved in actin polymerization, contributing to neuronal development and structural plasticity. Mutating serine-968 to phenylalanine (S968F) in CYFIP2 causes an altered cocaine response in mice. The neuronal mechanisms underlying this response remain unknown. We performed cocaine reward-related behavioural tests and examined changes in synaptic protein phenotypes and neuronal morphology in the nucleus accumbens (NAc), using CYFIP2 S968F knock-in mice to investigate the role of CYFIP2 in regulating cocaine reward. CYFIP2 S968F mutation attenuated cocaine-induced behavioural sensitization and conditioned place preference. Cocaine-induced c-Fos was not observed in the NAc of CYFIP2 S968F knock-in mice. However, c-Fos induction was still evident in the medial prefrontal cortex (mPFC). CYFIP2 S968F mutation altered cocaine-associated CYFIP2 signalling, glutamatergic protein expression and synaptic density in the NAc following cocaine exposure. To further determine the role of CYFIP2 in NAc neuronal activity and the mPFC projecting to the NAc activity-mediating reward response, we used optogenetic tools to stimulate the NAc or mPFC-NAc pathway and observed that optogenetic activation of the NAc or mPFC-NAc pathway induced reward-related behaviours. This effect was not observed in the S968F mutation in CYFIP2. These results suggest that CYFIP2 plays a role in controlling cocaine-mediated neuronal function and structural plasticity in the NAc, and that CYFIP2 could serve as a target for regulating cocaine reward.

Presynaptic structural and functional plasticity are coupled by convergent Rap1 signaling.

Dynamic presynaptic actin remodeling drives structural and functional plasticity at synapses, but the underlying mechanisms remain largely unknown. Previous work has shown that actin regulation via Rac1 guanine exchange factor (GEF) Vav signaling restrains synaptic growth via bone morphogenetic protein (BMP)-induced receptor macropinocytosis and mediates synaptic potentiation via mobilization of reserve pool vesicles in presynaptic boutons. Here, we find that Gef26/PDZ-GEF and small GTPase Rap1 signaling couples the BMP-induced activation of Abelson kinase to this Vav-mediated macropinocytosis. Moreover, we find that adenylate cyclase Rutabaga (Rut) signaling via exchange protein activated by cAMP (Epac) drives the mobilization of reserve pool vesicles during post-tetanic potentiation (PTP). We discover that Rap1 couples activation of Rut-cAMP-Epac signaling to Vav-mediated synaptic potentiation. These findings indicate that Rap1 acts as an essential, convergent node for Abelson kinase and cAMP signaling to mediate BMP-induced structural plasticity and activity-induced functional plasticity via Vav-dependent regulation of the presynaptic actin cytoskeleton.

Structural heterogeneity and plasticity of a Zr-based metallic glass modulated by high-temperature deformation

Metallic glasses (MGs) are of high strength but limited plasticity at room temperature (RT) due to localized shear in the intrinsically heterogeneous structure. Here, we investigate the variation of structural heterogeneity and plasticity of a Zr-based MG after high-temperature (T) tension under different stresses (σ) at 579 K (0.9Tg, where Tg is the glass transition temperature). The correlation length (ξ) of the heterogeneous structure and the average Young's modulus (E¯) increase with σ when σ is below 160 MPa; when σ exceeds 160 MPa, both ξ and E¯ decrease with σ, leading to the improvement of the plasticity. This research could be enlightening for improving the plasticity of MGs at RT through tuning their structural heterogeneity with high-T deformation.

Substance Addiction Rehabilitation Drugs.

The relapse rate of substance abusers is high, and addiction rehabilitation adjunct drugs need to be developed urgently. There have been numerous reports on blocking the formation of substance addiction, but studies on drugs that can alleviate withdrawal symptoms are very limited. Both the dopamine transporter (DAT) hypothesis and D3 dopamine receptor (D3R) hypothesis are proposed. DAT activators reduce the extracellular dopamine level, and D3R antagonists reduce the neuron's sensitivity to dopamine, both of which may exacerbate the withdrawal symptoms subsequently. The D3R partial agonist SK608 has biased signaling properties via the G-protein-dependent pathway but did not induce D3R desensitization and, thus, may be a promising drug for the withdrawal symptoms. Drugs for serotoninergic neurons or GABAergic neurons and anti-inflammatory drugs may have auxiliary effects to addiction treatments. Drugs that promote structural synaptic plasticity are also discussed.

Mapping proteomic composition of excitatory postsynaptic sites in the cerebellar cortex.

Functions of the cerebellar cortex, from motor learning to emotion and cognition, depend on the appropriate molecular composition at diverse synapse types. Glutamate receptor distributions have been partially mapped using immunogold electron microscopy. However, information is lacking on the distribution of many other components, such as Shank2, a postsynaptic scaffolding protein whose cerebellar dysfunction is associated with autism spectrum disorders. Here, we used an adapted Magnified Analysis of the Proteome, an expansion microscopy approach, to map multiple glutamate receptors, scaffolding and signaling proteins at single synapse resolution in the cerebellar cortex. Multiple distinct synapse-selective distribution patterns were observed. For example, AMPA receptors were most concentrated at synapses on molecular layer interneurons and at climbing fiber synapses, Shank1 was most concentrated at parallel fiber synapses on Purkinje cells, and Shank2 at both climbing fiber and parallel fiber synapses on Purkinje cells but little on molecular layer interneurons. Our results are consistent with gene expression data but also reveal input-selective targeting within Purkinje cells. In specialized glomerular structures of the granule cell layer, AMPA receptors as well as most other synaptic components preferentially targeted to synapses. However, NMDA receptors and the synaptic GTPase activating protein SynGAP preferentially targeted to extrasynaptic sites. Thus, glomeruli may be considered integrative signaling units through which mossy fibers differentially activate synaptic AMPA and extrasynaptic NMDA receptor complexes. Furthermore, we observed NMDA receptors and SynGAP at adherens junctions, suggesting a role in structural plasticity of glomeruli. Altogether, these data contribute to mapping the cerebellar 'synaptome'.

Mitral Cell Dendritic Morphology in the Adult Zebrafish Olfactory Bulb following Growth, Injury and Recovery.

The role of afferent target interactions in dendritic plasticity within the adult brain remains poorly understood. There is a paucity of data regarding the effects of deafferentation and subsequent dendritic recovery in adult brain structures. Moreover, although adult zebrafish demonstrate ongoing growth, investigations into the impact of growth on mitral cell (MC) dendritic arbor structure and complexity are lacking. Leveraging the regenerative capabilities of the zebrafish olfactory system, we conducted a comprehensive study to address these gaps. Employing an eight-week reversible deafferentation injury model followed by retrograde labeling, we observed substantial morphological alterations in MC dendrites. Our hypothesis posited that cessation of injury would facilitate recovery of MC dendritic arbor structure and complexity, potentially influenced by growth dynamics. Statistical analyses revealed significant changes in MC dendritic morphology following growth and recovery periods, indicating that MC total dendritic branch length retained significance after 8 weeks of deafferentation injury when normalized to individual fish physical characteristics. This suggests that regeneration of branch length could potentially function relatively independently of growth-related changes. These findings underscore the remarkable plasticity of adult dendritic arbor structures in a sophisticated model organism and highlight the efficacy of zebrafish as a vital implement for studying neuroregenerative processes.

Gaming expertise induces meso‑scale brain plasticity and efficiency mechanisms as revealed by whole-brain modeling

Video games are a valuable tool for studying the effects of training and neural plasticity on the brain. However, the underlying mechanisms related to plasticity-associated brain structural changes and their impact on brain dynamics are unknown. Here, we used a semi-empirical whole-brain model to study structural neural plasticity mechanisms linked to video game expertise. We hypothesized that video game expertise is associated with neural plasticity-mediated changes in structural connectivity that manifest at the meso‑scale level, resulting in a more segregated functional network topology. To test this hypothesis, we combined structural connectivity data of StarCraft II video game players (VGPs, n = 31) and non-players (NVGPs, n = 31), with generic fMRI data from the Human Connectome Project and computational models, to generate simulated fMRI recordings. Graph theory analysis on simulated data was performed during both resting-state conditions and external stimulation. VGPs’ simulated functional connectivity was characterized by a meso‑scale integration, with increased local connectivity in frontal, parietal, and occipital brain regions. The same analyses at the level of structural connectivity showed no differences between VGPs and NVGPs. Regions that increased their connectivity strength in VGPs are known to be involved in cognitive processes crucial for task performance such as attention, reasoning, and inference. In-silico stimulation suggested that differences in FC between VGPs and NVGPs emerge in noisy contexts, specifically when the noisy level of stimulation is increased. This indicates that the connectomes of VGPs may facilitate the filtering of noise from stimuli. These structural alterations drive the meso‑scale functional changes observed in individuals with gaming expertise. Overall, our work sheds light on the mechanisms underlying structural neural plasticity triggered by video game experiences.

The distribution and structural plasticity of excitatory synapses along interneuron dendrites in the adult hippocampus

Hippocampal interneurons form a large, heterogeneous group with differing structural, physiological, and chemical phenotypes. Most CA1 interneuron dendrites, however, lack spines. To investigate structural synaptic plasticity along interneuron dendrites, we generated three-dimensional (3D) reconstructions from serial section electron microscopy (EM) of excitatory synapses along aspiny dendrites in CA1 stratum radiatum of young adult rats under control conditions and at 2 h during LTP induced with theta-burst stimulation. In total, 43 aspiny dendritic segments and their synapses were identified and reconstructed in 3D. Aspiny dendrites were categorized as smooth or varicose based on dendritic volume contours along each segment. We further sub-segmented varicose dendrites varicosities and inter-varicose regions using automated and manual methods. We found synapses and total synaptic input per length were distributed uniformly along smooth dendrites. Synapses along varicose dendrites, however, occurred preferentially at varicosities. While synaptic input per length along varicosities was similar to that along smooth dendrites, both synapse number and total synaptic input per length along inter-varicose regions were lower. Dendritic segments were also analyzed for mitochondria and glycogen content. We found that mitochondria and glycogen were also distributed uniformly along smooth dendrites. In varicose dendrites, however, mitochondrial volume and glycogen granule numbers were highest in varicosities, while inter-varicose regions were comparatively devoid of these resources. The spatial distribution of synapses and dendritic resources in both smooth and varicose dendrites was preserved at 2 h during LTP when compared to control conditions. These findings suggest that synapses occur along interneuron dendrites where dendritic resources are most available. When dendritic resources are distributed uniformly throughout the dendrite, as occurs in smooth dendrites, synapse distribution is also uniform. Varicosities, on the other hand, represent resource-rich sites along varicose dendrites where synaptic clustering occurs. This work was supported by the National Science Foundation (NSF 1707356, NSF 2014862) and the National Institutes of Health (R01 5R01MH09598). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The caloric value of food intake structurally adjusts a neuronal mushroom body circuit mediating olfactory learning in Drosophila.

Associative learning enables the adaptive adjustment of behavioral decisions based on acquired, predicted outcomes. The valence of what is learned is influenced not only by the learned stimuli and their temporal relations, but also by prior experiences and internal states. In this study, we used the fruit fly Drosophila melanogaster to demonstrate that neuronal circuits involved in associative olfactory learning undergo restructuring during extended periods of low-caloric food intake. Specifically, we observed a decrease in the connections between specific dopaminergic neurons (DANs) and Kenyon cells at distinct compartments of the mushroom body. This structural synaptic plasticity was contingent upon the presence of allatostatin A receptors in specific DANs and could be mimicked optogenetically by expressing a light-activated adenylate cyclase in exactly these DANs. Importantly, we found that this rearrangement in synaptic connections influenced aversive, punishment-induced olfactory learning but did not impact appetitive, reward-based learning. Whether induced by prolonged low-caloric conditions or optogenetic manipulation of cAMP levels, this synaptic rearrangement resulted in a reduction of aversive associative learning. Consequently, the balance between positive and negative reinforcing signals shifted, diminishing the ability to learn to avoid odor cues signaling negative outcomes. These results exemplify how a neuronal circuit required for learning and memory undergoes structural plasticity dependent on prior experiences of the nutritional value of food.

The SNX17-Retriever endosomal recycling pathway is a key regulator of synaptic function and plasticity in hippocampal neurons

The insertion and removal of integral membrane proteins is a key mechanism for the regulation of synaptic function. Once surface proteins are internalized, they can either be routed to lysosomes for degradation or can be recycled back to the cell surface. Two recycling protein complexes - the SNX27-Retromer complex and the recently discovered SNX17-Retriever complex - are the main drivers in recycling internalized cargoes in non-neuronal cells. In neurons, the SNX27-Retromer pathway has been shown to regulate surface expression of AMPA-type glutamate receptors (AMPARs) during long-term potentiation (LTP), but almost nothing is known regarding the role of the SNX17-Retriever pathway at synapses. Here, using cultured hippocampal neurons, we demonstrate that the SNX17-Retriever pathway localizes to both synaptic and extra-synaptic sites and that RNAi-mediated disruption of this pathway leads to the functional and structural loss of excitatory synapses. Moreover, we find that synaptic stimulation leads to the recruitment of SNX17 to synaptic sites in a manner that depends on Ca2+ influx through NMDARs, activation of CaMKII, and Retriever complex binding. Knockdown of either SNX17 or the Retriever subunit DSCR3 prevents structural plasticity of dendritic spines during LTP. Finally, this loss of structural plasticity is associated with altered traffcking of the cell adhesion molecule β1 Integrin, which is a SNX17 cargo in non-neuronal cells and as we show, in neurons as well. Additionally, SNX17-Retriever is shown to not play a role in AMPAR recycling. Preliminary studies suggest that SNX27 and SNX17 sort distinct cargos in neurons, suggesting that these two recycling pathways each play important, but unique, roles at synaptic sites. National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) under award numbers R01-NS129198 to L.S. Weisman and M.A. Sutton, R01-NS099340 and R01- NS064015 to L.S. Weisman, R01-NS097498 to M.A. Sutton, and R21-NS125449, and R01-NS116008 to S. Iwase, by the National Institute of Mental Health (NIMH) of the NIH under award number R21-MH127485 to S. Iwase. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exploring the Role of Neuroplasticity in Stroke Rehabilitation: Mechanisms, Interventions and Clinical Implications

Neuroplasticity, the brain's remarkable ability to reorganize and adapt throughout life, has emerged as a central focus in neuroscience research. This abstract delves into the mechanisms underlying neuroplasticity and its profound implications for learning, memory, rehabilitation, and neurological disorders. At the cellular level, neuroplasticity involves synaptic plasticity, where the strength and efficacy of connections between neurons can be modified through activity-dependent processes such as long-term potentiation (LTP) and long-term depression (LTD). Molecular mechanisms, including changes in neurotransmitter release, receptor expression, and intracellular signaling pathways, mediate these synaptic changes. Beyond synaptic plasticity, structural plasticity encompasses alterations in neuronal morphology, including dendritic branching, spine density, and axonal sprouting. These structural changes facilitate the formation of new neural circuits and underlie learning and memory processes. Neuroplasticity is not limited to developmental stages but persists throughout life, with experience and environmental factors continuously shaping the brain's structure and function. Experience-dependent plasticity is evident in various contexts, from skill acquisition to recovery from brain injuries. Understanding neuroplasticity has profound implications for education, as it highlights the importance of enriched environments and active learning strategies in promoting cognitive development. Additionally, neuroplasticity forms the basis for rehabilitative interventions following brain damage, with therapies focusing on promoting adaptive neural rewiring and functional recovery. Moreover, dysregulation of neuroplasticity is implicated in numerous neurological and psychiatric disorders, including Alzheimer's disease, stroke, and depression. Elucidating the mechanisms underlying aberrant plasticity holds promise for developing targeted interventions to treat these conditions. In conclusion, neuroplasticity represents a fundamental property of the nervous system, allowing for adaptation and optimization in response to environmental demands. Continued research into the mechanisms governing neuroplasticity promises to unveil new therapeutic avenues and deepen our understanding of brain function and dysfunction.

Exploring the Structural Plasticity Mechanism of Corticospinal Tract during Stroke Rehabilitation Based Automated Fiber Quantification Tractography.

Corticospinal tract (CST) is the principal motor pathway; we aim to explore the structural plasticity mechanism in CST during stroke rehabilitation. A total of 25 patients underwent diffusion tensor imaging before rehabilitation (T1), 1-month post-rehabilitation (T2), 2 months post-rehabilitation (T3), and 1-year post-discharge (T4). The CST was segmented, and fractional anisotropy (FA), axial diffusion (AD), mean diffusivity (MD), and radial diffusivity (RD) were determined using automated fiber quantification tractography. Baseline level of laterality index (LI) and motor function for correlation analysis. The FA values of all segments in the ipsilesional CST (IL-CST) were lower compared with normal CST. Repeated measures analysis of variance showed time-related effects on FA, AD, and MD of the IL-CST, and there were similar dynamic trends in these 3 parameters. At T1, FA, AD, and MD values of the mid-upper segments of IL-CST (around the core lesions) were the lowest; at T2 and T3, values for the mid-lower segments were lower than those at T1, while the values for the mid-upper segments gradually increased; at T4, the values for almost entire IL-CST were higher than before. The highest LI was observed at T2, with a predominance in contralesional CST. The LIs for the FA and AD at T1 were positively correlated with the change rate of motor function. IL-CST showed aggravation followed by improvement from around the lesion to the distal end. Balance of interhemispheric CST may be closely related to motor function, and LIs for FA and AD may have predictive value for mild-to-moderate stroke rehabilitation. Clinical Trial Registration. URL: http://www.chictr.org.cn; Unique Identifier: ChiCTR1800019474.

Abstinence and Fear Experienced during This Period Produce Distinct Cortical and Hippocampal Adaptations in Alcohol-Dependent Rats.

Previous studies demonstrate that ethanol dependence induced by repeating cycles of chronic intermittent ethanol vapor exposure (CIE) followed by protracted abstinence produces significant gray matter damage via myelin dysfunction in the rodent medial prefrontal cortex (mPFC) and alterations in neuronal excitability in the mPFC and the dentate gyrus (DG) of the hippocampus. Specifically, abstinence-induced neuroadaptations have been associated with persistent elevated relapse to drinking. The current study evaluated the effects of forced abstinence for 1 day (d), 7 d, 21 d, and 42 d following seven weeks of CIE on synaptic plasticity proteins in the mPFC and DG. Immunoblotting revealed reduced expression of CaMKII in the mPFC and enhanced expression of GABAA and CaMKII in the DG at the 21 d time point, and the expression of the ratio of GluN2A/2B subunits did not change at any of the time points studied. Furthermore, cognitive performance via Pavlovian trace fear conditioning (TFC) was evaluated in 3 d abstinent rats, as this time point is associated with negative affect. In addition, the expression of the ratio of GluN2A/2B subunits and a 3D structural analysis of neurons in the mPFC and DG were evaluated in 3 d abstinent rats. Behavioral analysis revealed faster acquisition of fear responses and reduced retrieval of fear memories in CIE rats compared to controls. TFC produced hyperplasticity of pyramidal neurons in the mPFC under control conditions and this effect was not evident or blunted in abstinent rats. Neurons in the DG were unaltered. TFC enhanced the GluN2A/2B ratio in the mPFC and reduced the ratio in the DG and was not altered by abstinence. These findings indicate that forced abstinence from CIE produces distinct and divergent alterations in plasticity proteins in the mPFC and DG. Fear learning-induced changes in structural plasticity and proteins contributing to it were more profound in the mPFC during forced abstinence.

MiR-145a-5p/SIK1/cAMP-dependent alteration of synaptic structural plasticity drives cognitive impairment induced by coke oven emissions

Exposure to fine particulate matter (PM) is associated with the neurodegenerative diseases. Coke oven emissions (COEs) in occupational environment are important sources of PM. However, its neurotoxicity is still unclear. Therefore, evaluating the toxicological effects of COE on the nervous system is necessary. In the present study, we constructed mouse models of COE exposure by tracheal instillation. Mice exposed to COE showed signs of cognitive impairment. This was accompanied by a decrease in miR-145a-5p and an increase in SIK1 expression in the hippocampus, along with synaptic structural damage. Our results demonstrated that COE-induced miR-145a-5p downregulation could increase the expression of SIK1 and phosphorylated SIK1, inhibiting the cAMP/PKA/CREB pathway by activating PDE4D, which was associated with reduced synaptic structural plasticity. Furthermore, restoring of miR-145a-5p expression based on COE exposure in HT22 cells could partially reversed the negative effects of COE exposure through the SIK1/PDE4D/cAMP axis. Collectively, our findings link epigenetic regulation with COE-induced neurotoxicity and imply that miR-145a-5p could be an early diagnostic marker for neurological diseases in patients with COE occupational exposure.

Molecular mechanisms underlying structural plasticity of electroconvulsive therapy in major depressive disorder.

Although previous studies reported structural changes associated with electroconvulsive therapy (ECT) in major depressive disorder (MDD), the underlying molecular basis of ECT remains largely unknown. Here, we combined two independent structural MRI datasets of MDD patients receiving ECT and transcriptomic gene expression data from Allen Human Brain Atlas to reveal the molecular basis of ECT for MDD. We performed partial least square regression to explore whether/how gray matter volume (GMV) alterations were associated with gene expression level. Functional enrichment analysis was conducted using Metascape to explore ontological pathways of the associated genes. Finally, these genes were further assigned to seven cell types to determine which cell types contribute most to the structural changes in MDD patients after ECT. We found significantly increased GMV in bilateral hippocampus in MDD patients after ECT. Transcriptome-neuroimaging association analyses showed that expression levels of 726 genes were positively correlated with the increased GMV in MDD after ECT. These genes were mainly involved in synaptic signaling, calcium ion binding and cell-cell signaling, and mostly belonged to excitatory and inhibitory neurons. Moreover, we found that the MDD risk genes of CNR1, HTR1A, MAOA, PDE1A, and SST as well as ECT related genes of BDNF, DRD2, APOE, P2RX7, and TBC1D14 showed significantly positive associations with increased GMV. Overall, our findings provide biological and molecular mechanisms underlying structural plasticity induced by ECT in MDD and the identified genes may facilitate future therapy for MDD.