Engaging Mood Brain Circuits with Psilocybin (EMBRACE): a study protocol for a randomized, placebo-controlled and delayed-start, neuroimaging trial in depression.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide across domains of health and cognition, affecting overall quality of life. Approximately one third of individuals with depression do not fully respond to treatments (e.g., conventional antidepressants, psychotherapy) and alternative strategies are needed. Recent early phase trials suggest psilocybin may be a safe and efficacious intervention with rapid-acting antidepressant properties. Psilocybin is thought to exert therapeutic benefits by altering brain network connectivity and inducing neuroplastic changes that endure for weeks post-treatment. Although early clinical results are encouraging, psilocybin's acute neurobiological effects on neuroplasticity have not been fully investigated. We aim to examine for the first time how psilocybin acutely (intraday) and subacutely (weeks) alters functional brain networks implicated in depression. METHODS: Fifty participants diagnosed with MDD or persistent depressive disorder (PDD) will be recruited from a tertiary mood disorders clinic and undergo 1:1 randomization into either an experimental or control arm. Participants will be given either 25 mg psilocybin or 25 mg microcrystalline cellulose (MCC) placebo for the first treatment. Three weeks later, those in the control arm will transition to receiving 25 mg psilocybin. We will investigate whether treatments are associated with changes in arterial spin labelling and blood oxygenation level-dependent contrast neuroimaging assessments at acute and subacute timepoints. Primary outcomes include testing whether psilocybin demonstrates acute changes in (1) cerebral blood flow and (2) functional brain activity in networks associated with mood regulation and depression when compared to placebo, along with changes in MADRS score over time compared to placebo. Secondary outcomes include changes across complementary clinical psychiatric, cognitive, and functional scales from baseline to final follow-up. Serum peripheral neurotrophic and inflammatory biomarkers will be collected at baseline and follow-up to examine relationships with clinical response, and neuroimaging measures. DISCUSSION: This study will investigate the acute and additive subacute neuroplastic effects of psilocybin on brain networks affected by depression using advanced serial neuroimaging methods. Results will improve our understanding of psilocybin's antidepressant mechanisms versus placebo response and whether biological measures of brain function can provide early predictors of treatment response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06072898. Registered on 6 October 2023.

ZBTB21 suppresses CRE-mediated transcription to impair synaptic function in Down syndrome.

Down syndrome (DS) is the most common chromosomal disorder and a major cause of intellectual disability. The genetic etiology of DS is the extra copy of chromosome 21 (HSA21)-encoded genes; however, the contribution of specific HSA21 genes to DS pathogenesis remains largely unknown. Here, we identified ZBTB21, an HSA21-encoded zinc-finger protein, as a transcriptional repressor in the regulation of synaptic function. We found that normalization of the Zbtb21 gene copy number in DS mice corrected deficits in cognitive performance, synaptic function, and gene expression. Moreover, we demonstrated that ZBTB21 binds to canonical cAMP-response element (CRE) DNA and that its binding to CRE could be competitive with CRE-binding factors such as CREB. ZBTB21 represses CRE-dependent gene expression and results in the negative regulation of synaptic plasticity, learning and memory. Together, our results identify ZBTB21 as a CRE-binding protein and repressor in cAMP-dependent gene regulation, contributing to cognitive defects in DS.

Aberrant Hippocampal Neuroregenerative Plasticity in Schizophrenia: Reactive Neuroblastosis as a Possible Pathocellular Mechanism of Hallucination.

Hallucination is a sensory perception that occurs in the absence of external stimuli during abnormal neurological disturbances and various mental diseases. Hallucination is recognized as a core psychotic symptom and is particularly more prevalent in individuals with schizophrenia. Strikingly, a significant number of subjects with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and other neurological diseases like cerebral stroke and epileptic seizure also experience hallucination. While aberrant neurotransmission has been linked to the neuropathogenic events of schizophrenia, the precise cellular mechanism accounting for hallucinations remains obscure. Neurogenesis is a cellular process of producing new neurons from the neural stem cells (NSC)-derived neuroblasts in the brain that contribute to the regulation of pattern separation, mood, olfaction, learning, and memory in adulthood. Impaired neurogenesis in the hippocampus of the adult brain has been linked to stress, anxiety, depression, and dementia. Notably, many neurodegenerative disorders are characterized by the mitotic and functional activation of neuroblasts and cell cycle re-entry of mature neurons leading to a drastic alteration in neurogenic process, known as reactive neuroblastosis. Considering their neurophysiological properties, the abnormal integration of neuroblasts into the existing neural network or withdrawal of their connections can lead to abnormal synaptogenesis, and neurotransmission. Eventually, this would be expected to result in altered perception accounting for hallucination. Thus, this article emphasizes a hypothesis that aberrant neurogenic processes at the level of reactive neuroblastosis could be an underlying mechanism of hallucination in schizophrenia and other neurological diseases.

Astrocytic NMDA Receptors.

Astrocytic NMDA receptors (NMDARs) are heterotetramers, whose expression and properties are largely determined by their subunit composition. Astrocytic NMDARs are characterized by a low sensitivity to magnesium ions and low calcium conductivity. Their activation plays an important role in the regulation of various intracellular processes, such as gene expression and mitochondrial function. Astrocytic NMDARs are involved in calcium signaling in astrocytes and can act through the ionotropic and metabotropic pathways. Astrocytic NMDARs participate in the interactions of the neuroglia, thus affecting synaptic plasticity. They are also engaged in the astrocyte-vascular interactions and contribute to the regulation of vascular tone. Astrocytic NMDARs are involved in various pathologies, such as ischemia and hyperammonemia, and their blockade prevents negative changes in astrocytes during these diseases.

Monoallelic de novo AJAP1 loss-of-function variants disrupt trans-synaptic control of neurotransmitter release.

Adherens junction-associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed significantly decreased presynaptic GBR levels in Ajap1-/- and Ajap1W183C/+ mice. Consequently, these mice exhibited reduced GBR-mediated presynaptic inhibition at excitatory and inhibitory synapses, along with impaired synaptic plasticity. Our study reveals that AJAP1 enables the postsynaptic neuron to regulate the level of presynaptic GBR-mediated inhibition, supporting the clinical relevance of loss-of-function AJAP1 variants.

CPEB2-activated axonal translation of VGLUT2 mRNA promotes glutamatergic transmission and presynaptic plasticity.

BACKGROUND: Local translation at synapses is important for rapidly remodeling the synaptic proteome to sustain long-term plasticity and memory. While the regulatory mechanisms underlying memory-associated local translation have been widely elucidated in the postsynaptic/dendritic region, there is no direct evidence for which RNA-binding protein (RBP) in axons controls target-specific mRNA translation to promote long-term potentiation (LTP) and memory. We previously reported that translation controlled by cytoplasmic polyadenylation element binding protein 2 (CPEB2) is important for postsynaptic plasticity and memory. Here, we investigated whether CPEB2 regulates axonal translation to support presynaptic plasticity. METHODS: Behavioral and electrophysiological assessments were conducted in mice with pan neuron/glia- or glutamatergic neuron-specific knockout of CPEB2. Hippocampal Schaffer collateral (SC)-CA1 and temporoammonic (TA)-CA1 pathways were electro-recorded to monitor synaptic transmission and LTP evoked by 4 trains of high-frequency stimulation. RNA immunoprecipitation, coupled with bioinformatics analysis, were used to unveil CPEB2-binding axonal RNA candidates associated with learning, which were further validated by Western blotting and luciferase reporter assays. Adeno-associated viruses expressing Cre recombinase were stereotaxically delivered to the pre- or post-synaptic region of the TA circuit to ablate Cpeb2 for further electrophysiological investigation. Biochemically isolated synaptosomes and axotomized neurons cultured on a microfluidic platform were applied to measure axonal protein synthesis and FM4-64FX-loaded synaptic vesicles. RESULTS: Electrophysiological analysis of hippocampal CA1 neurons detected abnormal excitability and vesicle release probability in CPEB2-depleted SC and TA afferents, so we cross-compared the CPEB2-immunoprecipitated transcriptome with a learning-induced axonal translatome in the adult cortex to identify axonal targets possibly regulated by CPEB2. We validated that Slc17a6, encoding vesicular glutamate transporter 2 (VGLUT2), is translationally upregulated by CPEB2. Conditional knockout of CPEB2 in VGLUT2-expressing glutamatergic neurons impaired consolidation of hippocampus-dependent memory in mice. Presynaptic-specific ablation of Cpeb2 in VGLUT2-dominated TA afferents was sufficient to attenuate protein synthesis-dependent LTP. Moreover, blocking activity-induced axonal Slc17a6 translation by CPEB2 deficiency or cycloheximide diminished the releasable pool of VGLUT2-containing synaptic vesicles. CONCLUSIONS: We identified 272 CPEB2-binding transcripts with altered axonal translation post-learning and established a causal link between CPEB2-driven axonal synthesis of VGLUT2 and presynaptic translation-dependent LTP. These findings extend our understanding of memory-related translational control mechanisms in the presynaptic compartment.

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.

Synaptic reorganization of synchronized neuronal networks with synaptic weight and structural plasticity.

Abnormally strong neural synchronization may impair brain function, as observed in several brain disorders. We computationally study how neuronal dynamics, synaptic weights, and network structure co-emerge, in particular, during (de)synchronization processes and how they are affected by external perturbation. To investigate the impact of different types of plasticity mechanisms, we combine a network of excitatory integrate-and-fire neurons with different synaptic weight and/or structural plasticity mechanisms: (i) only spike-timing-dependent plasticity (STDP), (ii) only homeostatic structural plasticity (hSP), i.e., without weight-dependent pruning and without STDP, (iii) a combination of STDP and hSP, i.e., without weight-dependent pruning, and (iv) a combination of STDP and structural plasticity (SP) that includes hSP and weight-dependent pruning. To accommodate the diverse time scales of neuronal firing, STDP, and SP, we introduce a simple stochastic SP model, enabling detailed numerical analyses. With tools from network theory, we reveal that structural reorganization may remarkably enhance the network's level of synchrony. When weaker contacts are preferentially eliminated by weight-dependent pruning, synchrony is achieved with significantly sparser connections than in randomly structured networks in the STDP-only model. In particular, the strengthening of contacts from neurons with higher natural firing rates to those with lower rates and the weakening of contacts in the opposite direction, followed by selective removal of weak contacts, allows for strong synchrony with fewer connections. This activity-led network reorganization results in the emergence of degree-frequency, degree-degree correlations, and a mixture of degree assortativity. We compare the stimulation-induced desynchronization of synchronized states in the STDP-only model (i) with the desynchronization of models (iii) and (iv). The latter require stimuli of significantly higher intensity to achieve long-term desynchronization. These findings may inform future pre-clinical and clinical studies with invasive or non-invasive stimulus modalities aiming at inducing long-lasting relief of symptoms, e.g., in Parkinson's disease.

Recent progress in dendritic pruning of Drosophila C4da sensory neurons.

The brain can adapt to changes in the environment through alterations in the number and structure of synapses. During embryonic and early postnatal stages, the synapses in the brain undergo rapid expansion and interconnections to form circuits. However, many of these synaptic connections are redundant or incorrect. Neurite pruning is a conserved process that occurs during both vertebrate and invertebrate development. It requires precise spatiotemporal control of local degradation of cellular components, comprising cytoskeletons and membranes, refines neuronal circuits, and ensures the precise connectivity required for proper function. The Drosophila's class IV dendritic arborization (C4da) sensory neuron has a well-characterized architecture and undergoes dendrite-specific sculpting, making it a valuable model for unravelling the intricate regulatory mechanisms underlie dendritic pruning. In this review, I attempt to provide an overview of the present state of research on dendritic pruning in C4da sensory neurons, as well as potential functional mechanisms in neurodevelopmental disorders.

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.

Development of ocular dominance columns across rodents and other species: revisiting the concept of critical period plasticity.

The existence of cortical columns, regarded as computational units underlying both lower and higher-order information processing, has long been associated with highly evolved brains, and previous studies suggested their absence in rodents. However, recent discoveries have unveiled the presence of ocular dominance columns (ODCs) in the primary visual cortex (V1) of Long-Evans rats. These domains exhibit continuity from layer 2 through layer 6, confirming their identity as genuine ODCs. Notably, ODCs are also observed in Brown Norway rats, a strain closely related to wild rats, suggesting the physiological relevance of ODCs in natural survival contexts, although they are lacking in albino rats. This discovery has enabled researchers to explore the development and plasticity of cortical columns using a multidisciplinary approach, leveraging studies involving hundreds of individuals-an endeavor challenging in carnivore and primate species. Notably, developmental trajectories differ depending on the aspect under examination: while the distribution of geniculo-cortical afferent terminals indicates matured ODCs even before eye-opening, consistent with prevailing theories in carnivore/primate studies, examination of cortical neuron spiking activities reveals immature ODCs until postnatal day 35, suggesting delayed maturation of functional synapses which is dependent on visual experience. This developmental gap might be recognized as 'critical period' for ocular dominance plasticity in previous studies. In this article, I summarize cross-species differences in ODCs and geniculo-cortical network, followed by a discussion on the development, plasticity, and evolutionary significance of rat ODCs. I discuss classical and recent studies on critical period plasticity in the venue where critical period plasticity might be a component of experience-dependent development. Consequently, this series of studies prompts a paradigm shift in our understanding of species conservation of cortical columns and the nature of plasticity during the classical critical period.

Obesity- and diet-induced plasticity in systems that control eating and energy balance.

In April 2023, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in partnership with the National Institute of Child Health and Human Development, the National Institute on Aging, and the Office of Behavioral and Social Sciences Research, hosted a 2-day online workshop to discuss neural plasticity in energy homeostasis and obesity. The goal was to provide a broad view of current knowledge while identifying research questions and challenges regarding neural systems that control food intake and energy balance. This review includes highlights from the meeting and is intended both to introduce unfamiliar audiences with concepts central to energy homeostasis, feeding, and obesity and to highlight up-and-coming research in these areas that may be of special interest to those with a background in these fields. The overarching theme of this review addresses plasticity within the central and peripheral nervous systems that regulates and influences eating, emphasizing distinctions between healthy and disease states. This is by no means a comprehensive review because this is a broad and rapidly developing area. However, we have pointed out relevant reviews and primary articles throughout, as well as gaps in current understanding and opportunities for developments in the field.

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.

Transcranial direct current stimulation-induced changes in motor cortical connectivity are associated with motor gains following ischemic stroke.

Understanding the response of the injured brain to different transcranial direct current stimulation (tDCS) montages may help explain the variable tDCS treatment results on poststroke motor gains. Cortical connectivity has been found to reflect poststroke motor gains and cortical plasticity, but the changes in connectivity following tDCS remain unknown. We aimed to investigate the relationship between tDCS-induced changes in cortical connectivity and poststroke motor gains. In this study, participants were assigned to receive four tDCS montages (anodal, cathodal, bilateral, and sham) over the primary motor cortex (M1) according to a single-blind, randomized, crossover design. Electroencephalography (EEG) and Jebsen-Taylor hand function test (JTT) were performed before and after the intervention. Motor cortical connectivity was measured using beta-band coherence with the ipsilesional and contralesional M1 as seed regions. Motor gain was evaluated based on the JTT completion time. We examined the relationship between baseline connectivity and clinical characteristics and that between changes in connectivity and motor gains after different tDCS montages. Baseline functional connectivity, motor impairment, and poststroke duration were correlated. High ipsilesional M1-frontal-temporal connectivity was correlated with a good baseline motor status, and increased connectivity was accompanied by good functional improvement following anodal tDCS treatment. Low contralesional M1-frontal-central connectivity was correlated with a good baseline motor status, and decreased connectivity was accompanied by good functional improvement following cathodal tDCS treatment. In conclusion, EEG-based motor cortical connectivity was correlated with stroke characteristics, including motor impairment and poststroke duration, and motor gains induced by anodal and cathodal tDCS.

Early attentional processing and cortical remapping strategies of tactile stimuli in adults with an early and late-onset visual impairment: A cross-sectional study.

Neuroplastic changes appear in people with visual impairment (VI) and they show greater tactile abilities. Improvements in performance could be associated with the development of enhanced early attentional processes based on neuroplasticity. Currently, the various early attentional and cortical remapping strategies that are utilized by people with early (EB) and late-onset blindness (LB) remain unclear. Thus, more research is required to develop effective rehabilitation programs and substitution devices. Our objective was to explore the differences in spatial tactile brain processing in adults with EB, LB and a sighted control group (CG). In this cross-sectional study 27 participants with VI were categorized into EB (n = 14) and LB (n = 13) groups. They were then compared with a CG (n = 15). A vibrotactile device and event-related potentials (ERPs) were utilized while participants performed a spatial tactile line recognition task. The P100 latency and cortical areas of maximal activity were analyzed during the task. The three groups had no statistical differences in P100 latency (p>0.05). All subjects showed significant activation in the right superior frontal areas. Only individuals with VI activated the left superior frontal regions. In EB subjects, a higher activation was found in the mid-frontal and occipital areas. A higher activation of the mid-frontal, anterior cingulate cortex and orbitofrontal zones was observed in LB participants. Compared to the CG, LB individuals showed greater activity in the left orbitofrontal zone, while EB exhibited greater activity in the right superior parietal cortex. The EB had greater activity in the left orbitofrontal region compared to the LB. People with VI may not have faster early attentional processing. EB subjects activate the occipital lobe and right superior parietal cortex during tactile stimulation because of an early lack of visual stimuli and a multimodal information processing. In individuals with LB and EB the orbitofrontal area is activated, suggesting greater emotional processing.

Systemic pharmacological suppression of neural activity reverses learning impairment in a mouse model of Fragile X syndrome.

The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments can result from saturation of the plasticity mechanism (Nguyen-Vu et al., 2017), or, more generally, from a history-dependent change in the threshold for plasticity. This hypothesis was based on experimental results from mice lacking two class I major histocompatibility molecules, MHCI H2-Kb and H2-Db (MHCI KbDb-/-), which have enhanced associative long-term depression at the parallel fiber-Purkinje cell synapses in the cerebellum (PF-Purkinje cell LTD). Here, we extend this work by testing predictions of the threshold metaplasticity hypothesis in a second mouse line with enhanced PF-Purkinje cell LTD, the Fmr1 knockout mouse model of Fragile X syndrome (FXS). Mice lacking Fmr1 gene expression in cerebellar Purkinje cells (L7-Fmr1 KO) were selectively impaired on two oculomotor learning tasks in which PF-Purkinje cell LTD has been implicated, with no impairment on LTD-independent oculomotor learning tasks. Consistent with the threshold metaplasticity hypothesis, behavioral pre-training designed to reverse LTD at the PF-Purkinje cell synapses eliminated the oculomotor learning deficit in the L7-Fmr1 KO mice, as previously reported in MHCI KbDb-/-mice. In addition, diazepam treatment to suppress neural activity and thereby limit the induction of associative LTD during the pre-training period also eliminated the learning deficits in L7-Fmr1 KO mice. These results support the hypothesis that cerebellar LTD-dependent learning is governed by an experience-dependent sliding threshold for plasticity. An increased threshold for LTD in response to elevated neural activity would tend to oppose firing rate stability, but could serve to stabilize synaptic weights and recently acquired memories. The metaplasticity perspective could inform the development of new clinical approaches for addressing learning impairments in autism and other disorders of the nervous system.

Spotlight on plasticity-related genes: Current insights in health and disease.

The development of the central nervous system is highly complex, involving numerous developmental processes that must take place with high spatial and temporal precision. This requires a series of complex and well-coordinated molecular processes that are tighly controlled and regulated by, for example, a variety of proteins and lipids. Deregulations in these processes, including genetic mutations, can lead to the most severe maldevelopments. The present review provides an overview of the protein family Plasticity-related genes (PRG1-5), including their role during neuronal differentiation, their molecular interactions, and their participation in various diseases. As these proteins can modulate the function of bioactive lipids, they are able to influence various cellular processes. Furthermore, they are dynamically regulated during development, thus playing an important role in the development and function of synapses. First studies, conducted not only in mouse experiments but also in humans, revealed that mutations or dysregulations of these proteins lead to changes in lipid metabolism, resulting in severe neurological deficits. In recent years, as more and more studies have shown their involvement in a broad range of diseases, the complexity and broad spectrum of known and as yet unknown interactions between PRGs, lipids, and proteins make them a promising and interesting group of potential novel therapeutic targets.

High-frequency repetitive transcranial magnetic stimulation ameliorates memory impairment by inhibiting neuroinflammation in the chronic cerebral hypoperfusion mice.

BACKGROUND: High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has been found to ameliorate cognitive impairment. However, the effects of HF-rTMS remain unknown in chronic cerebral hypoperfusion (CCH). AIM: To investigate the effects of HF-rTMS on cognitive improvement and its potential mechanisms in CCH mice. MATERIALS AND METHODS: Daily HF-rTMS therapy was delivered after bilateral carotid stenosis (BCAS) and continued for 14 days. The mice were randomly assigned to three groups: the sham group, the model group, and the HF-rTMS group. The Y maze and the new object recognition test were used to assess cognitive function. The expressions of MAP-2, synapsis, Myelin basic protein(MBP), and brain-derived growth factors (BDNF) were analyzed by immunofluorescence staining and western blot to evaluate neuronal plasticity and white matter myelin regeneration. Nissl staining and the expression of caspase-3, Bax, and Bcl-2 were used to observe neuronal apoptosis. In addition, the activation of microglia and astrocytes were evaluated by fluorescence staining. The inflammation levels of IL-1ß, IL-6, and Tumor Necrosis Factor(TNF)-α were detected by qPCR in the hippocampus of mice in each group. RESULTS: Via behavioral tests, the BCAS mice showed reduced a rate of new object preference and decreased a rate of spontaneous alternations, while HF-rTMS significantly improved hippocampal learning and memory deficits. In addition, the mice in the model group showed decreased levels of MAP-2, synapsis, MBP, and BDNF, while HF-rTMS treatment reversed these effects. As expected, activated microglia and astrocytes increased in the model group, but HF-rTMS treatment suppressed these changes. HF-rTMS decreased BCAS-induced neuronal apoptosis and the expression of pro-apoptotic protein (Caspase-3 and Bax) and increased the expression of anti-apoptotic protein (Bcl-2). In addition, HF-rTMS inhibited the expression of inflammatory cytokines (IL-1ß, IL-6, and TNF-α). CONCLUSIONS: HF-rTMS alleviates cognitive impairment in CCH mice by enhancing neuronal plasticity and inhibiting inflammation, thus serving as a potential method for vascular cognitive impairment.

Co-existence of synaptic plasticity and metastable dynamics in a spiking model of cortical circuits.

Evidence for metastable dynamics and its role in brain function is emerging at a fast pace and is changing our understanding of neural coding by putting an emphasis on hidden states of transient activity. Clustered networks of spiking neurons have enhanced synaptic connections among groups of neurons forming structures called cell assemblies; such networks are capable of producing metastable dynamics that is in agreement with many experimental results. However, it is unclear how a clustered network structure producing metastable dynamics may emerge from a fully local plasticity rule, i.e., a plasticity rule where each synapse has only access to the activity of the neurons it connects (as opposed to the activity of other neurons or other synapses). Here, we propose a local plasticity rule producing ongoing metastable dynamics in a deterministic, recurrent network of spiking neurons. The metastable dynamics co-exists with ongoing plasticity and is the consequence of a self-tuning mechanism that keeps the synaptic weights close to the instability line where memories are spontaneously reactivated. In turn, the synaptic structure is stable to ongoing dynamics and random perturbations, yet it remains sufficiently plastic to remap sensory representations to encode new sets of stimuli. Both the plasticity rule and the metastable dynamics scale well with network size, with synaptic stability increasing with the number of neurons. Overall, our results show that it is possible to generate metastable dynamics over meaningful hidden states using a simple but biologically plausible plasticity rule which co-exists with ongoing neural dynamics.

Hemispheric functional organization, as revealed by naturalistic neuroimaging, in pediatric epilepsy patients with cortical resections.

Functional changes in the pediatric brain following neural injuries attest to remarkable feats of plasticity. Investigations of the neurobiological mechanisms that underlie this plasticity have largely focused on activation in the penumbra of the lesion or in contralesional, homotopic regions. Here, we adopt a whole-brain approach to evaluate the plasticity of the cortex in patients with large unilateral cortical resections due to drug-resistant childhood epilepsy. We compared the functional connectivity (FC) in patients' preserved hemisphere with the corresponding hemisphere of matched controls as they viewed and listened to a movie excerpt in a functional magnetic resonance imaging (fMRI) scanner. The preserved hemisphere was segmented into 180 and 200 parcels using two different anatomical atlases. We calculated all pairwise multivariate statistical dependencies between parcels, or parcel edges, and between 22 and 7 larger-scale functional networks, or network edges, aggregated from the smaller parcel edges. Both the left and right hemisphere-preserved patient groups had widespread reductions in FC relative to matched controls, particularly for within-network edges. A case series analysis further uncovered subclusters of patients with distinctive edgewise changes relative to controls, illustrating individual postoperative connectivity profiles. The large-scale differences in networks of the preserved hemisphere potentially reflect plasticity in the service of maintained and/or retained cognitive function.