Activity-dependent Mechanisms Research Articles

AgRP neurons mediate activity-dependent development of oxytocin connectivity and autonomic regulation.

Hypothalamic neural circuits maintain homeostasis by coordinating endocrine signals with autonomic responses and behavioral outputs to ensure that physiological responses remain in tune with environmental demands. The paraventricular nucleus of the hypothalamus (PVH) plays a central role in metabolic regulation, and the architecture of its neural inputs and axonal projections is a defining feature of how it receives and conveys neuroendocrine information. In adults, leptin regulates multiple aspects of metabolic physiology, but it also functions during development to direct formation of circuits controlling homeostatic functions. Here we demonstrate that leptin acts to specify the input-output architecture of PVH circuits through an activity-dependent, transsynaptic mechanism, which represents a novel means of sculpting neuroendocrine circuitry, with lasting effects on how the brain controls energy balance.

Activity-dependent dendrite patterning in the postnatal barrel cortex.

For neural circuit construction in the brain, coarse neuronal connections are assembled prenatally following genetic programs, being reorganized postnatally by activity-dependent mechanisms to implement area-specific computational functions. Activity-dependent dendrite patterning is a critical component of neural circuit reorganization, whereby individual neurons rearrange and optimize their presynaptic partners. In the rodent primary somatosensory cortex (barrel cortex), driven by thalamocortical inputs, layer 4 (L4) excitatory neurons extensively remodel their basal dendrites at neonatal stages to ensure specific responses of barrels to the corresponding individual whiskers. This feature of barrel cortex L4 neurons makes them an excellent model, significantly contributing to unveiling the activity-dependent nature of dendrite patterning and circuit reorganization. In this review, we summarize recent advances in our understanding of the activity-dependent mechanisms underlying dendrite patterning. Our focus lays on the mechanisms revealed by in vivo time-lapse imaging, and the role of activity-dependent Golgi apparatus polarity regulation in dendrite patterning. We also discuss the type of neuronal activity that could contribute to dendrite patterning and hence connectivity.

Microglia: Activity-dependent regulators of neural circuits.

It has been more than a century since Pío del Río-Hortega first characterized microglia in histological stains of brain tissue. Since then, significant advances have been made in understanding the role of these resident central nervous system (CNS) macrophages. In particular, it is now known that microglia can sense neural activity and modulate neuronal circuits accordingly. We review the mechanisms by which microglia detect changes in neural activity to then modulate synapse numbers in the developing and mature CNS. This includes responses to both spontaneous and experience-driven neural activity. We further discuss activity-dependent mechanisms by which microglia regulate synaptic function and neural circuit excitability. Together, our discussion provides a comprehensive review of the activity-dependent functions of microglia within neural circuits in the healthy CNS, and highlights exciting new open questions related to understanding more fully microglia as key components and regulators of neural circuits.

A Method to Collect Cerebrospinal Fluid from Mouse Cisterna Magna to Determine Extracellular Tau Levels.

Despite being a cytoplasmic protein abundant in neurons, tau is detectable in various extracellular fluids. In addition to being passively released from dying/degenerating neurons, tau is also actively released from living neurons in a neuronal activity-dependent mechanism. In vivo, tau released from neurons first appears in brain interstitial fluid (ISF) and subsequently drains into cerebrospinal fluid (CSF) by glymphatic system. Changes in CSF tau levels alter during the course of AD pathogenesis and are considered to predict the disease-progression of AD. A method to collect CSF from various mouse models of AD will serve as a valuable tool to investigate the dynamics of physiological/pathological tau released from neurons. In this chapter, we describe and characterize a method that reliably collects a relatively large volume of CSF from anesthetized mice.

Activity-Dependent Stabilization of Nascent Dendritic Spines Requires Nonenzymatic CaMKIIα Function.

The outgrowth and stabilization of nascent dendritic spines are crucial processes underlying learning and memory. Most new spines retract shortly after growth; only a small subset is stabilized and integrated into the new circuit connections that support learning. New spine stabilization has been shown to rely upon activity-dependent molecular mechanisms that also contribute to long-term potentiation (LTP) of synaptic strength. Indeed, disruption of the activity-dependent targeting of the kinase CaMKIIα to the GluN2B subunit of the NMDA-type glutamate receptor disrupts both LTP and activity-dependent stabilization of new spines. Yet it is not known which of CaMKIIα's many enzymatic and structural functions are important for new spine stabilization. Here, we used two-photon imaging and photolysis of caged glutamate to monitor the activity-dependent stabilization of new dendritic spines on hippocampal CA1 neurons from mice of both sexes in conditions where CaMKIIα functional and structural interactions were altered. Surprisingly, we found that inhibiting CaMKIIα kinase activity either genetically or pharmacologically did not impair activity-dependent new spine stabilization. In contrast, shRNA knockdown of CaMKIIα abolished activity-dependent new spine stabilization, which was rescued by co-expressing shRNA-resistant full-length CaMKIIα, but not by a truncated monomeric CaMKIIα. Notably, overexpression of phospho-mimetic CaMKIIα-T286D, which exhibits activity-independent targeting to GluN2B, enhanced basal new spine survivorship in the absence of additional glutamatergic stimulation, even when kinase activity was disrupted. Together, our results support a model in which nascent dendritic spine stabilization requires structural and scaffolding interactions mediated by dodecameric CaMKIIα that are independent of its enzymatic activities.

Nucleolus activity-dependent recruitment and biomolecular condensation by pH sensing

DEAD-box ATPases are major regulators of biomolecular condensates and orchestrate diverse biochemical processes that are critical for the functioning of cells. How DEAD-box proteins are selectively recruited to their respective biomolecular condensates is unknown. We explored this in the context of the nucleolus and DEAD-box protein DDX21. We find that the pH of the nucleolus is intricately linked to the transcriptional activity of the organelle and facilitates the recruitment and condensation of DDX21. We identify an evolutionarily conserved feature of the C terminus of DDX21 responsible for nucleolar localization. This domain is essential for zebrafish development, and its intrinsically disordered and isoelectric properties are necessary and sufficient for the ability of DDX21 to respond to changes in pH and form condensates. Molecularly, the enzymatic activities of poly(ADP-ribose) polymerases contribute to maintaining the nucleolar pH and, consequently, DDX21 recruitment and nucleolar partitioning. These observations reveal an activity-dependent physicochemical mechanism for the selective recruitment of biochemical activities to biomolecular condensates.

CNSC-33. MOLECULAR AND FUNCTIONAL DRIVERS OF ACTIVITY DEPENDENT GLIOBLASTOMA PROLIFERATION

Abstract Glioblastoma, the most common primary brain tumor in adults, is a major cause of neurological morbidity and mortality with no effective therapies. Its proliferation and invasion are regulated by direct and paracrine-mediated neuronal activity. In this study, we uncover molecular targets and protein-protein signaling driving activity dependent proliferation. To identify candidate molecular pathways, we used high-density electrode arrays in vivo to record human local field potentials. Single-cell RNA sequencing identified Netrin-G1 (NTNG1) and thrombospondin-1 (TSP1) elevation in glioblastoma clonal population that proliferates in response to the presence of neurons. The amino acid sequence of NTNG1 and the TSR1 domain of TSP1 were utilized to predict the 3D interaction surface of NTNG1 and TSP1. Compared to structure predictions of NTNG1 and its known binding partner NGL1, NTNG1 and TSP1 complex predictions showed agreement between machine learning predicted models and lower predicted aligned error in interdomain regions of the complex, suggesting higher confidence in the relative position of NTNG1-TSP1 as compared to NTNG1-NGL1. We performed 45 protein structure predictions and two molecular dynamics simulations of mutant and WT TSP1 in complex with NTNG1. Each simulation box consisted of >263,000 atoms, each run for 50 million 2 femtosecond timesteps for a total simulation time of 200 ns. These calculations confirmed a stable complex in the WT condition and significant conformational change in the R46A condition, emphasizing the importance of this residue in mediating NTNG1-TSP1 binding. Computational affinity models between NTNG1 and TSP1 were validated by pull-down assays and immunofluorescence labelling using cerebral organoid and human glioma-neuronal coculture models. Finally, we design small molecule and fusion-protein inhibitors disrupting this interaction. Here we advance the development of targeted precision-medicine therapies to treat glioblastoma proliferation through activity-dependent mechanisms.

CNSC-26. GLIOBLASTOMA-NEURONAL CIRCUIT INTEGRATION IS MODULATED BY INTERLEUKIN-6

Abstract The pleiotropic cytokine interleukin-6 (IL-6) is known to be involved in both pro- and anti-inflammatory signaling cascades. In glioblastoma studies using animal and human models, IL-6 promotes immunosuppression and tumor progression and is negatively associated with survival. Intriguingly, IL-6 also contributes to increased synaptogenesis during development and following focal brain injury. Glioblastoma remodeling of neuronal circuits influences patient survival; therefore, it is possible that IL-6 has mechanistic significance. Here, we investigated IL-6 as a driver of activity-dependent glioblastoma proliferation using patient-derived xenograft (PDX) mouse and human glioblastoma models. We assessed neuronal activity by microelectrode arrays and in vitro calcium imaging using weighted mean firing rate (WMFR), network burst frequency (NBF), and synchrony index. Next, we used bulk and single-cell RNA sequencing on 13,731 cells from ten tumors including pair-matched samples to identify differentially expressed genes in intratumoral regions with elevated functional connectivity and found IL6 to be highly upregulated. Mouse embryonic cortical neurons and cerebral organoids co-cultured with primary patient-derived glioblastoma cells demonstrated concentration-dependent neuronal hyperexcitability (increased WMFR and NBF) in IL-6-overexpressing conditions compared to the neuron-only condition. Pharmacological inhibition using the humanized IL-6 receptor antibody tocilizumab reduced network synchrony across models. These findings suggest that IL-6-induced glioma-neuronal hyperexcitability may be inhibited by the FDA-approved tocilizumab, thereby providing preclinical support for its use to treat activity-dependent mechanisms of glioblastoma proliferation. Future studies are needed to uncover mechanisms and clinical efficacy.

Activity-dependent mechanisms of neuroprotection: promising avenues against dementia.

Activity-dependent mechanisms of neuroprotection: promising avenues against dementia.

2 Water-Based Exercise Improves Cognition and Reduces Neurological-Related Plasma Proteins in Older Adults.

Objective:In the United States, Alzheimer’s disease (AD) is the most common cause of dementia and the seventh leading cause of death. Exercise has demonstrated health benefits in older adults and reduces the risk of developing AD. Exploring underlying biological mechanisms of exercise could aid in identifying therapeutic targets to prevent AD progression, especially for high-risk individuals such as those with Mild Cognitive Impairment (MCI). Many studies of dementia focus on memory; however, executive function and processing speed are also vulnerable to the neuropathology that causes AD. This exploratory study aimed to identify potential mechanisms by which physical activity can facilitate change in cognitive functioning in older adults. This was accomplished by investigating correlations between changes in neurology-related plasma proteins and changes in measures of executive function and processing speed after participation in a water-based exercise intervention.Participants and Methods:The sample included 20 older adults with amnestic MCI, ages 55-82 years (mean 68.15 ±7.75). Participants were predominately male (90%), White (70%), and non-Hispanic (85%), with more than high school education (95%). Participants engaged in supervised high-intensity water-based exercise three times per week for six months. Neuropsychological assessments and blood samples were assessed at baseline and after completion of the exercise intervention. Cognitive measures included: the Digit Span subtests from the Wechsler Adult Intelligence Scale, 4th Edition, Trail-Making Test (TMT), Stroop Color Word Test (SCWT), and the Symbol Digit Modalities Test (SDMT). Plasma protein levels were analyzed using the Olink Target 96 Neurology assay (Uppsala, Sweden), selected a priori for the established markers linked to neurobiological processes and diseases. Changes in cognitive measures and protein levels were assessed using paired-sample t-tests, and Pearson’s correlations were calculated for significant findings.Results:Participants’ cognitive performance significantly improved on the SCWT color trial (t = -2.19, p = 0.042) and SDMT (t = -2.17, p = .043). Significant decreases in plasma proteins levels were found for GDNF family receptor alpha-1 ([GFRA1]: t =2.05, p = 0.055), neuroblastoma suppressor tumorigenicity-1 ([NBL1]: t = 2.13, p= .046), and neuropilin-2 ([NRP2]: t = 2.61 p= 0.017). Correlational analyses showed reductions in NBL1 were significantly associated with changes in both SDMT (r = -.61, p = 0.006) and the color trial of SCWT (r = .48, p = .038), and NRP2 was significantly associated with improvement on the SDMT (r = -.46, p = 0.045). GFRA1 was not significantly associated with change on any cognitive measure.Conclusions:In a sample of older adults with MCI, participation in high-intensity water-based exercise led to significant improvements in cognitive function as well as changes in neurological plasma proteome. Improved outcomes in processing speed, attention, visuospatial scanning, and working memory were associated with changes in specific plasma protein concentrations. This highlights potential activity-dependent neurobiological mechanisms that may underlie the cognitive benefits derived from physical activity. Future studies should explore these findings in Randomized Control Trials with a comparative condition and larger sample size.

Protein kinase A-dependent plasticity of local inhibitory synapses from hilar somatostatin-expressing neurons.

Hippocampal Inhibitory Neurons (INs) contact local targets and project to different brain areas to form synapses on distal neurons. Despite the importance of INs for hippocampal function and interregional brain communication, the impact of activity-dependent plasticity mechanisms on local and long-range GABAergic synapses formed by hippocampal INs remains to be fully elucidated. Here, we use optogenetic-coupled electrophysiology in mice to show that protein kinase A (PKA), a master regulator of GABAergic synapse plasticity, causes a form of long-term potentiation of inhibitory synapses (iLTP) in hippocampal granule cells (GCs). This form of iLTP is observed in GCs synapses originated in local INs expressing the marker somatostatin (SST) but not in those expressing parvalbumin (PV). Long-range synapses formed by SST INs onto medial septum neurons are unaffected by PKA activation. iLTP of local SST synapses on GCs is accompanied by changes in presynaptic probability of release and is occluded by pharmacological increase of synaptic activity in vivo Our results suggest that PKA-dependent inhibitory synapse plasticity is expressed in local but not long-range targets of SST INs and selectively modifies inhibitory microcircuits essential for hippocampal function.Significance StatementThe hippocampus, a brain region essential for memory, is populated by a diverse group of inhibitory neurons (INs) that form synaptic contacts onto local principal cells and long-range targets. Changes in inhibitory synapse strength shape local and inter-regional brain communication. However, how synapse plasticity mechanisms are implemented in the rich assortment of hippocampal INs remains to be fully defined. Here we show that protein kinase A, a signaling protein involved in memory, enhances inhibitory neurotransmission from local but not long-range projecting hippocampal INs expressing the molecular marker somatostatin. The consequences of this plasticity are observed after increasing neuronal activity in vivo Our work describes a form of activity-dependent synapse plasticity that regulates inhibitory microcircuits essential for hippocampal memory function.

AMPA and GABAA receptor nanodomains assemble in the absence of synaptic neurotransmitter release.

Postsynaptic neurotransmitter receptors and their associated scaffolding proteins assemble into discrete, nanometer-scale subsynaptic domains (SSDs) within the postsynaptic membrane at both excitatory and inhibitory synapses. Intriguingly, postsynaptic receptor SSDs are mirrored by closely apposed presynaptic active zones. These trans-synaptic molecular assemblies are thought to be important for efficient neurotransmission because they concentrate postsynaptic receptors near sites of presynaptic neurotransmitter release. While previous studies have characterized the role of synaptic activity in sculpting the number, size, and distribution of postsynaptic SSDs at established synapses, it remains unknown whether neurotransmitter signaling is required for their initial assembly during synapse development. Here, we evaluated synaptic nano-architecture under conditions where presynaptic neurotransmitter release was blocked prior to, and throughout synaptogenesis with tetanus neurotoxin (TeNT). In agreement with previous work, neurotransmitter release was not required for the formation of excitatory or inhibitory synapses. The overall size of the postsynaptic specialization at both excitatory and inhibitory synapses was reduced at chronically silenced synapses. However, both AMPARs and GABAARs still coalesced into SSDs, along with their respective scaffold proteins. Presynaptic active zone assemblies, defined by RIM1, were smaller and more numerous at silenced synapses, but maintained alignment with postsynaptic AMPAR SSDs. Thus, basic features of synaptic nano-architecture, including assembly of receptors and scaffolds into trans-synaptically aligned structures, are intrinsic properties that can be further regulated by subsequent activity-dependent mechanisms.

Novel mechanism of DNA repair in neurons opens promising avenues for combatting neurodegenerative diseases and brain aging

A recent study, titled “A NPAS4-NuA4 Complex Couples Synaptic Activity to DNA Repair,” reveals an exciting new mechanism by which neurons maintain genomic stability in response to external stimuli. Published in Nature on February 23, 2023,1 this paper provides valuable insights into the molecular mechanisms underlying neurodegenerative diseases and brain aging that pave the way for the development of new therapeutic strategies. This commentary reviews the research findings and their potential for future applications. The brain is a highly dynamic and plastic organ that relies on neurons to modify their gene expression under a variety of pathophysiological conditions. Excessive or prolonged neuronal response to external stimuli can lead to DNA damage and genomic instability, thereby being harmful to the brain. Cumulative DNA damage in the neuronal genome is also a hallmark of neurodegeneration and brain aging. Until recently, the molecular mechanism by which neurons repair DNA and maintain genomic stability in response to external stimuli remained unclear. Neuronal PAS Domain Protein 4 (NPAS4) is an activity-induced transcription factor that is selectively expressed in neurons following membrane depolarization and subsequent calcium signaling. Through a series of biochemical and genomic experiments on mice, the researchers first determined that NPAS4 exists as part of a 21-protein complex called NPAS4-NuA4. They then measured DNA damage using γH2AX ChIP-seq, sBLISS-seq, END-seq and SAR-seq, which indicated that NPAS4 preferentially binds to active DNA breaking-induced sites in neurons. These advanced techniques can be used to analyze the binding sites of transcription factors,2 provide whole-genome maps with DNA double-strand breaks,3 monitor DNA terminal excision,4 and localize DNA repair synthesis in vivo and in various cell types.5 Thus, they could contribute greatly to future research in neuroscience and other biomedical fields. In addition, the NPAS4-NuA4 complex serves as a critical mediator in the mechanism underlying neurodegenerative diseases and aging in the brain. Activated in response to neuronal activity driven by changes in sensory experience, NPAS4-NuA4 binds to periodically damaged transcriptional regulatory elements and recruits DNA repair machinery to prevent age-dependent somatic mutation accumulation. Furthermore, impaired NPAS4-NuA4 leads to a range of cellular defects that result in a shortened lifespan, including dysregulation of neuronal activity-dependent transcriptional responses, loss of somatic inhibition of pyramidal neurons, impaired localization of protective repair machinery, and genomic instability. One of the most exciting aspects of this study is its discovery of a link between damage and neuronal activity-dependent regulatory elements and neuronal dysfunction in neurodegenerative diseases. Preventing mutations in the NPAS4-NuA4 complex during neurodevelopment and carefully balancing the proper ratio of excitatory and inhibitory neurons are key to sustaining neuronal survival. This conclusion suggests a new avenue for the development of drugs for Alzheimer's and Parkinson's diseases that target the NPAS4-NuA4 complex and its molecular pathways. The research also provides insight into the complex interplay between gene expression and DNA repair in aging. By targeting the DNA of hippocampal neurons in mice of different ages, researchers found that gene regulatory elements to which NPAS4–NuA4 binds are partially protected against age-dependent accumulation of somatic mutations. This finding suggests that promoting the protection of those recurrently broken sites can help maintain genome integrity and thus prevent mutation. It is worth considering whether all cell types in the body (i.e., beyond neurons) may regulate transcriptional activity, protect vulnerable DNA sites, and maintain genomic stability according to the type of stimulation they receive. There may be activity-dependent protective mechanisms for genome stability that remains unknown and thus need to be explored. Moreover, the unique repair mechanism proposed in this paper was based on mouse models and has not yet been verified in the human nervous system. If this could be explored in humans, the functions and upstream regulatory mechanisms of various protein components of the NPAS4-NuA4 complex could be further clarified to provide a better understanding of the occurrence and development of neurodegeneration. In conclusion, this study demonstrates the complex interplay between neuronal activity, gene expression, and DNA repair in the brain. Its findings broaden our knowledge of the pathogenesis of neurodegenerative diseases and aging in the brain and contribute to the field of neuroscience with important implications for the development of novel therapeutic approaches. Conglin Wang: Writing – original draft. Xintong Ge: Writing – original draft; Writing – review & editing. Wenqiang Xin: Writing – review & editing. Ping Lei: Writing – review & editing. This research was supported by Haihe Laboratory of Cell Ecosystem Innovation Fund (HH22KYZX0048), the National Natural Science Foundation of China (82271401, 82071394, 82072166), Science and Technology Foundation of Tianjin (21JCYBJC01180), and Science and Technology Project of Tianjin Municipal Health Commission (TJWJ2021QN005). The authors declare no conflicts of interest.

A NPAS4–NuA4 complex couples synaptic activity to DNA repair

Neuronal activity is crucial for adaptive circuit remodelling but poses an inherent risk to the stability of the genome across the long lifespan of postmitotic neurons1–5. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is unknown. Here we identify an activity-dependent DNA repair mechanism in which a new form of the NuA4–TIP60 chromatin modifier assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex from the brain and demonstrate its functions in eliciting activity-dependent changes to neuronal transcriptomes and circuitry. By characterizing the landscape of activity-induced DNA double-strand breaks in the brain, we show that NPAS4–NuA4 binds to recurrently damaged regulatory elements and recruits additional DNA repair machinery to stimulate their repair. Gene regulatory elements bound by NPAS4–NuA4 are partially protected against age-dependent accumulation of somatic mutations. Impaired NPAS4–NuA4 signalling leads to a cascade of cellular defects, including dysregulated activity-dependent transcriptional responses, loss of control over neuronal inhibition and genome instability, which all culminate to reduce organismal lifespan. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental and autism spectrum disorders. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation, the disruption of which may contribute to developmental disorders, neurodegeneration and ageing.

Sensitization of supra-threshold pain responses-Translational aspects and mechanisms.

A substantial translational gap in pain research has been reflected by a mismatch of relevant primary pain assessment endpoints in preclinical vs. clinical trials. Since activity-dependent mechanisms may be neglected during reflexive tests, this may add as a confounding factor during preclinical pain assessment. In this perspective, we consider the evidence for a need for supra-threshold pain assessment in the pain research literature. In addition to that, we focus on previous results that may demonstrate an example mechanism, where the detection of neuron-glial interactions on pain seems to be substantially depending on the assessment of pain intensity beyond threshold levels.

The novel type II toxin-antitoxin PacTA modulates Pseudomonas aeruginosa iron homeostasis by obstructing the DNA-binding activity of Fur.

Type II toxin–antitoxin (TA) systems are widely distributed in bacterial and archaeal genomes and are involved in diverse critical cellular functions such as defense against phages, biofilm formation, persistence, and virulence. GCN5-related N-acetyltransferase (GNAT) toxin, with an acetyltransferase activity-dependent mechanism of translation inhibition, represents a relatively new and expanding family of type II TA toxins. We here describe a group of GNAT-Xre TA modules widely distributed among Pseudomonas species. We investigated PacTA (one of its members encoded by PA3270/PA3269) from Pseudomonas aeruginosa and demonstrated that the PacT toxin positively regulates iron acquisition in P. aeruginosa. Notably, other than arresting translation through acetylating aminoacyl-tRNAs, PacT can directly bind to Fur, a key ferric uptake regulator, to attenuate its DNA-binding affinity and thus permit the expression of downstream iron-acquisition-related genes. We further showed that the expression of the pacTA locus is upregulated in response to iron starvation and the absence of PacT causes biofilm formation defect, thereby attenuating pathogenesis. Overall, these findings reveal a novel regulatory mechanism of GNAT toxin that controls iron-uptake-related genes and contributes to bacterial virulence.

Structural plasticity driven by task performance leads to criticality signatures in neuromorphic oscillator networks

Oscillator networks rapidly become one of the promising vehicles for energy-efficient computing due to their intrinsic parallelism of execution. The criticality property of the oscillator-based networks is regarded to be essential for performing complex tasks. There are numerous bio-inspired synaptic and structural plasticity mechanisms available, especially for spiking neural networks, which can drive the network towards the criticality. However, there is no solid connection between these self-adaption mechanisms and the task performance, and it is not clear how and why particular self-adaptation mechanisms contribute to the solution of the task, although their relation to criticality is understood. Here we propose an evolutionary approach for the structural plasticity that relies solely on the task performance and does not contain any task-independent adaptation mechanisms, which usually contribute towards the criticality of the network. As a driver for the structural plasticity, we use a direct binary search guided by the performance of the classification task that can be interpreted as an interaction of the network with the environment. Remarkably, such interaction with the environment brings the network to criticality, although this property was not a part of the objectives of the employed structural plasticity mechanism. This observation confirms a duality of criticality and task performance, and legitimizes internal activity-dependent plasticity mechanisms from the viewpoint of evolution as mechanisms contributing to the task performance, but following the dual route. Finally, we analyze the trained network against task-independent information-theoretic measures and identify the interconnection graph’s entropy to be an essential ingredient for the classification task performance and network’s criticality.

Unmasking Schizophrenia: Synaptic Pruning in Adolescence Reveals a Latent Physiological Vulnerability in Prefrontal Recurrent Networks

Theories of the pathophysiology in schizophrenia are converging on the synapse. This special issue of Biological Psychiatry collects papers from leading researchers that suggest a hypothesis that multiple factors spanning many levels lead to synaptic dysfunction in recurrent circuits in the prefrontal cortex (PFC). The hypothesis (Figure 1) suggests that the defect within the PFC is established during early development but remains latent through childhood. Pruning of excitatory synapses during adolescence, resulting in lower synaptic density in persons with schizophrenia, triggers the emergence of symptoms. The lower synaptic density results in deficits in cognitive processes, including working memory, because overpruned neural circuits cannot support the relevant computations ( 1 Averbeck B.B. Pruning recurrent neural networks replicates adolescent changes in working memory and reinforcement learning. Proc Natl Acad Sci U S A. 2022; 119e2121331119 Crossref Scopus (0) Google Scholar ). Additionally, excessive prefrontal pruning leads to striatal hyperdopaminergia through increased activation of midbrain dopamine neurons by prefrontal input. The decreased synaptic density following adolescent pruning could be due to genetic or epigenetic effects that lead to an inability to build stable synapses or excessive pruning of established synapses. The excessive pruning could follow from overactive pruning mechanisms or from decreased excitatory synaptic activity due to synaptic changes local to the PFC or prolonged decreases in thalamic input across development. All of these factors may converge to alter spike timing dynamics in prefrontal recurrent circuits in adolescence, reducing synchronous neural activity and accelerating synaptic disconnection via activity-dependent mechanisms ( 2 Zick J.L. Crowe D.A. Blackman R.K. Schultz K. Bergstrand D.W. DeNicola A.L. et al. Disparate insults relevant to schizophrenia converge on impaired spike synchrony and weaker synaptic interactions in prefrontal local circuits. Curr Biol. 2022; 32: 14-25.e4 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar ). Further, synaptic pruning is mediated by components of the immune system, and in utero immune challenge may affect adolescent pruning. Decreased synaptic activity can also lead to increased pruning as pruning removes weak synapses. Thus, multiple effects converging on the synapse could lead to a PFC with fewer excitatory synaptic connections, and this decreased recurrent connectivity could lead to cognitive deficits and increased striatal dopamine and psychosis.

Spontaneous Thalamic Activity Modulates the Cortical Innervation of the Primary Visual Nucleus of the Thalamus

Sensory processing relies on the correct development of thalamocortical loops. Visual corticothalamic axons (CTAs) invade the dorsolateral geniculate nucleus (dLGN) of the thalamus in early postnatal mice according to a regulated program that includes activity-dependent mechanisms. Spontaneous retinal activity influences the thalamic incursion of CTAs, yet the perinatal thalamus also generates intrinsic patterns of spontaneous activity whose role in modulating afferent connectivity remains unknown. Here, we found that patterned spontaneous activity in the dLGN contributes to proper spatial and temporal innervation of CTAs. Disrupting patterned spontaneous activity in the dLGN delays corticogeniculate innervation under normal conditions and upon eye enucleation. The delayed innervation was evident throughout the first two postnatal weeks but resumes after eye-opening, suggesting that visual experience is necessary for the homeostatic recovery of corticogeniculate innervation.

Exploring links between 2-oxoglutarate-dependent oxygenases and Alzheimer's disease.

Hypoxia, that is, an inadequate oxygen supply, is linked to neurodegeneration and patients with cardiovascular disease are prone to Alzheimer's disease (AD). 2-Oxoglutarate and ferrous iron-dependent oxygenases (2OGDD) play a key role in the regulation of oxygen homeostasis by acting as hypoxia sensors. 2OGDD also have roles in collagen biosynthesis, lipid metabolism, nucleic acid repair, and the regulation of transcription and translation. Many biological processes in which the >60 human 2OGDD are involved are altered in AD patient brains, raising the question as to whether 2OGDD are involved in the transition from normal aging to AD. Here we give an overview of human 2OGDD and critically discuss their potential roles in AD, highlighting possible relationships with synapse dysfunction/loss. 2OGDD may regulate neuronal/glial differentiation through enzyme activity-dependent mechanisms and modulation of their activity has potential to protect against synapse loss. Work linking 2OGDD and AD is at an early stage, especially from a therapeutic perspective; we suggest integrated pathology and in vitro discovery research to explore their roles in AD is merited. We hope to help enable long-term research on the roles of 2OGDD and, more generally, oxygen/hypoxia in AD. We also suggest shorter term empirically guided clinical studies concerning the exploration of 2OGDD/oxygen modulators to help maintain synaptic viability are of interest for AD treatment.