Artificial neural networks (ANNs) were originally modeled after their biological counterparts, but have since conceptually diverged in many ways. The resulting network architectures are not well understood, and furthermore, we lack the quantitative tools to characterize their structures. Network science provides an ideal mathematical framework with which to characterize systems of interacting components, and has transformed our understanding across many domains, including the mammalian brain. Yet, little has been done to bring network science to ANNs. In this work, we propose tools that leverage and adapt network science methods to measure both global- and local-level characteristics of ANNs. Specifically, we focus on the structures of efficient multilayer perceptrons as a case study, which are sparse and systematically pruned such that they share many characteristics with real-world networks. We use adapted network science metrics to show that the pruning process leads to the emergence of a spanning subnetwork (lottery ticket multilayer perceptrons) with complex architecture. This complex network exhibits global and local characteristics, including heavy-tailed nodal degree distributions and dominant weighted pathways, that mirror patterns observed in human neuronal connectivity. Furthermore, alterations in network metrics precede catastrophic decay in performance as the network is heavily pruned. This network science-driven approach to the analysis of artificial neural networks serves as a valuable tool to establish and improve biological fidelity, increase the interpretability, and assess the performance of artificial neural networks. Significance Statement Artificial neural network architectures have become increasingly complex, often diverging from their biological counterparts in many ways. To design plausible "brain-like" architectures, whether to advance neuroscience research or to improve explainability, it is essential that these networks optimally resemble their biological counterparts. Network science tools offer valuable information about interconnected systems, including the brain, but have not attracted much attention for analyzing artificial neural networks. Here, we present the significance of our work: •We adapt network science tools to analyze the structural characteristics of artificial neural networks. •We demonstrate that organizational patterns similar to those observed in the mammalian brain emerge through the pruning process alone. The convergence on these complex network features in both artificial neural networks and biological brain networks is compelling evidence for their optimality in information processing capabilities. •Our approach is a significant first step towards a network science-based understanding of artificial neural networks, and has the potential to shed light on the biological fidelity of artificial neural networks.

Glutamate transporters are important for regulating extracellular glutamate levels, impacting neural function and metabolic homeostasis. This study explores the behavioral, lifespan, and proteomic profiles in Caenorhabditis elegans strains with either glt-4 or glt-5 null mutations, highlighting contrasting phenotypes. Δglt-4 mutants displayed impaired mechanosensory and chemotactic responses, reduced lifespans, and decreased expression levels of ribosomal proteins and chaperonins involved in protein synthesis and folding. In contrast, Δglt-5 mutants displayed heightened chemorepulsion, extended lifespans, and upregulation of mitochondrial pyruvate carriers and cytoskeletal proteins. Proteomic profiling via mass spectrometry identified 53 differentially expressed proteins in Δglt-4 mutants and 45 in Δglt-5 mutants. Δglt-4 mutants showed disruptions in ribonucleoprotein complex organization and translational processes, including downregulation of glycogen phosphorylase and V-type ATPase subunits, while Δglt-5 mutants revealed altered metabolic protein expression, such as increased levels of mitochondrial pyruvate carriers and decreased levels of fibrillarin and ribosomal proteins. Gene ontology enrichment analysis highlighted differential regulation of protein biosynthesis and metabolic pathways between the strains. Overall, these findings underscore the distinct, tissue-specific roles of GLT-4 and GLT-5 in C. elegans, with broader implications for glutamate regulation and systemic physiology. The results also reinforce the utility of C. elegans as a model for studying glutamate transporters' impact on behavior, longevity, and proteostasis.

Mitochondria are central to cellular energy metabolism, contributing to synaptic transmission and plasticity. The mitochondrial membranes present the cannabinoid type-1 receptor (mito-CB1R), which has been functionally linked to neuronal energy supply and cognitive processing. Prenatal exposure to Δ9-tetrahydrocannabinol (pTHC) has been associated with cognitive impairments associated with molecular cellular and functional abnormalities in several brain regions, including the hippocampus. This study aims at assessing whether, besides the memory impairment, pTHC exposure may result in mitochondrial molecular and functional alterations in the hippocampus of the offspring. Moreover, the assessment of CB1R expression is also carried out as a proxy of CB1 signalling in pTHC-exposed offspring. THC (2 mg/Kg), or vehicle, was administered to the dams from gestational day (GD) 5 to GD20, and the offspring were tested for declarative memory using the Novel Object Recognition test in the L-maze. We also assessed: mitochondrial respiration by high-resolution respirometry; mitochondrial respiratory complex-I subunit NDUFS1 protein levels, and mito-CB1R expression by ELISA. Our results revealed: significant memory impairment in pTHC-exposed offspring; attenuated mitochondrial respiration in the hippocampus alongside a marked reduction in complex-I-subunit NDUFS1; a significant increase in mito-CB1R expression. This is the first evidence of pTHC exposure-induced impairment in memory processing in the offspring that suggests a functional link between an attenuation in mitochondrial bioenergetics and abnormal CB1R signalling in the hippocampus.

Mitochondrial metabolism in neurons is necessary for energetically costly processes like synaptic transmission and plasticity. As post-mitotic cells, neurons are therefore faced with the challenge of maintaining healthy functioning mitochondria throughout lifetime. The precise mechanisms of mitochondrial maintenance in neurons, and particularly in morphologically complex dendrites and axons, are not fully understood. Evidence from several biological systems suggests the regulation of cellular metabolism by extracellular vesicles (EVs), secretory lipid-enclosed vesicles that have emerged as important mediators of cell communication. In the nervous system, neuronal and glial EVs were shown to regulate neuronal circuit development and function, at least in part via the transfer of protein and RNA cargo. Interestingly, EVs have been implicated in diseases characterized by altered metabolism, such as cancer and neurodegenerative diseases. Furthermore, nervous system EVs were shown to contain proteins related to metabolic processes, mitochondrial proteins and even intact mitochondria. Here, we present the current knowledge of the mechanisms underlying neuronal mitochondrial maintenance, and highlight recent evidence suggesting the regulation of synaptic mitochondria by neuronal and glial cell EVs. We further discuss the potential implications of EV-mediated regulation of mitochondrial maintenance and function in neuronal circuit development and synaptic plasticity.

α-Synucleinopathies are progressive neurodegenerative disorders characterized by intracellular aggregation of α-synuclein, but their molecular pathogenesis remains unknown. Here, we explore cell-specific changes in gene expression across different α-synucleinopathies. We perform single-nucleus RNA sequencing on nearly 300 000 nuclei from the prefrontal cortex of individuals with idiopathic Parkinson's disease (PD, n = 20), Parkinson's disease caused by LRRK2 mutations (LRRK2-PD, n = 7), multiple system atrophy (n = 6) and healthy controls (n = 13). Idiopathic PD and LRRK2-PD exhibit a largely overlapping cell type-specific signature, which is distinct from that of multiple system atrophy and includes an overall decrease of the transcriptional output in neurons. Notably, most of the differential expression signal in idiopathic PD and LRRK2-PD is concentrated in a specific deep cortical neuronal subtype expressing adrenoceptor alpha 2A. Although most differentially expressed genes are highly cell type and disease specific, PDE10A is found to be downregulated consistently in most cortical neurons and across all three diseases. Finally, exploiting the variable presence and/or severity of α-synuclein pathology in LRRK2-PD and idiopathic PD, we identify cell type-specific signatures associated with α-synuclein pathology, including a neuronal upregulation of SNCA itself, encoding α-synuclein. Our findings provide new insights into the cell-specific transcriptional landscape of the α-synucleinopathy spectrum.

Morphine is among the most powerful analgesic, but its long-term use can cause tolerance. Synaptic ATP supply is critical for maintaining synaptic transmission. Microtubule-based mitochondrial transport ensures synaptic energy supply. How synaptic energy changes with morphine and the role of microtubule tracks in synaptic mitochondrial energy supply remain elusive. Chronic morphine treatment can destroy microtubule cytoskeletons. We investigated the effect of the microtubule cytoskeleton on synaptic mitochondrial energy supply and the mechanism of microtubule dynamics after morphine exposure.

Rats were treated with long-term morphine and the effect on thermal pain thresholds was evaluated by the tail-flick latency test. Various antagonists and agonists were used elucidated the role and mechanism of synaptic mitochondrial energy supply and microtubules in morphine tolerance in vivo and in SH-SY5Y cells.

Chronic morphine treatment reduced synaptic mitochondrial ATP production. Improving mitochondrial oxidative phosphorylation (OXPHOS) alleviated the downregulation of synaptic ATP levels. Microtubule-stabilizing agents prevented microtubule disruption and ameliorated synaptic energy deficit via microtubule-based microtubule transport. In SH-SY5Y cells, morphine exposure reduced microtubule expression. And re-opening the synaptic Ca2+ channel by agonist alleviated microtubule decrease by calcium/calmodulin-dependent protein kinase 2 (CAMKK2)/AMP-activated protein kinase (AMPK) pathway.

This study demonstrates that the microtubule cytoskeleton regulated by the Ca2+-CAMKK2-AMPK axis is critical for synaptic mitochondrial transport and ATP production, explaining an interplay between chronic morphine-induced abnormal neuroadaptation and synaptic energetic dysfunction. These findings implicated a potential clinical strategy for prolonging the opioid antinociceptive effect during long-term pain control.

Emerging research suggests the brain operates as a "prediction machine," continuously anticipating sensory, motor, and cognitive outcomes. Central to this capability is the brain's spontaneous activity-ongoing internal processes independent of external stimuli. Neuroimaging and computational studies support that this activity is integral to maintaining and refining mental models of our environment, body, and behaviors, akin to generative models in computation. During rest, spontaneous activity expands the variability of potential representations, enhancing the accuracy and adaptability of these models. When performing tasks, internal models direct brain regions to anticipate sensory and motor states, optimizing performance. This review synthesizes evidence from various species, from C. elegans to humans, highlighting three key aspects of spontaneous brain activity's role in prediction: the similarity between spontaneous and task-related activity, the encoding of behavioral and interoceptive priors, and the high metabolic cost of this activity, underscoring prediction as a fundamental function of brains across species.

Neurodevelopment is a multifaceted and tightly regulated process essential for the formation, maturation, and functional specialization of the nervous system. It spans critical stages, including cellular proliferation, differentiation, migration, synaptogenesis, and synaptic pruning, which collectively establish the foundation for cognitive, behavioral, and emotional functions. Metabolism serves as a cornerstone for neurodevelopment, providing the energy and substrates necessary for biosynthesis, signaling, and cellular activities.

Key metabolic pathways, including glycolysis, lipid metabolism, and amino acid metabolism, support processes such as cell proliferation, myelination, and neurotransmitter synthesis. Crucial signaling pathways, such as insulin, mTOR, and AMPK, further regulate neuronal growth, synaptic plasticity, and energy homeostasis. Dysregulation of these metabolic processes is linked to a spectrum of neurodevelopmental disorders, including autism spectrum disorders (ASDs), intellectual disabilities, and epilepsy.

This review investigates the intricate interplay between metabolic processes and neurodevelopment, elucidating the molecular mechanisms that govern brain development and the pathogenesis of neurodevelopmental disorders. Additionally, it highlights potential avenues for the development of innovative strategies aimed at enhancing brain health and function.

Cortical neurons often establish multiple synaptic contacts with the same postsynaptic neuron. To avoid functional redundancy of these parallel synapses, it is crucial that each synapse exhibits distinct computational properties. Here we model the current to the soma contributed by each synapse as a sigmoidal transmission function of its presynaptic input, with learnable parameters such as amplitude, slope, and threshold. We evaluate the classification capacity of a neuron equipped with such nonlinear parallel synapses, and show that with a small number of parallel synapses per axon, it substantially exceeds that of the Perceptron. Furthermore, the number of correctly classified data points can increase superlinearly as the number of presynaptic axons grows. When training with an unrestricted number of parallel synapses, our model neuron can effectively implement an arbitrary aggregate transmission function for each axon, constrained only by monotonicity. Nevertheless, successful learning in the model neuron often requires only a small number of parallel synapses. We also apply these parallel synapses in a feedforward neural network trained to classify MNIST images, and show that they can increase the test accuracy. This demonstrates that multiple nonlinear synapses per input axon can substantially enhance a neuron's computational power.

The brain is immensely complex, with diverse components and dynamic interactions building upon one another to orchestrate a wide range of behaviors. Understanding patterns of these complex interactions and how they are coordinated to support collective neural function is critical for parsing human and animal behavior, treating mental illness, and developing artificial intelligence. Rapid experimental advances in imaging, recording, and perturbing neural systems across various species now provide opportunities to distill underlying principles of brain organization and function. Here, we take stock of recent progress and review methods used in the statistical analysis of brain networks, drawing from fields of statistical physics, network theory, and information theory. Our discussion is organized by scale, starting with models of individual neurons and extending to large-scale networks mapped across brain regions. We then examine organizing principles and constraints that shape the biological structure and function of neural circuits. We conclude with an overview of several critical frontiers, including expanding current models, fostering tighter feedback between theory and experiment, and leveraging perturbative approaches to understand neural systems. Alongside these efforts, we highlight the importance of contextualizing their contributions by linking them to formal accounts of explanation and causation.

Chronic cold exposure is a stressor that may adversely affect the hippocampal structure and cognitive function. Critical for memory formation and learning processes, the hippocampus is particularly susceptible to hypothalamic-pituitary-adrenal (HPA) axis activity and elevated glucocorticoid levels. Vitamin D plays a complex role in regulating mitochondrial function and may provide neuroprotection. This study aimed to investigate the effects of chronic cold exposure on proteins associated with signaling pathways, mitochondrial function, and oxidative stress in the hippocampus of rats and to evaluate the neuroprotective potential of vitamin D3 supplementation. Male Wistar rats (n = 26) were assigned to four groups: control (CON; n = 4), sham stress (WW; n = 6), chronic cold water immersion (CCWI) (CW group; n = 8), and CCWI with 600 IU/kg/day vitamin D3 (VD3) supplementation (CW + D group; n = 8). Exposure to CCWI significantly reduced the hippocampal mass of rats, an effect not reversed by vitamin D3 supplementation. However, vitamin D3 improved mitochondrial function and exhibited antioxidant effects, partially reducing markers of protein and lipid free radicals damage in neural tissue. Our findings demonstrate the antioxidant properties of VD3 and its potential role in mitigating hippocampal damage during prolonged cold exposure, although its neuroprotective effects remain limited.

Synapses are elegantly integrated signaling hubs containing the canonical synaptic elements, neuronal pre- and postsynapses, along with other components of the neuropil, including perisynaptic astroglia and extracellular matrix proteins, as well as microglia and oligodendrocytes. Signaling within these multipartite hubs is essential for synaptic function and is often disrupted in neuropsychiatric disorders. We review data that have refined our understanding of how environmental stimuli shape signaling and synaptic plasticity within synapses. We propose working models that integrate what is known about how different cell types within the perisynaptic neuropil regulate synaptic functions and dysfunctions that are elicited by addictive drugs. While these working models integrate existing findings, they are constrained by a need for new technology. Accordingly, we propose directions for improving reagents and experimental approaches to better probe how signaling between cell types within perisynaptic ecosystems creates the synaptic plasticity necessary to establish and maintain adaptive and maladaptive behaviors.

Living organisms can sense and adapt to constant changes in food availability. Maintaining a homeostatic supply of energy molecules is crucial for animal survival and normal organ functioning, particularly the brain, due to its high-energy demands. However, the mechanisms underlying brain adaptive responses to food availability have not been completely established. The nervous system is separated from the rest of the body by a physical barrier called the blood-brain barrier (BBB). In addition to its structural role, the BBB regulates the transport of metabolites and nutrients into the nervous system. This regulation is achieved through adaptive mechanisms that control the transport of nutrients, including glucose and monocarboxylates such as lactate, pyruvate, and ketone bodies. In Drosophila melanogaster, carbohydrate transporters increase their expression in glial cells of the BBB in response to starvation. However, changes in the expression or activity of Drosophila monocarboxylate transporters (dMCTs) at the BBB have not yet been reported. Here, we show that neuronal ATP levels remain unaffected despite reduced energy-related metabolites in the hemolymph of Drosophila larvae during starvation. Simultaneously, the transport of lactate and beta-hydroxybutyrate increases in the glial cells of the BBB. Using genetically encoded sensors, we identified Yarqay as a proton-coupled monocarboxylate transporter whose expression is upregulated in the subperineurial glia of the BBB during starvation. Our findings reveal a novel component of the adaptive response of the brain to starvation: the increase in the transport of monocarboxylates across the BBB, mediated by Yarqay, a novel dMCT enriched in the BBB.

Mitochondrial dysfunction and disrupted bioenergetic processes are critical in the pathogenesis of bipolar disorder (BD), with cognitive impairment being a prominent symptom linked to mitochondrial anomalies. The tricarboxylic acid (TCA) cycle, integral to mitochondrial energy production, may be implicated in this cognitive dysfunction, yet its specific association with BD remains underexplored. In this cross-sectional study, 144 first-episode, drug-naive BD patients and 51 healthy controls were assessed. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), serum TCA cycle metabolites were quantified, and cognitive function was evaluated through the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Stroop color-word test. The study found that BD patients exhibited significantly elevated serum levels of several TCA metabolites compared to healthy controls, alongside lower cognitive function scores. Correlational analyses revealed that certain bioenergetic metabolites were significantly positively associated with anxiety and negatively correlated with cognitive performance in BD patients. Notably, succinic acid, α-Ketoglutaric acid (α-KG), and malic acid emerged as independent risk factors for BD, with their combined profile demonstrating diagnostic utility. These findings underscore the potential of serum bioenergetic metabolites as biomarkers for BD, providing insights into the mitochondrial dysfunction underlying cognitive impairment and offering a basis for early diagnosis and targeted therapeutic strategies.

A combination of intracellular and extracellular abnormalities of the nervous system, coupled with inflammation and intestinal dysbiosis, form the hallmarks of neurodegenerative diseases (NDDs). While it is difficult to identify the precise order in which these hallmarks manifest in NDDs because of their mutualistic nature, they cumulatively result in nervous or neuronal damage that characterizes neurodegeneration. In this review we discuss the roles of microRNAs (miRNAs) in the maintenance of nervous system homeostasis and their implication for NDDs. We further highlight recent advances in, and limitations of, miRNA therapeutics in NDDs and their future potential.

Despite decades of research in brain energy metabolism and to what extent different cell types utilize distinct substrates for their energy metabolism, this topic remains a vibrant area of neuroscience research. In this review, we focus on the substrates utilized by the inhibitory GABAergic neurons, which has been less explored than glutamatergic neurons. First, we discuss how GABAergic neurons may utilize both glucose, lactate, or ketone bodies under different functional conditions, and provide some preliminary data suggesting that unlike glutamatergic neurons, GABAergic neurons work well when substrate supply is restricted to lactate. We end by discussing the role of GABAergic neuron energy metabolism in pathologies where failure of inhibitory function play a central role, namely epilepsy, hepatic encephalopathy, and Alzheimer's disease.

Metastability, a concept from dynamical systems theory, provides a framework for understanding how the brain shifts between various functional states and underpins essential cognitive, behavioural, and social function. While studied in adults, metastability in early brain development has only received recent attention. As the brain undergoes dramatic functional and structural changes over the third gestational trimester, here we review how these are reflected in changes in brain metastable dynamics in preterm, preterm at term-equivalent and full-term neonates. We synthesize findings from EEG, fMRI, fUS, and computational models, focusing on the spatial distribution and temporal dynamics of metastable states, which include functional integration and segregation, signal predictability and complexity. Despite fragmented evidence, studies suggest that neonatal metastability develops over the equivalent of the third gestational trimester, with increasing ability for integration-segregation, broader range of metastable states, faster metastable state transitions and greater signal complexity. Preterms at term-equivalent age exhibit immature metastability features compared to full-terms. We explain and interpret these changes in terms of maturation of the brain in a free energy landscape and establishment of cognitive functions.

In the human brain, interactions between multiple regions organize stable dynamics that enable enhanced cognitive processes. However, it is unclear how collective activities in the brain network can generate stable states while preserving unity across the whole brain scale under successive environmental changes. Herein, a network model was introduced in which network connections were adjusted to reduce the energy consumption level by avoiding excess changes in the activated states of each region during successive interactions. For time series data obtained from fMRI images, a connection matrix was generated by a simulation, and the predictions made by this matrix yielded accurate results relative to the real data. In this simulation, the adjustment process was activity-dependent, in which the interregional connections between intense active regions were reinforced to prohibit free behaviours. This resulted in a reduced excess energy loss and the integration of multiple regional activities into integrated dynamic states under constraints imposed by other regions. It was suggested that the simple rule of saving excess energy costs plays an important role in the mechanism that regulates large-scale brain networks and dynamics.

This paper presents an interpretation of stuttering behavior, based on the principles of the active inference framework. Stuttering is a neurodevelopmental disorder characterized by speech disfluencies such as repetitions, prolongations, and blocks. The principles of active inference, a theory of predictive processing and sentient behavior, can be used to conceptualize stuttering as a disruption in perception-action cycling underlying speech production. The theory proposed here posits that stuttering arises from aberrant sensory precision and prediction error dynamics, inhibiting syllable initiation. Relevant to this theory, two hypothesized mechanisms are proposed: (1) a mistiming in precision dynamics, and (2) excessive attentional focus. Both highlight the role of neural oscillations, prediction error, and hierarchical integration in speech production. This framework also explains the contextual variability of stuttering behaviors, including adaptation effects and fluency-inducing conditions. Reframing stuttering as a synaptopathy integrates neurobiological, psychological, and behavioral dimensions, suggesting disruptions in precision-weighting mediated by neuromodulatory systems. This active inference perspective provides a unified account of stuttering and sets the stage for innovative research and therapeutic approaches.

Mitochondrial dysfunction is a hallmark of idiopathic neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease and Huntington disease. Familial forms of Parkinson disease and amyotrophic lateral sclerosis are often characterized by mutations in genes associated with mitophagy deficits. Therefore, enhancing the mitophagy pathway may represent a novel therapeutic approach to targeting an underlying pathogenic cause of neurodegenerative diseases, with the potential to deliver neuroprotection and disease modification, which is an important unmet need. Accumulating genetic, molecular and preclinical model-based evidence now supports targeting mitophagy in neurodegenerative diseases. Despite clinical development challenges, small-molecule-based approaches for selective mitophagy enhancement - namely, USP30 inhibitors and PINK1 activators - are entering phase I clinical trials for the first time.

Disruptions of energy supply to the brain are associated with many neurodegenerative pathologies and are difficult to study due to numerous interlinked metabolic pathways. We explored the effects of diminished energy supply on brain metabolism using a computational model of the neuro-glia-vasculature ensemble, in the form of a neuron, an astrocyte and local blood supply. As a case study, we investigated the glucose transporter type-1 deficiency syndrome (GLUT1-DS), a childhood affliction characterized by impaired glucose utilization and associated with phenotypes including seizures. Compared to neurons, astrocytes exhibited markedly higher metabolite concentration variabilities for all but a few redox species. This effect could signal a role for astrocytes in absorbing the shock of blood nutrient fluctuations. Redox balances were disrupted in GLUT1-DS with lower levels of reducing equivalent carriers NADH and ATP. The best non-glucose nutrient or pharmacotherapies for re-establishing redox normalcy involved lactate, the keto-diet (β-hydroxybutyrate), NAD and Q10 supplementation, suggesting a possible glucose sparing mechanism. GLUT1-DS seizures resulted from after-discharge neuronal firing caused by post-stimulus ATP reductions and impaired Na+/K+-ATPase, which can be rescued by restoring either normal glucose or by relatively small increases in neuronal ATP.

Sexual selection has strong effects on gonad size, which has been proposed to shift energetic allocations resulting in concomitant decreases to brain size. However, mixed findings leave it unclear whether negative correlations arise from direct energetic trade-offs or correlated selection. We tested whether male reproductive tactics impose energetic trade-offs by comparing brain and gonad sizes in Poecilia parae, a fish with discrete alternative male morphs specializing in three reproductive strategies: coercion, display, and sneaking. The obligate sneaker morph had substantially larger gonads and smaller brains than the other morphs, consistent with an energetic trade-off. However, examining individuals within morphs revealed a positive relationship, contradicting energetic trade-offs. To resolve which morphs reflect the ancestral state, we examined two closely related species whose males utilize more flexible reproductive strategies, Poecilia picta and Poecilia reticulata. Within these species, a negative correlation between gonad and brain size was observed, consistent with correlated selection shaping traits towards multiple reproductive peaks. Additionally, neuron-to-glia ratio (a proxy for energetic demands) showed no link to gonad size. Our results suggest that reproductive strategies shape brain evolution through correlated selection rather than direct energetic trade-offs, challenging assumptions of sexually selected traits imposing constraints through direct resource allocation.

Working memory (WM) is a dynamic process linked to whole-brain functional connectome time-varying re-configuration. The neural dynamics underlying WM deficits in adolescents with early-onset schizophrenia (EOS), who have higher genetic loads and immature WM neural substrates, still remain unclear.

We used dynamic voxel-wise degree centrality (dDC) to explore the dynamic profile of whole-brain functional connectome in 51 adolescents with EOS and 45 healthy controls (HCs) during an n-back task. We assessed the group-related dDC time-varying variability and clustered meta-states differences between EOS and HCs. Correlation analysis also applied between the detected areas with clinical symptoms and WM performances, and detected areas further allowed for image transcription analyses.

We did not observe any group-related differences in the dDC time-varying instability. In the clustered dominant state 1, when facing with increased WM loads, EOS showed decreased dDC compared with HCs in the left insula, anterior and posterior lobe of the cerebellum, bilateral inferior parietal lobule, left pons, bilateral superior temporal gyrus, rectus gyrus, precuneus, bilateral inferior frontal gyrus (IFG), etc. Enrichment analysis reveals these detected areas related to synaptic function, neuronal communication, and metabolic processes.

This is the first study to investigate the abnormal time-varying pattern of the whole-brain connectome in EOS during the WM task and its molecular foundation. It demonstrated impaired neural resource allocation between frontoparietal, default-mode, and salience networks and the associated metabolic processes may underlie WM deficits in EOS, which can provide knowledge for targeted interventions and future research.

Organisms have evolved protective strategies that are geared toward limiting cellular damage and enhancing organismal survival in the face of environmental stresses, but how these protective mechanisms are coordinated remains unclear. Here, we define a requirement for neural activity in mobilizing the antioxidant defenses of the nematode Caenorhabditis elegans both during chronic oxidative stress and prior to its onset. We show that acetylcholine-deficient mutants are particularly vulnerable to chronic oxidative stress. We find that extended oxidative stress mobilizes a broad transcriptional response which is strongly dependent on both cholinergic signaling and activation of the muscarinic G-protein acetylcholine coupled receptor (mAChR) GAR-3. Gene enrichment analysis revealed a lack of upregulation of proteasomal proteolysis machinery in both cholinergic-deficient and gar-3 mAChR mutants, suggesting that muscarinic activation is critical for stress-responsive upregulation of protein degradation pathways. Further, we find that GAR-3 overexpression in cholinergic motor neurons prolongs survival during chronic oxidative stress. Our studies demonstrate neuronal modulation of antioxidant defenses through cholinergic activation of G protein-coupled receptor signaling pathways, defining new potential links between cholinergic signaling, oxidative damage, and neurodegenerative disease.

Redox dysregulation has been proposed as a convergent point of childhood trauma and the emergence of psychiatric disorders, such as schizophrenia (SCZ). A critical region particularly vulnerable to environmental insults during adolescence is the ventral hippocampus (vHip). However, the impact of severe stress on vHip redox states and their functional consequences, including behavioral and electrophysiological changes related to SCZ, are not entirely understood.

After exposing adolescent animals to physical stress (postnatal day, PND31-40), we explored social and cognitive behaviors (PND47-49), the basal activity of pyramidal glutamate neurons, the number of parvalbumin (PV) interneurons, and the transcriptomic signature of the vHip (PND51). We also evaluated the impact of stress on the redox system, including mitochondrial respiratory function, reactive oxygen species (ROS) production, and glutathione (GSH) levels in the vHip and serum.

Adolescent-stressed animals exhibited loss of sociability, cognitive impairment, and vHip excitatory/inhibitory (E/I) imbalance. Genome-wide transcriptional profiling unveiled the impact of stress on redox system- and synaptic-related genes. Stress impacted mitochondrial respiratory function and changes in ROS levels in the vHip. GSH and glutathione disulfide (GSSG) levels were elevated in the serum of stressed animals, while GSSG was also increased in the vHip and negatively correlated with sociability. Additionally, PV interneuron deficits in the vHip caused by adolescent stress were associated with oxidative stress.

Our results highlight the negative impact of adolescent stress on vHip redox regulation and mitochondrial function, which are partially associated with E/I imbalance and behavioral abnormalities related to SCZ.

Fish are facing compromised health with mass mortality due to the decreased water quality of aquatic bodies. The brain, a complex body organ that controls whole body physiology, is influenced first by any kind of water fluctuations, and by keeping it relaxed and nourished, fish health can be improved. Among freshwater fish, catfish Heteropneustes fossilis has importance not only as a rich nutrient source but also due to medicinal significance. This study evaluated the impact of pyrimidine, a well-known organic compound with several therapeutic properties, on the cerebral health of the freshwater catfish H. fossilis as a bioremediation of aquatic environmental threats. In experiments, to get an effective concentration of pyrimidine, fish were incubated with different doses of pyrimidine (10 fg/mL-1 mg/mL) for 24 h, and brain histotexture and fish survival were recorded. As per the results of the previous experiment, an effective concentration of pyrimidine (10 pg/mL) was given for different durations (1-, 5- and 21-day incubation with pyrimidine and recovery; after 21-day treatment in only water for 7 days) along with the control group. Results exhibited that the level of cerebral antioxidant enzymes (catalase, superoxide dismutase, peroxidase) and lipid peroxidation were significantly lower, and macromolecules (carbohydrate, protein and lipid) were increased in pyrimidine-treated fish with duration of pyrimidine treatment as compared to the control group. Histo-neurological analysis of the brain with haematoxylin-eosin and cresyl violet revealed that an effective, nonlethal concentration of pyrimidine supported overall neuronal health without any histopathological changes. However, in the recovery experimental group, results showed reverting of pyrimidine induced positive changes in antioxidative enzyme and energy biomolecule levels, supporting the non-bio-accumulative nature of pyrimidine. However, microphotographs revealed that the neuronal quantity (cresyl violet) and cellular histotexture (haematoxylin-eosin) improvement due to pyrimidine were sustained in the recovery group. The results of this study suggested that effective concentration of pyrimidine improved the brain health of H. fossilis in a duration-dependent manner compared to control fish due to increased metabolism by upregulating energy macromolecule and cellular-neuronal texture along with downregulation of antioxidative stress.

Alzheimer's disease tau pathology spreads through neuronal pathways and synaptic connections. Alteration in synaptic activity facilitates tau spreading. Multiple neurotransmitter systems are shown to be implicated in Alzheimer's disease, but their influence on the trans-synaptic spread of tau is not well understood. I aimed to combine resting-state functional magnetic resonance imaging connectomics, neurotransmitter receptor profiles, and tau-PET data to explain the regional susceptibility to tau accumulation. The tau-PET imaging data of 161 amyloid-beta-negative cognitively unimpaired participants as control and 259 amyloid-beta-positive subjects were recruited from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Linear regression analysis revealed that a higher tau-PET z-score is associated with a lower density of nine receptors in the serotonin, dopamine, gamma-aminobutyric acid (GABA), acetylcholine, and glutamate systems. Furthermore, adding four neurotransmitter receptor density z-scores significantly increased the proportion of explained variance by 3% to 7% compared to the epicenter-connectivity distance model in the group-level analysis. Also, adding nine neurotransmitter receptor density z-scores to the epicenter-connectivity distance model increased the explanatory power of variability in individual levels of tau-PET z-score by 3% to 8%. The current study demonstrated the additive value of atlas-based neurotransmitter receptor mapping and individual-level amyloid-beta-PET scans to enhance the connectivity-based explanation of tau accumulation.

Mitochondria, often known as the cell's powerhouses, are primarily responsible for generating energy through aerobic oxidative phosphorylation. However, their functions extend far beyond just energy production. Mitochondria play crucial roles in maintaining calcium balance, regulating apoptosis (programmed cell death), supporting cellular signaling, influencing cell metabolism, and synthesizing reactive oxygen species (ROS). Recent research has highlighted a strong link between bipolar disorder (BD) and mitochondrial dysfunction. Mitochondrial dysfunction contributes to oxidative stress, particularly through the generation of ROS, which are implicated in the pathophysiology of BD. Oxidative stress arises when there is an imbalance between the production of ROS and the cell's ability to neutralize them. In neurons, excessive ROS can damage various cellular components, including proteins in neuronal membranes and intracellular enzymes. Such damage may interfere with neurotransmitter reuptake and the function of critical enzymes, potentially affecting brain regions involved in mood regulation and emotional control, which are key aspects of BD. In this review, we will explore how various types of mitochondrial dysfunction contribute to the production of ROS. These include disruptions in energy metabolism, impaired ROS management, and defects in mitochondrial quality control mechanisms such as mitophagy (the process by which damaged mitochondria are selectively degraded). We will also examine how abnormalities in calcium signaling, which is crucial for synaptic plasticity, can lead to mitochondrial dysfunction. Additionally, we will discuss the specific mitochondrial dysfunctions observed in BD, highlighting how these defects may contribute to the disorder's pathophysiology. Finally, we will identify potential therapeutic targets to improve mitochondrial function, which could pave the way for new treatments to manage or mitigate symptoms of BD.

The human brain is a complex system with high metabolic demands and extensive connectivity that requires control to balance energy consumption and functional efficiency over time. How this control is manifested on a whole-brain scale is largely unexplored, particularly what the associated costs are. Using the network control theory, here, we introduce a novel concept, time-averaged control energy (TCE), to quantify the cost of controlling human brain dynamics at rest, as measured from functional and diffusion MRI. Importantly, TCE spatially correlates with oxygen metabolism measures from the positron emission tomography, providing insight into the bioenergetic footing of resting-state control. Examining the temporal dimension of control costs, we find that brain state transitions along a hierarchical axis from sensory to association areas are more efficient in terms of control costs and more frequent within hierarchical groups than between. This inverse correlation between temporal control costs and state visits suggests a mechanism for maintaining functional diversity while minimizing energy expenditure. By unpacking the temporal dimension of control costs, we contribute to the neuroscientific understanding of how the brain governs its functionality while managing energy expenses.

Major depressive disorder (MDD) is a widespread psychiatric condition, recognized as the third leading cause of global disease burden in 2008. In the context of MDD, alterations in synaptic transmission within the prefrontal cortex (PFC) are associated with PFC hypoactivation, a key factor in cognitive function and mood regulation. Given the high energy demands of the central nervous system, these synaptic changes suggest a metabolic imbalance within the PFC of MDD patients. However, the cellular mechanisms underlying this metabolic dysregulation remain not fully elucidated. This study employs single-nucleus RNA sequencing (snRNA-seq) data to predict metabolic alterations in the dorsolateral PFC (DLPFC) of MDD patients. Our analysis revealed cell type-specific metabolic patterns, notably the disruption of oxidative phosphorylation and carbohydrate metabolism in the DLPFC of MDD patients. Gene set enrichment analysis based on human phenotype ontology predicted alterations in serum lactate levels in MDD patients, corroborated by the observed decrease in lactate levels in MDD patients compared to 47 age-matched healthy controls (HCs). This transcriptional analysis offers novel insights into the metabolic disturbances associated with MDD and the energy dynamics underlying DLPFC hypoactivation. These findings are instrumental for comprehending the pathophysiology of MDD and may guide the development of innovative therapeutic strategies.

Acupuncture significantly improves cognitive dysfunction in rats with chronic cerebral ischemia. However, the underlying signaling pathways remain unclear. This study investigates the role of the CKLF1/HIF-1α/VEGF/Notch1 signaling pathway in the acupuncture-mediated improvement of cognitive function in rats with chronic cerebral ischemia.

Male SD rats were randomly divided into the normal control group, sham-operated group, 2-VO model group, 2-VO + acupuncture group, and 2-VO + Ginaton group (Ginkgo biloba extract 14.4 mg/kg/day), with 10 rats in each group. The 2-VO + acupuncture group received acupuncture at the Shuigou, Baihui, bilateral Fengchi, and bilateral Zusanli points for 14 consecutive sessions over 2 weeks. The rats' memory function was assessed using the Morris water maze and novel object recognition tests. Cerebral blood volume changes were measured using laser speckle imaging. Ultrastructural changes in microvessels were observed via transmission electron microscopy. Neuronal and myelin alterations were evaluated using HE staining, Nissl staining, and LFB myelin staining. The expression levels of CKLF1, CCR5, HIF-1α, VEGF, and Notch1 proteins were measured using Western blot, and multiple immunofluorescence staining was performed to assess the colocalization of CKLF1 and neurons.

Compared with the 2-VO model group, acupuncture treatment reduced the latency period and increased the number of platform crossings in the Morris water maze test, and the 2-VO model group had a higher recognition index in the novel object recognition test. We found that acupuncture improved the condition of endothelial cells, repaired the morphology of the vascular lumen, and alleviated astrocyte edema. We also showed that acupuncture could ameliorate pathological damage in rats with chronic cerebral ischemia. Moreover, acupuncture reduced the expression of CKLF1, CCR5, and HIF-1α proteins in the hippocampus, decreased the fluorescence intensity of CKLF1 expression, and increased the fluorescence intensity of neurons in the hippocampal CA1 region.

Acupuncture may exert neuroprotective effects and improve cognitive dysfunction caused by chronic cerebral ischemia by regulating the CKLF1/HIF-1α/VEGF/Notch1 pathway to inhibit inflammatory factors and increase cerebral blood flow.

Synaptic homeostasis of the principal neurotransmitters glutamate and GABA is tightly regulated by an intricate metabolic coupling between neurons and astrocytes known as the glutamate/GABA-glutamine cycle. In this cycle, astrocytes take up glutamate and GABA from the synapse and convert these neurotransmitters into glutamine. Astrocytic glutamine is subsequently transferred to neurons, serving as the principal precursor for neuronal glutamate and GABA synthesis. The glutamate/GABA-glutamine cycle integrates multiple cellular processes, including neurotransmitter release, uptake, synthesis, and metabolism. All of these processes are deeply interdependent and closely coupled to cellular energy metabolism. Astrocytes display highly active mitochondrial oxidative metabolism and several unique metabolic features, including glycogen storage and pyruvate carboxylation, which are essential to sustain continuous glutamine release. However, new roles of oligodendrocytes and microglia in neurotransmitter recycling are emerging. Malfunction of the glutamate/GABA-glutamine cycle can lead to severe synaptic disruptions and may be implicated in several brain diseases. Here, I review central aspects and recent advances of the glutamate/GABA-glutamine cycle to highlight how the cycle is functionally connected to critical brain functions and metabolism. First, an overview of glutamate, GABA, and glutamine transport is provided in relation to neurotransmitter recycling. Then, central metabolic aspects of the glutamate/GABA-glutamine cycle are reviewed, with a special emphasis on the critical metabolic roles of glial cells. Finally, I discuss how aberrant neurotransmitter recycling is linked to neurodegeneration and disease, focusing on astrocyte metabolic dysfunction and brain lipid homeostasis as emerging pathological mechanisms. Instead of viewing the glutamate/GABA-glutamine cycle as individual biochemical processes, a more holistic and integrative approach is needed to advance our understanding of how neurotransmitter recycling modulates brain function in both health and disease.

The hippocampus has long been associated with cognition and memory function, the implications of lysine lactylation (Kla), a recently identified post-translational modification (PTM), in the role of the hippocampus remain largely unexplored.

An LC-MS/MS bottom-up proteomics analysis of three human hippocampal tissue samples was applied to profile the lactylation map in human hippocampi under normal physiological conditions.

We identified 2579 quantifiable Class I lactylated sites in 853 proteins, of which contained four types of modification motifs. Cellular localization analysis implies that a majority of lactylated proteins were distributed in the cytoplasm. Functional enrichment analysis showed that lactylated proteins were mainly involved in energy metabolic pathways. In addition, we found that the lactylation on histones exhibits a certain degree of conservation across different tissues. Compared with previously reported lactylation databases, 213 lactylated proteins were identified for the first time in this study.

The first global lactylated proteins atlas of human hippocampi was reported in this study. Our work provides a reliable foundation for further research on lactylation in the hippocampus under physiological conditions.

The dynamics of energy molecules in the mouse brain during metabolic challenges induced by epileptic seizures were examined. A transgenic mouse line expressing a fluorescence resonance energy transfer (FRET)-based adenosine triphosphate (ATP) sensor, selectively expressed in the cytosol of neurons, was used. An optical fiber was inserted into the hippocampus, and changes in cytosolic ATP concentration were estimated using the fiber photometry method. To induce epileptic neuronal hyperactivity, a train of electrical stimuli was delivered to a bipolar electrode placed alongside the optical fiber. Although maintaining a steady cytosolic ATP concentration is crucial for cell survival, a single episode of epileptic neuronal hyperactivity drastically reduced neuronal ATP levels. Interestingly, the magnitude of ATP reduction did not increase with the exacerbation of epilepsy, but rather decreased. This suggests that the primary consumption of ATP during epileptic neuronal hyperactivity may not be solely directed toward restoring the Na+ and K+ ionic imbalance caused by action potential bursts. Cytosolic ATP concentration reflects the balance between supply and consumption. To investigate the metabolic flux leading to neuronal ATP production, a new FRET-based pyruvate sensor was developed and selectively expressed in the cytosol of astrocytes in transgenic mice. Upon epileptic neuronal hyperactivity, an increase in astrocytic pyruvate concentration was observed. Changes in the supply of energy molecules, such as glucose and oxygen, due to blood vessel constriction or dilation, as well as metabolic alterations in astrocyte function, may contribute to cytosolic ATP dynamics in neurons.

Differentiation from neural progenitor to mature neuron requires a metabolic switch, whereby mature neurons become almost entirely dependent upon oxidative phosphorylation (OXPHOS) for ATP production. Although more efficient with respect to ATP production, OXPHOS produces additional reactive oxygen species, as compared to glycolysis; thus, endogenous mechanisms to quench free radicals are essential for the maintenance of neuronal health. Melatonin is synthesized in neuronal mitochondria and has a dual role as a free radical scavenger and as an inhibitor of mitochondrial-triggered cell death and proinflammatory pathways. Previously, we showed that loss of endogenous melatonin induced mitochondrial DNA (mtDNA) and cytochrome c (CytC) release triggering pathological inflammation and cell death pathways, respectively. Here we find that in mature neurons, but not undifferentiated neuronal cells, melatonin deficiency altered metabolic reprogramming in aralkylamine N-acetyltransferase knockout (AANAT-KO) neurons as compared with neurons expressing AANAT. Interestingly, there are no differences in neural progenitors regardless of AANAT status. In addition, AANAT-KO deficiency elevated BAK and BAX levels in AANAT-KO neurons. Further, we found that exogenous melatonin treatment of AANAT-KO cells during differentiation into mature neurons rescued metabolic reprogramming defects and restored normal BAK/BAX levels. Thus, we demonstrated that the metabolic reprogramming and subsequent consequences of the switch to OXPHOS that normally occurs during neuronal maturation are compromised by melatonin deficiency and rescued by melatonin supplementation.

Bipolar disorder (BD) and schizophrenia (SCZ) are uniquely human disorders with a complex pathophysiology that involves adverse neuropathological events in brain development. High disease polygenicity and limited access to live human brain tissue make these disorders exceedingly challenging to study mechanistically. Cellular cultures and brain organoids generated from human-derived pluripotent stem cells preserve the genetic background of the donor cells and recapitulate some of the defining characteristics of human brain architecture and early spatiotemporal development. These model systems have already proven successful in deciphering some of the neuropathological perturbations in BD and SCZ, and methodological advancements, such as the functional integration of 2 or more region-specific organoids and organoid transplantation in animals, promise to deliver increasingly refined insights. Here, we review a selection of recent discoveries achieved by stem cell-based models, with a particular focus on patterns of cellular and molecular convergence and divergence between BD and SCZ. First, we provide a brief overview of the evidence from glial and neuronal cell cultures and brain organoids, centering our discussion on several key functional domains, including neuroinflammation, neuronal excitability, and mitochondrial function. Then, we review recent findings demonstrating the power of integrating stem cell-based systems with gene editing technologies to elucidate the functional consequences of risk variants identified through genetic association studies. We end with a discussion of current challenges and some promising avenues for future research.

Long-lasting brain fatigue is a consequence of stroke or traumatic brain injury associated with emotional, psychological, and physical overload, distress in hypertension, atherosclerosis, viral infection, and aging-related chronic low-grade inflammatory disorders. The pathogenesis of brain fatigue is linked to disrupted neurotransmission, the glutamate-glutamine cycle imbalance, glucose metabolism, and ATP energy supply, which are associated with multiple molecular targets and signaling pathways in neuroendocrine-immune and blood circulation systems. Regeneration of damaged brain tissue is a long-lasting multistage process, including spontaneously regulating hypothalamus-pituitary (HPA) axis-controlled anabolic-catabolic homeostasis to recover harmonized sympathoadrenal system (SAS)-mediated function, brain energy supply, and deregulated gene expression in rehabilitation. The driving mechanism of spontaneous recovery and regeneration of brain tissue is a cross-talk of mediators of neuronal, microglia, immunocompetent, and endothelial cells collectively involved in neurogenesis and angiogenesis, which plant adaptogens can target. Adaptogens are small molecules of plant origin that increase the adaptability of cells and organisms to stress by interaction with the HPA axis and SAS of the stress system (neuroendocrine-immune and cardiovascular complex), targeting multiple mediators of adaptive GPCR signaling pathways. Two major groups of adaptogens comprise (i) phenolic phenethyl and phenylpropanoid derivatives and (ii) tetracyclic and pentacyclic glycosides, whose chemical structure can be distinguished as related correspondingly to (i) monoamine neurotransmitters of SAS (epinephrine, norepinephrine, and dopamine) and (ii) steroid hormones (cortisol, testosterone, and estradiol). In this narrative review, we discuss (i) the multitarget mechanism of integrated pharmacological activity of botanical adaptogens in stress overload, ischemic stroke, and long-lasting brain fatigue; (ii) the time-dependent dual response of physiological regulatory systems to adaptogens to support homeostasis in chronic stress and overload; and (iii) the dual dose-dependent reversal (hormetic) effect of botanical adaptogens. This narrative review shows that the adaptogenic concept cannot be reduced and rectified to the various effects of adaptogens on selected molecular targets or specific modes of action without estimating their interactions within the networks of mediators of the neuroendocrine-immune complex that, in turn, regulates other pharmacological systems (cardiovascular, gastrointestinal, reproductive systems) due to numerous intra- and extracellular communications and feedback regulations. These interactions result in polyvalent action and the pleiotropic pharmacological activity of adaptogens, which is essential for characterizing adaptogens as distinct types of botanicals. They trigger the defense adaptive stress response that leads to the extension of the limits of resilience to overload, inducing brain fatigue and mental disorders. For the first time, this review justifies the neurogenesis potential of adaptogens, particularly the botanical hybrid preparation (BHP) of Arctic Root and Ashwagandha, providing a rationale for potential use in individuals experiencing long-lasting brain fatigue. The review provided insight into future research on the network pharmacology of adaptogens in preventing and rehabilitating long-lasting brain fatigue following stroke, trauma, and viral infections.

Inflammation plays a key role in the development of neurodegenerative disorders that are currently incurable. Licochalcone A (LCA) has been described as an emerging anti-inflammatory drug with multiple therapeutical properties that could potentially prevent neurodegeneration. However, its neuroprotective mechanism remains unclear. Here, we investigated if LCA prevents cognitive decline induced by Lipopolysaccharide (LPS) and elucidated its potential benefits. For that, 8-week-old C57BL6/J male mice were intraperitonially (i.p.) treated with saline solution or LCA (15 mg/kg/day, 3 times per week) for two weeks. The last day, a single i.p injection of LPS (1 mg/kg) or saline solution was administered 24 h before sacrifice. The results revealed a significant reduction in mRNA expression in genes involved in oxidative stress (Sod1, Cat, Pkm, Pdha1, Ndyfv1, Uqcrb1, Cycs and Cox4i1), metabolism (Slc2a1, Slc2a2, Prkaa1 and Gsk3b) and synapsis (Bdnf, Nrxn3 and Nlgn2) in LPS group compared to saline. These findings were linked to memory impairment and depressive-like behavior observed in this group. Interestingly, LCA protected against LPS alterations through its anti-inflammatory effect, reducing gliosis and regulating M1/M2 markers. Moreover, LCA-treated animals showed a significant improvement of antioxidant mechanisms, such as citrate synthase activity and SOD2. Additionally, LCA demonstrated protection against metabolic disturbances, downregulating GLUT4 and P-AKT, and enhanced the expression of synaptic-related proteins (P-CREB, BDNF, PSD95, DBN1 and NLG3), leading all together to dendritic spine preservation. In conclusion, our results demonstrate that LCA treatment prevents LPS-induced cognitive decline by reducing inflammation, enhancing the antioxidant response, protecting against metabolic disruptions and improving synapsis related mechanisms.

Neuronal mitochondria are diverse across cell types and subcellular compartments in order to meet unique energy demands. While mitochondria are essential for synaptic transmission and synaptic plasticity, the mechanisms regulating mitochondria to support normal synapse function are incompletely understood. The mitochondrial calcium uniporter (MCU) is proposed to couple neuronal activity to mitochondrial ATP production, which would allow neurons to rapidly adapt to changing energy demands. MCU is uniquely enriched in hippocampal CA2 distal dendrites compared to proximal dendrites, however, the functional significance of this layer-specific enrichment is not clear. Synapses onto CA2 distal dendrites readily express plasticity, unlike the plasticity-resistant synapses onto CA2 proximal dendrites, but the mechanisms underlying these different plasticity profiles are unknown. Using a CA2-specific MCU knockout (cKO) mouse, we found that MCU deletion impairs plasticity at distal dendrite synapses. However, mitochondria were more fragmented and spine head area was diminished throughout the dendritic layers of MCU cKO mice versus control mice. Fragmented mitochondria might have functional changes, such as altered ATP production, that could explain the structural and functional deficits at cKO synapses. Differences in MCU expression across cell types and circuits might be a general mechanism to tune mitochondrial function to meet distinct synaptic demands.

Neurodegenerative diseases typically emerge after an extended prodromal period, underscoring the critical importance of initiating interventions during the early stages of brain aging to enhance later resilience. Changes in presynaptic active zone proteins ("PreScale") are considered a dynamic, resilience-enhancing form of plasticity in the process of early, still reversible aging of the Drosophila brain. Aging, however, triggers significant changes not only of synapses but also mitochondria. While the two organelles are spaced in close proximity, likely reflecting a direct functional coupling in regard to ATP and Ca2+ homeostasis, the exact modes of coupling in the aging process remain to understood. We here show that genetic manipulations of mitochondrial functional status, which alters brain oxidative phosphorylation, ATP levels, or the production of reactive oxygen species (ROS), can bidirectionally regulate PreScale during early Drosophila brain aging. Conversely, genetic mimicry of PreScale resulted in decreased oxidative phosphorylation and ATP production, potentially due to reduced mitochondrial calcium (Ca2+) import. Our findings indicate the existence of a positive feedback loop where mitochondrial functional state and PreScale are reciprocally coupled to optimize protection during the early stages of brain aging.

Acute injuries can progress into painful states that endure long after healing. The mechanism underlying this transition remains unclear, but metabolic adaptations to the bioenergy demands imposed by injury are plausible contributors. Here we show that peripheral injury activates AKT/mTORC1 in afferent segments of the mouse spinal cord, redirecting local core metabolism toward biomass production while simultaneously suppressing autophagy-mediated biomass reclamation. This metabolic shift supports neuroplasticity, but creates a resource bottleneck that depletes critical spinal cord nutrients. Preventing this depletion with a modified diet normalizes biomass generation and autophagy and halts the transition to chronic pain. This effect, observed across multiple pain models, requires activation of the nutrient sensors, sirtuin-1 and AMPK, as well as restoration of autophagy. The findings identify metabolic reprogramming as a key driver of the progression to pain chronicity and point to nutritional and pharmacological interventions that could prevent this progression after surgery or other physical traumas.