Brain Circuits Research Articles

Bridging Genetic Insights with Neuroimaging in Autism Spectrum Disorder-A Systematic Review.

Autism Spectrum Disorder (ASD) is an early onset neurodevelopmental disorder characterized by impaired social interaction and communication, and repetitive patterns of behavior. Family studies show that ASD is highly heritable, and hundreds of genes have previously been implicated in the disorder; however, the etiology is still not fully clear. Brain imaging and electroencephalography (EEG) are key techniques that study alterations in brain structure and function. Combined with genetic analysis, these techniques have the potential to help in the clarification of the neurobiological mechanisms contributing to ASD and help in defining novel therapeutic targets. To further understand what is known today regarding the impact of genetic variants in the brain alterations observed in individuals with ASD, a systematic review was carried out using Pubmed and EBSCO databases and following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This review shows that specific genetic variants and altered patterns of gene expression in individuals with ASD may have an effect on brain circuits associated with face processing and social cognition, and contribute to excitation-inhibition imbalances and to anomalies in brain volumes.

Unsupervised restoration of a complex learned behavior after large-scale neuronal perturbation.

Reliable execution of precise behaviors requires that brain circuits are resilient to variations in neuronal dynamics. Genetic perturbation of the majority of excitatory neurons in HVC, a brain region involved in song production, in adult songbirds with stereotypical songs triggered severe degradation of the song. The song fully recovered within 2 weeks, and substantial improvement occurred even when animals were prevented from singing during the recovery period, indicating that offline mechanisms enable recovery in an unsupervised manner. Song restoration was accompanied by increased excitatory synaptic input to neighboring, unmanipulated neurons in the same brain region. A model inspired by the behavioral and electrophysiological findings suggests that unsupervised single-cell and population-level homeostatic plasticity rules can support the functional restoration after large-scale disruption of networks that implement sequential dynamics. These observations suggest the existence of cellular and systems-level restorative mechanisms that ensure behavioral resilience.

Body mass index–dependent shifts along large-scale gradients in human cortical organization explain dietary regulatory success

Making healthy dietary choices is essential for keeping weight within a normal range. Yet many people struggle with dietary self-control despite good intentions. What distinguishes neural processing in those who succeed or fail to implement healthy eating goals? Does this vary by weight status? To examine these questions, we utilized an analytical framework of gradients that characterize systematic spatial patterns of large-scale neural activity, which have the advantage of considering the entire suite of processes subserving self-control and potential regulatory tactics at the whole-brain level. Using an established laboratory food task capturing brain responses in natural and regulatory conditions (N = 123), we demonstrate that regulatory changes of dietary brain states in the gradient space predict individual differences in dietary success. Better regulators required smaller shifts in brain states to achieve larger goal-consistent changes in dietary behaviors, pointing toward efficient network organization. This pattern was most pronounced in individuals with lower weight status (low-BMI, body mass index) but absent in high-BMI individuals. Consistent with prior work, regulatory goals increased activity in frontoparietal brain circuits. However, this shift in brain states alone did not predict variance in dietary success. Instead, regulatory success emerged from combined changes along multiple gradients, showcasing the interplay of different large-scale brain networks subserving dietary control and possible regulatory strategies. Our results provide insights into how the brain might solve the problem of dietary control: Dietary success may be easier for people who adopt modes of large-scale brain activation that do not require significant reconfigurations across contexts and goals.

Pathophysiology in cortico-amygdala circuits and excessive aversion processing: the role of oligodendrocytes and myelination.

Stress-related psychiatric illnesses, such as major depressive disorder, anxiety and post-traumatic stress disorder, present with alterations in emotional processing, including excessive processing of negative/aversive stimuli and events. The bidirectional human/primate brain circuit comprising anterior cingulate cortex and amygdala is of fundamental importance in processing emotional stimuli, and in rodents the medial prefrontal cortex-amygdala circuit is to some extent analogous in structure and function. Here, we assess the comparative evidence for: (i) Anterior cingulate/medial prefrontal cortex<->amygdala bidirectional neural circuits as major contributors to aversive stimulus processing; (ii) Structural and functional changes in anterior cingulate cortex<->amygdala circuit associated with excessive aversion processing in stress-related neuropsychiatric disorders, and in medial prefrontal cortex<->amygdala circuit in rodent models of chronic stress-induced increased aversion reactivity; and (iii) Altered status of oligodendrocytes and their oligodendrocyte lineage cells and myelination in anterior cingulate/medial prefrontal cortex<->amygdala circuits in stress-related neuropsychiatric disorders and stress models. The comparative evidence from humans and rodents is that their respective anterior cingulate/medial prefrontal cortex<->amygdala circuits are integral to adaptive aversion processing. However, at the sub-regional level, the anterior cingulate/medial prefrontal cortex structure-function analogy is incomplete, and differences as well as similarities need to be taken into account. Structure-function imaging studies demonstrate that these neural circuits are altered in both human stress-related neuropsychiatric disorders and rodent models of stress-induced increased aversion processing. In both cases, the changes include altered white matter integrity, albeit the current evidence indicates that this is decreased in humans and increased in rodent models. At the cellular-molecular level, in both humans and rodents, the current evidence is that stress disorders do present with changes in oligodendrocyte lineage, oligodendrocytes and/or myelin in these neural circuits, but these changes are often discordant between and even within species. Nonetheless, by integrating the current comparative evidence, this review provides a timely insight into this field and should function to inform future studies-human, monkey and rodent-to ascertain whether or not the oligodendrocyte lineage and myelination are causally involved in the pathophysiology of stress-related neuropsychiatric disorders.

Examining a punishment-related brain circuit with miniature fluorescence microscopes and deep learning

In humans experiencing substance use disorder (SUD), abstinence from drug use is often motivated by a desire to avoid some undesirable consequence of further use: health effects, legal ramifications, etc. This process can be experimentally modeled in rodents by training and subsequently punishing an operant response in a context-induced reinstatement procedure. Understanding the biobehavioral mechanisms underlying punishment learning is critical to understanding both abstinence and relapse in individuals with SUD. To date, most investigations into the neural mechanisms of context-induced reinstatement following punishment have utilized discrete loss-of-function manipulations that do not capture ongoing changes in neural circuitry related to punishment-induced behavior change. Here, we describe a two-pronged approach to analyzing the biobehavioral mechanisms of punishment learning using miniature fluorescence microscopes and deep learning algorithms. We review recent advancements in both techniques and consider a target neural circuit.

Zmiz1 is a novel regulator of brain development associated with autism and intellectual disability.

Neurodevelopmental disorders (NDDs) are a class of pathologies arising from perturbations in brain circuit formation and maturation with complex etiological triggers often classified as environmental and genetic. Neuropsychiatric conditions such as autism spectrum disorders (ASD), intellectual disability (ID), and attention deficit hyperactivity disorders (ADHD) are common NDDs characterized by their hereditary underpinnings and inherent heterogeneity. Genetic risk factors for NDDs are increasingly being identified in non-coding regions and proteins bound to them, including transcriptional regulators and chromatin remodelers. Importantly, de novo mutations are emerging as important contributors to NDDs and neuropsychiatric disorders. Recently, de novo mutations in transcriptional co-factor Zmiz1 or its regulatory regions have been identified in unrelated patients with syndromic ID and ASD. However, the role of Zmiz1 in brain development is unknown. Here, using publicly available databases and a Zmiz1 mutant mouse model, we reveal that Zmiz1 is highly expressed during embryonic brain development in mice and humans, and though broadly expressed across the brain, Zmiz1 is enriched in areas prominently impacted in ID and ASD such as cortex, hippocampus, and cerebellum. We investigated the relationship between Zmiz1 structure and pathogenicity of protein variants, the epigenetic marks associated with Zmiz1 regulation, and protein interactions and signaling pathways regulated by Zmiz1. Our analysis reveals that Zmiz1 regulates multiple developmental processes, including neurogenesis, neuron connectivity, and synaptic signaling. This work paves the way for future studies on the functions of Zmiz1 and highlights the importance of combining analysis of mouse models and human data.

Exosomal miR-1202 mediates Brodmann Area 44 functional connectivity changes in medication-free patients with major depressive disorder: An fMRI study

Previous large-sample postmortem study revealed that the expression of miR-1202 in brain tissues from Brodmann area 44 (BA44) was dysregulated in patients with major depressive disorder (MDDs). However, the specific in vivo neuropathological mechanism of miR-1202 as well as its interplay with BA44 circuits in the depressed brain are still unclear. Here, we performed a case-control study with imaging-genetic approach based on resting-state functional magnetic resonance imaging (MRI) data and miR-1202 quantification from 110 medication-free MDDs and 102 healthy controls. Serum-derived circulating exosomes that readily cross the blood-brain barrier were isolated to quantify miR-1202. For validation, repeated MR scans were performed after a six-week follow-up of antidepressant treatment on a cohort of MDDs. Voxelwise factorial analysis revealed two brain areas (including the striatal-thalamic region) in which the effect of depression on the functional connectivity with BA44 was significantly dependent on the expression level of exosomal miR-1202. Moreover, longitudinal change of the BA44 connectivity with the striatal-thalamic region in MDDs after antidepressant treatment was found to be significantly related to the level of miR-1202 expression. These findings revealed that the in vivo neuropathological effect of miR-1202 dysregulation in depression is possibly exerted by mediating neural functional abnormalities in BA44-striatal-thalamic circuits.

Analysis of hippocampal local field potentials by diffusion mapped delay coordinates

Spatial navigation through novel spaces and to known goal locations recruits multiple integrated structures in the mammalian brain. Within this extended network, the hippocampus enables formation and retrieval of cognitive spatial maps and contributes to decision making at choice points. Exploration and navigation to known goal locations produce synchronous activity of hippocampal neurons resulting in rhythmic oscillation events in local networks. Power of specific oscillatory frequencies and numbers of these events recorded in local field potentials correlate with distinct cognitive aspects of spatial navigation. Typically, oscillatory power in brain circuits is analyzed with Fourier transforms or short-time Fourier methods, which involve assumptions about the signal that are likely not true and fail to succinctly capture potentially informative features. To avoid such assumptions, we applied a method that combines manifold discovery techniques with dynamical systems theory, namely diffusion maps and Takens’ time-delay embedding theory, that avoids limitations seen in traditional methods. This method, called diffusion mapped delay coordinates (DMDC), when applied to hippocampal signals recorded from juvenile rats freely navigating a Y-maze, replicates some outcomes seen with standard approaches and identifies age differences in dynamic states that traditional analyses are unable to detect. Thus, DMDC may serve as a suitable complement to more traditional analyses of LFPs recorded from behaving subjects that may enhance information yield.

Reservoir computing system based on mutually delay-coupled semiconductor lasers with optical feedback

Reservoir Computing (RC), an evolution from Recurrent Neural Networks (RNN), not only represents a unique machine learning paradigm, but also serves as a neuromorphic framework that mirrors the intricate cortical circuits of the human brain. This paper proposes another new photonic RC system based on four basic photonic reservoir computing architectures (single photonic RC system, the parallel photonic RC system, the dual-feedback loop-based photonic RC system and the mutually coupled photonic RC system). System proposed uses optical injection for signal input and retains two parallel responsive semiconductor lasers (R-SLs) with self-feedback loops. Meanwhile, two relatively independent R-SLs are mutually coupled via two coupling lines. The new photonic RC system adds only two sections of fiber compared to the parallel photonic RC system and the mutually coupled photonic RC system. The experiments show that the system proposed has significant advantages on the nonlinear auto regressive moving average series tasks, the chaotic time series prediction tasks and the waveform classification task. More importantly, the memory capacity of system proposed can be adjust by controlling the delay time of the self-feedback loops, so it has higher memory capacity to handle the higher order nonlinear auto regressive moving average tasks (NARMA20 and NARMA30) after optimizing the parameters.

Novel insights into minipuberty and GnRH: Implications on neurodevelopment, cognition, and COVID-19 therapeutics.

In humans, the first 1000 days of life are pivotal for brain and organism development. Shortly after birth, gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus are activated, a phenomenon known as minipuberty. This phenomenon, observed in all mammals studied, influences the postnatal development of the hypothalamic-pituitary-gonadal (HPG) axis and reproductive function. This review will put into perspective the results of recent studies showing that the impact of minipuberty extends beyond reproductive function, influencing sensory and cognitive maturation. Studies in mice have revealed the role of nitric oxide (NO) in regulating minipuberty amplitude, with NO deficiency linked to cognitive and olfactory deficits. Additionally, findings indicate that cognitive and sensory defects in adulthood in a mouse model of Down syndrome are associated with an age-dependent decline of GnRH production, whose origin can be traced back to minipuberty, and point to the potential therapeutic role of pulsatile GnRH administration in cognitive disorders. Furthermore, this review delves into the repercussions of COVID-19 on GnRH production, emphasizing potential consequences for neurodevelopment and cognitive function in infected individuals. Notably, GnRH neurons appear susceptible to SARS-CoV-2 infection, raising concerns about potential long-term effects on brain development and function. In conclusion, the intricate interplay between GnRH neurons, GnRH release, and the activity of various extrahypothalamic brain circuits reveals an unexpected role for these neuroendocrine neurons in the development and maintenance of sensory and cognitive functions, supplementing their established function in reproduction. Therapeutic interventions targeting the HPG axis, such as inhaled NO therapy in infancy and pulsatile GnRH administration in adults, emerge as promising approaches for addressing neurodevelopmental cognitive disorders and pathological aging.

Brain areas interconnected to ventral pathway circuits are independently able to induce enhancement in object recognition memory and cause reversal in object recognition memory deficit.

Ventral pathway circuits are constituted by the interconnected brain areas that are distributed throughout the brain. These brain circuits are primarily involved in processing of object related information in brain. However, their role in object recognition memory (ORM) enhancement remains unknown. Here, we have studied on the implication of these circuits in ORM enhancement and in reversal of ORM deficit in aging. The brain areas interconnected to ventral pathway circuits in rat brain were activated by an expression of a protein called regulator of G-protein signaling 14 of 414 amino acids (RGS14414). RGS14414 is an ORM enhancer and therefore used here as a gain-in-function tool. ORM test and immunohistochemistry, lesions, neuronal arborization, and knockdown studies were performed to uncover the novel function of ventral pathway circuits. An activation of each of the brain areas interconnected to ventral pathway circuits individually induced enhancement in ORM; however, same treatment in brain areas not interconnected to ventral pathway circuits produced no effect. Further study in perirhinal cortex (PRh), area V2 of visual cortex and frontal cortex (FrC), which are brain areas that have been shown to be involved in ORM and are interconnected to ventral pathway circuits, revealed that ORM enhancement seen after the activation of any one of the three brain areas was unaffected by the lesions in other two brain areas either individually in each area or even concurrently in both areas. This ORM enhancement in all three brain areas was associated to increase in structural plasticity of pyramidal neurons where more than 2-fold higher dendritic spines were observed. Additionally, we found that an activation of either PRh, area V2, or FrC not only was adequate but also was sufficient for the reversal of ORM deficit in aging rats, and the blockade of RGS14414 activity led to loss in increase in dendritic spine density and failure in reversal of ORM deficit. These results suggest that brain areas interconnected to ventral pathway circuits facilitate ORM enhancement by an increase in synaptic connectivity between the local brain area circuits and the passing by ventral pathway circuits and an upregulation in activity of ventral pathway circuits. In addition, the finding of the reversal of ORM deficit through activation of an interconnected brain area might serve as a platform for developing not only therapy against memory deficits but also strategies for other brain diseases in which neuronal circuits are compromised.

Strength and resilience of developing brain circuits predict adolescent emotional and stress responses during the COVID-19 pandemic.

The COVID-19 pandemic has had profound but incompletely understood adverse effects on youth. To elucidate the role of brain circuits in how adolescents responded to the pandemic's stressors, we investigated their prepandemic organization as a predictor of mental/emotional health in the first ~15months of the pandemic. We analyzed resting-state networks from n = 2,641 adolescents [median age (interquartile range) = 144.0 (13.0) months, 47.7% females] in the Adolescent Brain Cognitive Development study, and longitudinal assessments of mental health, stress, sadness, and positive affect, collected every 2 to 3months from May 2020 to May 2021. Topological resilience and/or network strength predicted overall mental health, stress and sadness (but not positive affect), at multiple time points, but primarily in December 2020 and May 2021. Higher resilience of the salience network predicted better mental health in December 2020 (β = 0.19, 95% CI = [0.06, 0.31], P = 0.01). Lower connectivity of left salience, reward, limbic, and prefrontal cortex and its thalamic, striatal, amygdala connections, predicted higher stress (β = -0.46 to -0.20, CI = [-0.72, -0.07], P < 0.03). Lower bilateral robustness (higher fragility) and/or connectivity of these networks predicted higher sadness in December 2020 and May 2021 (β = -0.514 to -0.19, CI = [-0.81, -0.05], P < 0.04). These findings suggest that the organization of brain circuits may have played a critical role in adolescent stress and mental/emotional health during the pandemic.

Italian Validation of the Barcelona Music Reward Questionnaire

Music experience is considered a highly pleasant activity, with musical stimuli evoking emotions and activating reward brain circuits. The Barcelona Music Reward Questionnaire (BMRQ) evaluates the main facets of music experience that could describe individual differences in music-associated reward. In this work, we validated an Italian version of the BMRQ since only Spanish, English, and French versions are currently available. The original version was translated into Italian, adapted and validated following the methodology proposed in the original BMRQ. The questionnaire was administered to adult participants through an online survey. A total of 1,218 participants were considered for the analysis. Our primary factor analysis showed an overall good structural validity (goodness of fit index &amp;gt; .999). The reliability estimates of each facet varied from .839 and .930, with some items showing higher factor loadings for a different facet than the expected one. Similar findings resulted from an additional analysis performed on a restricted sample (age &amp;lt;= 30 years and upper secondary education level), more comparable with those of the other studies. The Italian BMRQ appears overall valid and reliable despite some differences with the previous studies, suggesting its applicability might be worth testing with different populations and contexts (e.g., clinical context).

Bidirectional brain-body interactions during natural story listening

Narratives can synchronize neural and physiological signals between individuals, but the relationship between these signals, and the underlying mechanism, is unclear. We hypothesized a top-down effect of cognition on arousal and predicted that auditory narratives will drive not only brain signals but also peripheral physiological signals. We find that auditory narratives entrained gaze variation, saccade initiation, pupil size, and heart rate. This is consistent with a top-down effect of cognition on autonomic function. We also hypothesized a bottom-up effect, whereby autonomic physiology affects arousal. Controlled breathing affected pupil size, and heart rate was entrained by controlled saccades. Additionally, fluctuations in heart rate preceded fluctuations of pupil size and brain signals. Gaze variation, pupil size, and heart rate were all associated with anterior-central brain signals. Together, these results suggest bidirectional causal effects between peripheral autonomic function and central brain circuits involved in the control of arousal.

Addiction and pregnancy: case report on gender perspective.

IntroductionIn recent years, interest has grown in understanding the particularities of addiction in women. One of these singularities, with an important impact on public health, is pregnancy. Substance use during pregnancy has increased in recent decades. Given that addiction is mainly a chronic disease of the brain circuits of reward, motivation and memory, an event such as pregnancy does not exempt people who suffer from substance use disorder (SUD) from the difficulties of achieving abstinence. Moreover, as addiction often involves cycles of relapse and remission, pregnant women can also suffer a relapse even if they previously had achieved abstinence. On the other hand, given that addiction is a disease with a significant social component, we can find patients in precarious economic and social situations who suffer unwanted and therefore unplanned pregnancies.ObjectivesTo describe the case of a pregnant woman with SUD for multiple drugs who is admitted to the inpatient ward of the Hospital Clínic of Barcelona for detoxification. Also to reflect, taking in to account gender perspective, on the particularities of substance use in women on childbearing age.MethodsWe present the case of a 25-year-old woman, six weeks pregnant and homeless, who was admitted to the inpatient ward for presumed psychotic symptoms. Even if the patient had a history of intravenous heroin, cocaine, and methamphetamine use, during the admission she only admitted current alcohol consumption (3 UBE/day). During admission, the patient decided to undergo a legal voluntary abortion. Regarding this case, we did a literature review on the consequences of different substances use to pregnancy (to both the fetus and the mother’s health). Likewise, we reflected on interventions that could be carried out in community mental health facilities to detect cases like the one exposed and provide help.Results Poor obstetric outcomes are six times higher in patients who use substances. Newborns can have withdrawal syndrome, spontaneous abortion, pre-term birth, fetal malformations and fetal growth restriction. More than 50% of women of reproductive age use drugs, mainly alcohol. Routine screening and education of women of reproductive age is the best way to reduce substance use during pregnancy.ConclusionsWe consider it essential for a better management of these patients to remember that the evidence suggests that the decisions that addicts make are mainly driven by a pathology, not by a moral failure. However, pregnancy can be a moment of greater motivation to stop using drugs, given that it is a high risk situation for the mother and the fetus.Disclosure of InterestNone Declared

Mismatch novelty exploration training shifts VPAC1 receptor-mediated modulation of hippocampal synaptic plasticity by endogenous VIP in male rats.

Novelty influences hippocampal-dependent memory through metaplasticity. Mismatch novelty detection activates the human hippocampal CA1 area and enhances rat hippocampal-dependent learning and exploration. Remarkably, mismatch novelty training (NT) also enhances rodent hippocampal synaptic plasticity while inhibition of VIP interneurons promotes rodent exploration. Since VIP, acting on VPAC1 receptors (Rs), restrains hippocampal LTP and depotentiation by modulating disinhibition, we now investigated the impact of NT on VPAC1 modulation of hippocampal synaptic plasticity in male Wistar rats. NT enhanced both CA1 hippocampal LTP and depotentiation unlike exploring an empty holeboard (HT) or a fixed configuration of objects (FT). Blocking VIP VPAC1Rs with PG 97269 (100 nM) enhanced both LTP and depotentiation in naïve animals, but this effect was less effective in NT rats. Altered endogenous VIP modulation of LTP was absent in animals exposed to the empty environment (HT). HT and FT animals showed mildly enhanced synaptic VPAC1R levels, but neither VIP nor VPAC1R levels were altered in NT animals. Conversely, NT enhanced the GluA1/GluA2 AMPAR ratio and gephyrin synaptic content but not PSD-95 excitatory synaptic marker. In conclusion, NT influences hippocampal synaptic plasticity by reshaping brain circuits modulating disinhibition and its control by VIP-expressing hippocampal interneurons while upregulation of VIP VPAC1Rs is associated with the maintenance of VIP control of LTP in FT and HT animals. This suggests VIP receptor ligands may be relevant to co-adjuvate cognitive recovery therapies in aging or epilepsy, where LTP/LTD imbalance occurs.

Mapping the Neural Substrates of Cocaine Craving: A Systematic Review.

Craving is one of the most important symptoms of cocaine use disorder (CUD) since it contributes to the relapse and persistence of such disorder. This systematic review aimed to investigate which brain regions are modulated during cocaine craving. The articles were obtained through searches in the Google Scholar, Regional BVS Portal, PubMed, and Scielo databases. Overall, there was a selection of 36 studies with 1574 individuals, the majority being participants with CUD, whereby about 61.56% were individuals with CUD and 38.44% were controls (mean age = 40.4 years). Besides the methodological points, the neurobiological investigations comprised fMRI (58.34%) and PET (38.89%). The induction of cocaine craving was studied using different methods: exposure to cocaine cues (69.45%), stressful stimuli, food cues, and methylphenidate. Brain activations demonstrated widespread activity across the frontal, parietal, temporal, and occipital lobes, basal ganglia, diencephalon, brainstem, and the limbic system. In addition to abnormalities in prefrontal cortex activity, abnormalities in various other brain regions' activity contribute to the elucidation of the neurobiology of cocaine craving. Abnormalities in brain activity are justified not only by the dysfunction of dopaminergic pathways but also of the glutamatergic and noradrenergic pathways, and distinct ways of inducing craving demonstrated the involvement of distinct brain circuits and regions.

CSMD1 regulates brain complement activity and circuit development

Complement proteins facilitate synaptic elimination during neurodevelopmental pruning, but neural complement regulation is not well understood. CUB and Sushi Multiple Domains 1 (CSMD1) can regulate complement activity in vitro, is expressed in the brain, and is associated with increased schizophrenia risk. Beyond this, little is known about CSMD1 including whether it regulates complement activity in the brain or otherwise plays a role in neurodevelopment. We used biochemical, immunohistochemical, and proteomic techniques to examine the regional, cellular, and subcellular distribution as well as protein interactions of CSMD1 in the brain. To evaluate whether CSMD1 is involved in complement-mediated synapse elimination, we examined Csmd1-knockout mice and CSMD1-knockout human stem cell-derived neurons. We interrogated synapse and circuit development of the mouse visual thalamus, a process that involves complement pathway activity. We also quantified complement deposition on synapses in mouse visual thalamus and on cultured human neurons. Finally, we assessed uptake of synaptosomes by cultured microglia. We found that CSMD1 is present at synapses and interacts with complement proteins in the brain. Mice lacking Csmd1 displayed increased levels of complement component C3, an increased colocalization of C3 with presynaptic terminals, fewer retinogeniculate synapses, and aberrant segregation of eye-specific retinal inputs to the visual thalamus during the critical period of complement-dependent refinement of this circuit. Loss of CSMD1 in vivo enhanced synaptosome engulfment by microglia in vitro, and this effect was dependent on activity of the microglial complement receptor, CR3. Finally, human stem cell-derived neurons lacking CSMD1 were more vulnerable to complement deposition. These data suggest that CSMD1 can function as a regulator of complement-mediated synapse elimination in the brain during development.

Light Cannabis Use and the Adolescent Brain: An 8-years Longitudinal Assessment of Mental Health, Cognition, and Reward Processing

RationaleFor decades, cannabis has been the most widely used illicit substance in the world, particularly among youth. Research suggests that mental health problems associated with cannabis use may result from its effect on reward brain circuit, emotional processes, and cognition. However, findings are mostly derived from correlational studies and inconsistent, particularly in adolescents.Objectives and MethodsUsing data from the IMAGEN study, participants (non-users, persistent users, abstinent users) were classified according to their cannabis use at 19 and 22 years-old. All participants were cannabis-naïve at baseline (14 years-old). Psychopathological symptoms, cognitive performance, and brain activity while performing a Monetary Incentive Delay task were used as predictors of substance use and to analyze group differences over time.ResultsHigher scores on conduct problems and lower on peer problems at 14 years-old (n = 318) predicted a greater likelihood of transitioning to cannabis use within 5 years. At 19 years of age, individuals who consistently engaged in low-frequency (i.e., light) cannabis use (n = 57) exhibited greater conduct problems and hyperactivity/inattention symptoms compared to non-users (n = 52) but did not differ in emotional symptoms, cognitive functioning, or brain activity during the MID task. At 22 years, those who used cannabis at both 19 and 22 years-old n = 17), but not individuals that had been abstinent for ≥ 1 month (n = 19), reported higher conduct problems than non-users (n = 17).ConclusionsImpairments in reward-related brain activity and cognitive functioning do not appear to precede or succeed cannabis use (i.e., weekly, or monthly use). Cannabis-naïve adolescents with conduct problems and more socially engaged with their peers may be at a greater risk for lighter yet persistent cannabis use in the future.

Joint Learning Neuronal Skeleton and Brain Circuit Topology with Permutation Invariant Encoders for Neuron Classification

Determining the types of neurons within a nervous system plays a significant role in the analysis of brain connectomics and the investigation of neurological diseases. However, the efficiency of utilizing anatomical, physiological, or molecular characteristics of neurons is relatively low and costly. With the advancements in electron microscopy imaging and analysis techniques for brain tissue, we are able to obtain whole-brain connectome consisting neuronal high-resolution morphology and connectivity information. However, few models are built based on such data for automated neuron classification. In this paper, we propose NeuNet, a framework that combines morphological information of neurons obtained from skeleton and topological information between neurons obtained from neural circuit. Specifically, NeuNet consists of three components, namely Skeleton Encoder, Connectome Encoder, and Readout Layer. Skeleton Encoder integrates the local information of neurons in a bottom-up manner, with a one-dimensional convolution in neural skeleton's point data; Connectome Encoder uses a graph neural network to capture the topological information of neural circuit; finally, Readout Layer fuses the above two information and outputs classification results. We reprocess and release two new datasets for neuron classification task from volume electron microscopy(VEM) images of human brain cortex and Drosophila brain. Experiments on these two datasets demonstrated the effectiveness of our model with accuracies of 0.9169 and 0.9363, respectively. Code and data are available at: https://github.com/WHUminghui/NeuNet.