bioRxiv Subject Collection: Neuroscience's Journal
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Sunday, July 20th, 2025
| Time |
Event |
| 5:36a |
Hierarchical Neural Circuit Theory of Normalization and Inter-areal Communication
The primate brain exhibits a hierarchical, modular architecture with conserved microcircuits executing canonical computations across reciprocally connected cortical areas. Though feedback connections are ubiquitous, their functions remain largely unknown. To investigate the role of feedback, we present a hierarchical neural circuit theory with feedback connections that dynamically implements divisive normalization across its hierarchy. In a two-stage instantiation (V1 - V2), increasing feedback from V2 to V1 amplifies responses in both areas, more so in the higher cortical area, consistent with experiments. We analytically derive power spectra (V1) and coherence spectra (V1-V2), and validate them against experimental observations: peaks in both spectra shift to higher frequencies with increased stimulus contrast, and power decays as 1/f4 at high frequencies (f). The theory further predicts distinctive spectral signatures of feedback and input gain modulation. Crucially, the theory offers a unified view of inter-areal communication, with emergent features commensurate with empirical observations of both communication subspaces and inter-areal coherence. It admits a low-dimensional communication subspace, where inter-areal communication is lower-dimensional than within-area communication, and frequency bands characterized by high inter-areal coherence. It further predicts that: i) increasing feedback strength enhances inter-areal communication and diminishes within-area communication, without altering the subspace dimensionality; ii) high-coherence frequencies are characterized by stronger communication (ability to estimate neural activity in one brain area from neural activity in another brain area) and reduced subspace dimensionality. Finally, a three-area (V1 - V4 and V1 - V5) instantiation of the theory demonstrates that differential feedback from higher to lower cortical areas dictates their dynamic functional connectivity. Altogether, our theory provides a robust and analytically tractable framework for generating experimentally-testable predictions about normalization, inter-areal communication, and functional connectivity. | | 5:36a |
Neural signatures of engagement and event segmentation during story listening in background noise
Speech in everyday life is often masked by background noise, making comprehension effortful. Characterizing brain activity patterns when individuals listen to masked speech can help clarify the mechanisms underlying such effort. However, most previous research has focused on neural activity related to short, disconnected sentences that little resemble the more continuous, story-like spoken speech individuals typically encounter. In the current study, we used functional magnetic resonance imaging (fMRI) in humans (both sexes) to investigate how neural signatures of story listening change in the presence of masking by 12-talker babble noise. We show that, as speech masking increases, spatial and temporal activation patterns in auditory regions become more idiosyncratic to each listener. In contrast, spatial (and to some extent temporal) activity patterns in brain networks linked to effort (e.g. cinguloopercular network involving the anterior insula and anterior cingulate) are more similar across listeners when speech is highly masked and less intelligible, suggesting shared neural processes. Moreover, at times during stories when one meaningful event ended and another began, neural activation increased over extensive regions in frontal, parietal, and medial cortices. This event-boundary response appeared little affected by background noise, suggesting that listeners process meaningful units and, in turn, the gist in naturalistic, continuous speech even when it is masked somewhat by background noise. Overall, the current data may indicate that people stay engaged and cognitive processes associated with naturalistic speech processing remain intact under moderate levels of background noise, whereas auditory processing becomes more idiosyncratic to each listener. | | 5:36a |
Dynamical independence reveals anaesthetic specific fragmentation of emergent structure in neural dynamics
Conscious experience depends on the coordinated activity of neural processes that span multiple scales--from synapses to whole-brain dynamics. A recently introduced measure, dynamical independence, identifies, characterises and quantifies these multi-scale relationships using an information-theoretic dimensionality-reduction approach. Here, we use DI to examine changes in emergent dynamical structure in the human brain under three pharmacologically-distinct anaesthetic interventions (propofol, xenon, ketamine). Applied to source-reconstructed EEG, our analysis reveals that propofol and xenon, anaesthetics that abolish conscious report, exhibit more emergent but highly variable dynamic structure, indicating fragmented macroscopic dynamical organisation. By contrast, ketamine, which preserves dream-like phenomenology, shows the opposite pattern: reduced overall emergence yet a partial preservation of the macroscopic structure, mirroring wake. Further exploratory analyses revealed spatially localised source-level contributions to emergent dynamical structure, highlighting regional variations. Together, our results highlight drug-specific reconfigurations of emergent dynamical structure under anaesthesia, dissociate the amount of emergence from the organisation of emergent dynamics, and caution against equating emergence with level of consciousness. | | 5:36a |
Distinct Synaptic Mechanisms Drive NRXN1 Variant-Mediated Pathogenesis in iPSC-Derived Neuronal Models of Autism and Schizophrenia
Copy number deletions in the 2p16.3/NRXN1 locus confer genome wide risk for autism spectrum disorder (ASD) and schizophrenia (SCZ). Prior work demonstrated that heterozygous NRXN1 deletions decreases synaptic strength and neurotransmitter release probability in human-iPSC derived cortical glutamatergic induced neurons and this synaptic phenotype is replicated in SCZ patient iPSCs with varying NRXN1 genomic deletions. What is unknown, however, is whether similar synaptic impairment exists in ASD patients carrying NRXN1 deletions. Answering this question is important to determine whether all NRXN1 deletion carriers should be treated similarly or individually, based on their genetic backgrounds and deletion breakpoints. Here, using previously uncharacterized ASD patient iPSC lines, we show that ASD-NRXN1 deletions impact cortical synaptic function and plasticity in unique ways compared to SCZ-NRXN1 deletions. Specifically, at a single neuronal level, ASD-NRXN1 deletions alter basal spontaneous synaptic transmission by selectively enhancing excitatory synaptic signaling with no changes at inhibitory synapses while SCZ-NRXN1 deletions reduce both excitatory and inhibitory synaptic transmission. At the neuronal network level, there exists enhanced transmission probability and irregular firing patterns in ASD-NRXN1 deletions. Such changes at the synaptic and network level connectivity patterns influence a critical form of developmental cortical plasticity, synaptic scaling, as ASD-NRXN1 deletions uniquely fail to upscale their synaptic strength in response to chronic neuronal silencing. Together, these findings highlight the disorder-specific consequences of NRXN1 deletions on synaptic function and connectivity, offering mechanistic insights with implications for therapeutic targeting and refinement strategies for NRXN1-associated synaptopathies. | | 6:48a |
MEG3 Enhances Survival of Developing Human Neurons with CLCN4-Linked Autophagy Impairment
Genetic variations in CLCN4, encoding the H+/Cl- exchanger CLC-4, are associated with human neurodevelopmental disorders with highly variable phenotypes. A lack of physiologically relevant models has hampered molecular understanding of pathogenic mechanisms. We now establish engineered brain organoid and neuronal cell systems to examine impacts of patient-relevant CLCN4 genetic variations. We find that CLCN4 variants reduced excitatory neuron numbers due to early-stage cell death, accompanied by altered endo-lysosomal dynamics and disrupted autophagic flux. Transcriptomic profiling showed significant downregulation of long non-coding RNA MEG3 in CLCN4-variant neurons. Restoring MEG3 expression is sufficient to rescue cellular defects and improve survival of CLCN4-variant neurons. These findings link CLCN4 dysfunction with impaired autophagy and neuronal cell death, highlighting MEG3 as a potential therapeutic target for neurodevelopmental disorders involving autophagic dysfunction. | | 6:48a |
A novel cost-benefit decision-making task involving cued punishment; effects of sex and psychostimulant administration
Chronic substance use is associated with alterations in multiple forms of cost-benefit decision making, which may prolong and exacerbate continued use. Cues that predict reward can cause substantial shifts in a variety of reward-directed behavior, including decision making. In contrast, how decision making is modulated by cues predictive of punishment is much less well understood. To begin to address these issues, male and female Long-Evans rats were tested in a novel decision-making task in which they chose between a small, safe reward and a large reward that was punished by a mild footshock when it was preceded by a probabilistically delivered cue prior to the choice. Rats of both sexes were sensitive to the cue, preferring the large reward in the absence of the cue but the small reward in the presence of the cue. Acute systemic amphetamine reduced choice of the large reward and diminished the efficacy of the cue in guiding choice behavior. Chronic cocaine led to divergent patterns of cue insensitivity in males and females; males increased choice of the large reward on cued trials, whereas females increased avoidance of the large reward on uncued trials. Similar to acute amphetamine, acute systemic administration of the D2/3 dopamine receptor agonist bromocriptine reduced preference for the large reward across all groups. These findings highlight the contributions of punishment cues to decision making, as well as the importance of sex as a biological variable in investigating cognitive alterations caused by chronic substance use. | | 7:15a |
Phosphorylation and DNA Damage Resolution Coordinate SOX2-Mediated Reprogramming in vivo
The stem cell factor SOX2 can reprogram resident glial cells into neurons in the adult mammalian central nervous system (CNS), but the molecular mechanisms underlying this process remain poorly understood. Here, we show that both SOX2 phosphorylation and the PRKDC-dependent non-homologous end joining (NHEJ) pathway are essential for SOX2-mediated in vivo glia-to-neuron reprogramming. A phospho-mimetic SOX2 mutant significantly enhances reprogramming efficiency without altering neuronal fate. Conversely, loss of PRKDC or knockdown of core NHEJ components KU80 and LIG4 abolishes reprogramming. Notably, p53 knockdown restores reprogramming in PRKDC-deficient mice. These findings demonstrate that SOX2-driven glial reprogramming requires both precise posttranslational regulation and effective DNA damage repair, and suggest that targeting these pathways could enhance regenerative strategies in the CNS. | | 7:15a |
Simulated Language Acquisition in a Biologically Realistic Model of the Brain
Despite tremendous progress in neuroscience, we do not have a compelling narrative for the precise way whereby the spiking of neurons in our brain results in high-level cognitive phenomena such as planning and language. We introduce a simple mathematical formulation of six basic and broadly accepted principles of neuroscience: excitatory neurons, brain areas, random synapses, Hebbian plasticity, local inhibition, and inter-area inhibition. We implement a simulated neuromorphic system based on this formalism, which is capable of basic language acquisition: Starting from a tabula rasa, the system learns, in any language, the semantics of words, their syntactic role (verb versus noun), and the word order of the language, including the ability to generate novel sentences, through the exposure to a modest number of grounded sentences in the same language. We discuss several possible extensions and implications of this result. | | 8:36p |
Selective life-long suppression of an odor processing channel in response to critical period experience
Sensory circuits undergo experience-dependent plasticity during early-life critical periods, attuning the nervous system to levels of key environmental stimuli. During a critical period in the Drosophila olfactory system, we found that exposure to ethyl butyrate (EB) induces glial phagocytosis of odorant receptor Or42a-positive olfactory sensory neuron (OSN) axon terminals which terminate in the VM7 glomerulus (Leier and Foden et al., 2025). Here, we extend these findings by establishing functional significance and circuit selectivity in this critical period paradigm. First, using a combination of two-photon Ca2+ imaging and the genetically-encoded voltage indicator ASAP5, we find that Or42a OSN odor-evoked responses are permanently suppressed in animals with critical period odor exposure. Thus, critical period odor exposure results in long-term changes to odor sensitivity in Or42a OSNs. Second, to establish the selectivity of glial pruning for Or42a axon terminals, we examined projection neurons (PNs) postsynaptic to Or42a OSNs as well as a second population of highly EB-responsive OSNs, called Or43b OSNs. We find that (1) within VM7, glial pruning is selective for Or42a terminals, and (2) while Or43b OSNs appear modestly pruned, they maintain their sensitivity to EB. To elucidate this difference, we turned to the Drosophila connectome. We identify striking differences in the scale of inhibitory connectivity to Or42a and Or43b OSNs, suggesting that Or42a OSNs may play a particularly central role in EB odor processing. This study expands our understanding of this critical period plasticity paradigm by demonstrating life-long suppression of pruned Or42a OSNs and establishing its specificity within and between sensory circuits. | | 8:36p |
A C. elegans model of familial Alzheimer's disease shows age-dependent synaptic degeneration independent of amyloid β-peptide
The membrane-embedded {gamma}-secretase complex is involved in the intramembrane cleavage of ~ 150 substrates. Cleavage of amyloid precursor protein (APP)-derived substrate C99 generates 38-43-residue secreted amyloid {beta}-peptides (A{beta}), with the aggregation-prone 42-residue form (A{beta}42) particularly implicated in the pathogenesis of Alzheimer's Disease (AD). However, whether A{beta}42 is the primary driver of neurodegeneration in AD remains unclear. Dominant mutations in APP or presenilin--the catalytic component of {gamma}-secretase--cause early-onset familial AD (FAD) and reduce one or more steps in the multi-step processive proteolysis of C99 to A{beta} peptides, apparently through stabilization of {gamma}-secretase enzyme-substrate (E-S) complexes. To investigate mechanisms of neurodegeneration in FAD, we developed new C. elegans models co-expressing wild-type or FAD-mutant C99 substrate and presenilin-1 (PSEN1) variants in neurons, allowing intramembrane processing of C99 to A{beta} in vivo. We demonstrate that while FAD-mutation of either C99 or PSEN1 leads to age-dependent synaptic loss, proteolytically inactive PSEN1 did not. Designed mutations that allow stable E-S complex formation without A{beta}42 or A{beta} production likewise result in synaptic degeneration. Moreover, replacement of C99 with variants of a Notch1-based substrate revealed that disrupted processing of another {gamma}-secretase substrate can similarly lead to synaptic degeneration. These results support a model in which synaptic loss can be triggered by toxic, stalled {gamma}-secretase E-S complexes in the absence of A{beta} production and not by simple loss of proteolytic function. This new C. elegans system provides a powerful platform to study the role of dysfunctional {gamma}-secretase substrate processing in FAD pathogenesis. | | 8:36p |
Inhibition of the Microglial Phagocytic Receptor MerTK Underlies ELA-induced Changes in Synapses and Behavior in Male Mice
Background: Early-life adversity (ELA) is a significant risk factor for emotional disorders like depression, likely by provoking changes in stress-related circuit development. We have previously shown that ELA increases the number of excitatory synapses onto corticotropin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus (PVN) by decreasing microglial synapse engulfment. Here, we hypothesize that ELA induces microglial dysfunction via inhibition of the microglial phagocytic receptor, MerTK, thus resulting in the observed changes in synapses and stress-related behavior. Methods: To determine whether deleting MerTK in microglia phenocopies the effects of ELA, microglia-specific (m)MerTK-KO (CX3CR1-Cre+::MerTKfl/fl) mice were crossed with "wild-type" (CX3CR1-Cre-::MerTKfl/fl) mice and their litters were reared in either a control or ELA (induced by limited bedding and nesting paradigm) environment, from postnatal days (P)2-10. Excitatory synapses in the PVN were assessed at P10, and adult offspring were tested in a behavioral battery to measure threat-response (known to be dependent on PVN-CRH+neurons) and anxiety-like behavior, followed by acute restraint stress to measure the neuroendocrine stress response. Results: Following ELA at P10, excitatory, but not inhibitory, synapses in the PVN were increased in males, which was mimicked by mMerTK-KO in control males, but caused no further increase in ELA males. However, females already had higher numbers of excitatory synapses at baseline, and showed no further increase with ELA or mMerTK-KO. Remarkably, the pattern of threat-response behavior in males closely matched the excitatory synapses, with mMerTK-KO control males escaping more from the simulated predator threat in the looming-shadow threat task, similar to ELA males. Again, females did not show any significant changes due to ELA or mMerTK-KO in the threat-response, although they did show ELA-induced changes in anxiety-like behavior. ELA provoked a greater corticosterone response to acute stress in males, but not females, although females were again higher at baseline. Conclusions: Our results demonstrate that ELA provokes increased excitatory synapses in the PVN, leading to an increased active response to threat in the looming-shadow test in males only. Deleting MerTK specifically from microglia recapitulates both the synaptic and behavioral effects in control males, but does not have an effect in ELA males or control females, suggesting that the MerTK pathway is already inhibited by ELA in males and less active in females at baseline. Our work is the first to elucidate the mechanisms underlying the male-biased microglial dysfunction caused by ELA, with promise for the development of better preventative and therapeutic strategies for at-risk children. | | 8:36p |
Concerted remodelling of the postsynaptic spine and RNA granule by cLTP
Synaptic plasticity is the cellular foundation of learning and memory and, for these plastic changes to be stabilised into long-term memory, proteins must be synthesised at the synapse1,2. RNA granules ensure that specific mRNAs are delivered and translated at the right time and place3,4, but the signalling mechanisms linking synaptic activation to local translation are still largely unknown. Here, to investigate how postsynaptic signals modulate the RNA granule, we employed a spatially-restricted biotinylation approach to quantify protein accessibility and proximity in the postsynaptic and RNA granule subproteomes. Upon chemical long-term potentiation (cLTP), we observed a sharp increase in the accessibility of ribosomes, translation factors and RNA binding proteins belonging to the RNA granule. Similarly, strong alterations were observed in proteins of the postsynaptic density, but mostly in those involved in signalling. Specific proximity to DBN1 and IGF2BP1 as postsynaptic and RNA granule reporters unveiled a shift of the translation machinery towards the postsynaptic compartment, whereas specific translation initiation factors and RNA helicases displayed marked changes in their proximity to DBN1 and/or IGF2BP1. Finally, alteration of synapse development and signalling by DBN1 downregulation caused a highly significant decrease in the proximity of RNA granule proteins to IGF2BP1 after synaptic stimulation, establishing a causal link between postsynaptic events and RNA granule dynamics. | | 8:36p |
Synaptic and intrinsic membrane defects disrupt early neural network dynamics in Down syndrome
Down syndrome, caused by trisomy 21, affects around six million people worldwide and features learning, memory and language deficits. However, the mechanisms underlying trisomy 21 neurophenotypes involving human cortical circuitry are unknown. By characterising developing neural network dynamics and single cell excitability profiles, with synaptic and voltage-dependent ion channel behaviour, using an isogenic induced pluripotent stem cell-derived neuronal model, we show that trisomy 21 impairs the activity and development of cortical circuitry. This is caused by deficient glutamatergic synaptic connectivity and by aberrant intrinsic membrane properties involving K+ and Na+ channels culminating in spike firing defects that weaken neural network activity and disrupt the synchrony of developing neurons. We also identify transiently activated A-type K+ channels, specifically Kv4.3 channels, as a key orchestrator for Down syndrome during neurodevelopment. Overall, these excitability changes will significantly contribute towards the aberrant neurophenotypes observed later on in life. |
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