bioRxiv Subject Collection: Neuroscience's Journal

REDUCED ALPHA-BAND PHASE COHERENCE AND CORTICAL COMPLEXITY IN FIBROMYALGIA: A TMS-EEG EXPLORATORY STUDY
Objectives: Cortico-spinal excitability of the primary motor cortex (M1) is reduced in fibromyalgia, and repetitive transcranial magnetic stimulation (TMS) targeting M1 normalizes these changes and relieves symptoms. TMS combined with electroencephalography (TMS-EEG) allows the measurement of M1 excitability and its connectivity to other regions, which may help clarify neurophysiological effects in fibromyalgia. We assessed cortical excitability, oscillatory activity, and complexity in individuals with fibromyalgia compared to pain-free healthy controls. Methods: Global and local mean field power, peak-to-peak amplitude, event-related spectral perturbation, intertrial coherence (ITC), natural frequency, and perturbational complexity index (PCIst) of the EEG response after left-M1 TMS were compared between groups (n=18 fibromyalgia; n=15 controls). Pain intensity, interference, relief of current therapy, mood, and quality of life were assessed in individuals with fibromyalgia. Results: Compared with controls, individuals with fibromyalgia showed a reduction in the alpha-band ITC in middle and right parieto-occipital areas (P<0.05). Middle-parieto-occipital ITC negatively correlated with reported pain relief (rho=-0.552, p=0.019). The PCIst was lower in fibromyalgia compared with controls (P<0.01) and correlated with higher pain interference in general activity (rho=-0.486, p=0.042). Conclusion: Individuals with fibromyalgia showed abnormal cortical connectivity compared with asymptomatic controls. Significance: TMS-EEG measurements may provide insights on brain connectivity relevant for therapy.

A Syntaxin1A protein mutation drives sleep reduction in Drosophila
Syntaxin1A is a key component in the regulation of the vesicle fusion nanomachine and, together with VAMP/synaptobrevin and SNAP-25, forms the core of the SNARE complex, that is the molecular nanomachine regulating neurotransmitter release. Syntaxin1A is localized on the cytosolic face of the presynaptic membrane and with Munc-18-1 is thought to be the starting point for the SNARE complex assembly. In flies, aspartic-to-arginine amino acid substitution at position 253 of the protein sequence reduces synaptic release by affecting the assembly of multiple SNARE complexes into a super-complex without interfering with the single complex formation per se. In this study, we analyzed sleep behavior in flies expressing this mutated isoform of Syntaxin1A pan-neuronally. According to the synaptic homeostasis hypothesis, the overall decrease of synaptic activity during the previous period of wakefulness should reduce the need for sleep. We observed a reduction in the total amount of sleep in flies expressing the mutated isoform compared to controls. Moreover, the sleep pattern of the Syntaxina1A mutant flies was more fragmented compared to controls. Video-tracking analysis of free walking flies in an open-field arena showed that these changes were not caused by higher locomotor activity during the daytime relative to controls. Our results suggest that the widespread effect of Syntaxin1A mutation on synapses may lead to a dampening of the information load among neurons and, consequently, impact the regulation of sleep at the cellular level.

Anesthesia Induces Shifts in Spatial Frequency Preference in the Primary Visual Cortex
General anesthesia markedly reduces overall brain responsiveness to external stimuli. Animal studies reveal that in individual neurons of the primary visual cortex (V1), anesthesia modulates the gain of neural responses while leaving orientation and direction tuning unaltered. However, the impact of anesthesia on spatial frequency (SF) tuning is largely unexplored despite it being a fundamental characteristic of visual perception. Furthermore, compared to excitatory neurons, the effects of anesthesia on the visual responsiveness of specific inhibitory neuron subtypes are poorly understood. Here, we directly compared visual responses from the same V1 neurons in mice under both anesthetized and awake states. We found that isoflurane anesthesia significantly shifts the preferred SFs of excitatory neurons to lower values. This downward shift was even more pronounced in inhibitory neurons. These downshifts selectively impaired the neural coding of high-SF information while leaving low-SF coding unaffected. We observed distinct patterns of anesthesia-induced downward shifts of preferred SFs between two major cortical inhibitory neuron subtypes: somatostatin-expressing (SOM) and parvalbumin-expressing (PV) neurons. Furthermore, anesthesia-induced changes in response gain and tuning sharpness were evident in SOM neurons but not in PV neurons. These results highlight the diverse effects of anesthesia on sensory responses, varying significantly based on both the visual feature processed and the specific neuron subtype involved. The consistent decrease in preferred SFs during anesthesia not only suggests a potential mechanism for anesthesia-induced alterations in sensory experience but also emphasizes the critical role of heightened SF preference during wakefulness for fine object perception.

Mena-dependent local translation of PI3K-p85 coordinates the axonal regenerative program upon injury
Local translation (LT) is one of the first processes activated after nerve injury and is critically coupled with the intrinsic ability of axons to grow and regenerate. However, regulation of LT in adult axons remains highly unexplored. Here we identify the actin regulator Mena, as a key mediator of adult axon regeneration, via its control of local protein synthesis. We show that Mena directly associates with PI3K-p85 mRNA and regulates its LT in injured sciatic nerve axons, thereby activating the downstream AKT/mTOR pathway. Genetic ablation of Mena disrupts this intrinsic response, resulting in impaired axonal LT and diminished axon regeneration in vivo. Our findings identify a Mena-dependent mechanism that remodels the local axonal proteome and reveal a critical link between mRNA regulation and metabolic signaling during axon regeneration.

Evolutionarily Conserved and Divergent Mechanisms of Dual Ca2+ Sensors in Synaptic Vesicle Exocytosis
Neurotransmitter release at the C. elegans neuromuscular junction is governed by a dual Ca2+ sensor system composed of SNT-1 and SNT-3, which are functional analogs of synaptotagmin-1 and -7 (Syt1/Syt7) in mammalian central synapses. In this study, we investigated how SNT-1 and SNT-3 mediate fast and slow neurotransmitter release through their potential interactions with the SNARE complex and their polybasic motifs. AlphaFold 3 models of SNT-1--SNARE and SNT-3--SNARE complexes accurately recapitulated the canonical Syt1 C2B--SNARE primary interface (Zhou et al., 2015, Nature) and precisely identified conserved binding residues within the C2B domains, as well as in SNAP-25 and Syntaxin, highlighting the evolutionary conservation of this interaction. Electrophysiological analyses using targeted mutagenesis demonstrated that both SNT-1 and SNT-3 require C2B--SNARE interactions and polybasic motifs within their C2 domains to drive evoked fast and slow neurotransmitter release. Notably, SNT-1 and SNT-3 exhibited differential dependence on distinct regions of the C2B--SNARE interface and their respective polybasic motifs, suggesting that Ca2+-triggered fast and slow release operate via distinct mechanistic strategies. Furthermore, we found that SNT-1 mediates spontaneous neurotransmitter release through multiple pathways, involving not only the primary C2B--SNARE interface but also additional putative SNARE-binding interactions. Together, our findings uncover both conserved and divergent mechanisms for synaptic exocytosis regulated by the dual Ca2+ sensors in C. elegans.

Persistent chromatin loops shape gene expression plasticity upon stimulation and restimulation of human neurons
Persistent molecular correlates of long-term memory storage remain an open question. Here, we stimulate and re-stimulate human neurons and use multi-modal single-nucleus technologies to query DNA methylation, higher-order chromatin folding, and gene expression. We find enduring traces of activity-gained and activity-lost chromatin loops. Genes anchoring persistent activity-gained loops exhibit activity-upregulated expression, whereas persistent activity-lost loops anchor activity-downregulated genes that remain repressed five days post-stimulation. CTCF-bound looped enhancers and promoters are refractory to activity-dynamic DNA methylation. Looped enhancers bound by CTCF can exhibit memory of activity-induced histone modifications and persistent expression of activity-upregulated genes. Upon second stimulation, activity-upregulated genes are robustly re-induced when unlooped but remain nonresponsive at persistent loops akin to habituation. Activity-independent gene expression can be downregulated when unlooped but protected from homeostatic downscaling when anchored in persistent loops. Our data reveal long-term genome folding persistence linked to plasticity of activity-dependent gene expression during recall in human neurons.

Theta and gamma transcranial alternating current stimulation modulate Mandarin consonant and lexical tone perception
A theta/gamma oscillatory neural mechanism has been postulated to explain the auditory sampling of hierarchical syllable-phoneme structure with corresponding speech rates or linguistic hierarchies (theta for syllable and gamma for phoneme). Yet, whether such a mechanism is generalizable to Mandarin Chinese, a language that both has suprasegmental phonemes in the form of lexical tones and contains more monosyllabic words, which may lead to higher reliance on either phonemic-level or syllabic-level perceptual representations, is unclear. In this study, we applied transcranial electric stimulation with either theta or gamma alternating currents (tACS) to bilateral auditory cortices in healthy Mandarin-speaking participants during a consonant or tone identification task in quiet or noisy environments. Results showed that theta tACS impaired consonant identification in quiet, specifically, and generally prolonged reaction times across tasks and environments. Gamma tACS, however, only delayed tone identification in quiet. Besides, both theta and gamma tACS modulated perceptual decision-making parameters, leading to increased boundary thresholds (cautiousness of decision) and altered response biases in the perceptual decision of both consonants and tones, as evidenced by the hierarchical drift-diffusion model (HDDM). These findings indicate that theta oscillations causally support the perception of Mandarin syllables, with consonants and lexical tones presumably embedded in syllable-level representations, regardless of task difficulty. Gamma activity, however, is presumably engaged in supporting fast-changing and fine-grained acoustic features in a modulatory manner.

Diagnosis-Optimized Dynamic Feature Learning Reveals Altered Default Mode Network Connectivity in Schizophrenia
Schizophrenia (SZ) is characterized by widespread neural dysconnectivity, with particularly pronounced alterations in the default mode network (DMN)- a set of brain regions involved in self-referential thought and mind-wandering. We investigated dynamic functional connectivity within the DMN in SZ by analyzing resting-state fMRI data from two independent cohorts (FBIRN and COBRE). Using a novel iterative feature-removal clustering approach focusing on DMN independent components, we identified distinct recurring connectivity states while iteratively removing dominant connectivity features to reveal subtler network patterns. This approach iteratively refines the set of features considered, ensuring a more balanced representation and facilitating the identification of significant interactions that would otherwise be overlooked. Cluster centroids for the four connectivity states were highly similar across both datasets, reflecting stable shared DMN patterns. State occupancy was compared between participants with SZ and healthy controls, and associations with clinical symptom severity were examined. The SZ group exhibited significant alterations in DMN connectivity dynamics, spending more time than controls in certain connectivity states characterized by atypical DMN coupling and less time in a state reflecting a normative DMN configuration. A comparison between the FBIRN and COBRE datasets reveals both similarities and differences in occupancy rate (OCR) states. Overall, the pattern of group effects converged while state-specific divergences likely reflected protocol/sample differences rather than conflicting biology. Crucially, the explainability pipeline yielded a highly similar feature-removal order across datasets, indicating that the same DMN edges drive the diagnostic signal in both cohorts. Several OCR effects also tracked symptom ratings, linking abnormal DMN dynamics to clinical expression. Our findings suggest that SZ is characterized by reproducible disturbances in the temporal organization of DMN connectivity. These dynamic DMN features may serve as potential biomarkers for SZ, offering diagnostic and clinical utility by capturing network dysfunction that static connectivity measures could overlook.

Cholinergic-dependent dopamine signals in mouse dorsal striatum are regulated by frontal but not sensory cortices
Everyday decisions depend on linking sensory stimuli with actions and outcomes. The striatum supports these sensorimotor associations through dopamine-dependent plasticity. Thus, the timing and magnitude of dopamine release is critical for learning. Recent work has characterized a local striatal microcircuit in which cholinergic interneurons (CINs) modulate dopamine release via acetylcholine activation of nicotinic receptors on dopamine axons. Here, we show that visual stimuli evoke dopamine responses in the dorsomedial striatum through this cholinergic-dependent mechanism. Using anatomical and functional methods to identify which pathways elicit these signals, we found that primary visual cortex and early sensory areas that project to the striatum exhibited only weak connectivity to CINs, despite robust connectivity to projection neurons, and were unable to drive dopamine release. In contrast, frontal cortical regions, including the prelimbic and anterior cingulate cortices, strongly recruited CINs and acetylcholine, producing robust dopamine release both ex vivo and in vivo. These findings reveal a fundamental distinction between sensory and frontal cortical inputs to the striatum, demonstrating that only the latter provide effective access to cholinergic-dependent dopamine signaling. This work establishes a framework for understanding how cortical circuits shape striatal dopamine to support reinforcement learning.

Synaptic and potential fluctuations drive representational drift with differential effects on discrimination learning
Large-scale neuronal measurements have revealed continual drift of neural representations without explicit learning, raising fundamental questions about how the brain maintains reliable perception. While representational drift has been studied both experimentally and theoretically, the underlying mechanisms and computational consequences remain unclear. Here, we systematically compare two drift mechanisms -fluctuations in synaptic weights versus membrane potential -using an analytically tractable neural network model with aligned drift magnitude and timescale. We found that both mechanisms preserve representational structure across time regardless of the drift magnitude. However, only synaptic fluctuations maintain discriminability between representations under large drift magnitude. We use a selectivity space to explain how these similar and differential effects on representational drift emerge from the dynamics of individual neuronal tuning. We further examine functional consequences of drift using reversal learning tasks where stimulus-reward associations switch. Both mechanisms enhance single stimulus learning by gradually removing the old associations, but only synaptic fluctuations substantially improved learning of multiple stimuli by preserving the representational structure during drift. Our results reveal distinct computations performed by specific fluctuation mechanisms and explain how representational drift can support both stable and adaptive behavior.

Modulation of hippocampal synaptic transmission by mast cells at the hippocampal-thalamic border during early brain development
Synaptic development is a highly structured process and can be modulated by the biogenic amine, histamine, whose dysregulation during brain development can be part of the aetiology of the neurodevelopmental disorders Tourettes syndrome and OCD. Well documented in the literature is the extensive histaminergic axonal innervation originating from neurons in tuberomammillary nucleus of the hypothalamus, however, less is known about non-neuronal sources of histamine, such as mast cells, and their potential functional importance in development. Here we set out to investigate the spatiotemporal localisation of mast cells in the developing C57Bl/6 mouse brain and the potential impact of their degranulation on developing synapses. Firstly, we find that the mouse brain contains relatively larger numbers of mast cells during the first and second postnatal week. Secondly, that in this period the highest density of mast cells is found just below the hippocampus at the hippocampal-thalamic border with lower numbers found in other brain regions. Thirdly, using the mast cell degranulator C48/80 we observe that their degranulation can facilitate synaptic transmission at the perforant pathway inputs to the ventral portion of the dentate gyrus which could not be blocked by co-application of the histamine H3 receptor antagonist thioperamide. In contrast histamine superfusion tended to decrease synaptic transmission at this pathway which was sensitive to thioperamide co-application. In conclusion, these results suggest that mast cells are present in the developing C57Bl/6 mouse brain and in particular at the hippocampal-thalamic border where upon degranulation they appear to modulate hippocampal synaptic transmission.

Schizophrenia, variability, and the Anna Karenina principle
In neuroimaging studies of people with schizophrenia there is often higher within group variancein the patient group compared to the control group. This is counterintuitive - why would asubset of people selected because they all have the same disease be more varied than the generalpopulation? We used simulated data and real neuroimaging data to identify a potential cause ofelevated variance in populations of patients with schizophrenia. We demonstrated that elevatedvariance can arise within variables that are unrelated to disease status simply because peoplewith a set of neurological perturbations that cause schizophrenia are more likely to have highernumbers of perturbations overall. Additionally, we showed that observed elevated variances inpeople with schizophrenia can be reproduced by models that only rely on perturbation count.These results highlight an important barrier in our attempts to understand the pathophysiology ofschizophrenia. Standard statistical practices in schizophrenia research do not account for the factthat schizophrenia is, at every level of analysis that has been studied, highly heterogeneous. Thisheterogeneity by itself is sufficient to produce elevated variances. Our work suggests that themost effective way to prevent schizophrenia may not be to identify and mitigate specificpathologies but rather to reduce the impact of broadly damaging factors such as those associatedwith poverty.

Gestational psychedelic exposure disrupts brain development and offspring behavior in mice
Despite increasing non-medical use and clinical investigation of psychedelics, the consequences of prenatal exposure remain unknown. In mice, maternal lysergic acid diethylamide (LSD; 0.3 mg/kg) crossed the placenta, appearing in embryonic cerebrospinal fluid (CSF) within minutes at E12.5 and E16.5. Within 30 minutes, LSD and other serotonergic psychedelics activated the embryonic choroid plexus via 5-HT2C, triggered apical remodeling, and increased CSF protein. A single E12.5 exposure altered cerebral cortical laminar organization and composition at postnatal day 8, and repeated dosing (E12.5 - E16.5) amplified male-biased shifts from SATB2+ to CTIP2+ neuronal identities and increased microglia. Adult offspring showed reduced prepulse inhibition (male-predominant) and rotational stereotypy. These data identify an embryo-facing interface that detects maternal psychedelics and link CSF access to enduring neurodevelopmental and behavioral consequences.

Brain injury reactivates a developmental program driving genesis and integration of transient LGE-class interneurons
Brain lesions can unlock a latent neurogenic potential in parenchymal astrocytes. However, the identity of their neuronal progeny has remained unclear. Here, we show that neurons generated by striatal astrocytes following excitotoxic lesions are transient, yet they reach advanced stages of morphological and functional maturation and integrate into cortico-striatal-thalamic circuits. Single-cell RNA-seq mapping onto an embryonic reference revealed that these cells are not related to adult striatal neuron types but instead belong to the LGE-MEIS2/PAX6 interneuron class. Notch abrogation, which mimics neurogenic activation, drives both cortical and striatal astrocytes toward this same interneuron class, revealing a shared intrinsic commitment. In primates, LGE-MEIS2/PAX6 cells transiently populate the embryonic striatum and cortex, and through spatial transcriptomics, we reveal that in mice these cells are also present and widely distributed throughout the telencephalon during embryonic and postnatal development. Thus, unlike other vertebrates in which adult telencephalic astroglia preserve the potential to generate constitutive region-specific neurons, the homologous cells in mammals converge on the generation of a specific transient neuron class, possibly representing a reservoir for circuit plasticity in adult life.

Dynamic Meta-Networking Identifies Distinct Network Correlates of Positive and Negative Formal Thought Disorder in Schizophrenia
Formal thought disorder (FTD) is a core symptom of schizophrenia, yet the neural network mechanisms underlying this phenotype remain poorly understood. In this study, we applied a dynamic meta-networking framework, which captures temporally recurring functional network states, to investigate alterations in the language and executive control networks and their associations with positive and negative FTD. Resting-state fMRI data were collected from three independent cohorts: a discovery cohort comprising 150 first-episode, drug-naive patients with schizophrenia and 175 healthy controls (HCs); a replication cohort including 183 first-episode, drug-naive patients and 109 HCs; and a third cohort consisting of 71 patients who had received two weeks of antipsychotic treatment and 71 HCs. Meta-networking analysis identified four distinct resting-state meta-states within both the language and executive control networks. Connectivity-behavior correlation analyses and machine-learning regression models revealed that positive FTD was associated with aberrant connectivity across specific meta-states in both networks. In contrast, negative FTD was linked exclusively to dysfunction within two meta-states of the executive control network. Notably, these polarity-specific, multi-state connectivity disruptions normalized following short-term antipsychotic treatment, highlighting their potential as clinically relevant neuroimaging biomarkers.

Translating Music to Touch: Exploring Tactile Perception of Pitch, Roughness, and Pleasantness
Music is a rich multisensory experience, yet individuals with hearing impairments often lack access to this important aspect of culture. As tactile technologies advance, there is growing interest in whether musical information can be conveyed through vibration. This study investigates how core dimensions of auditory music perception, pitch, roughness, and pleasantness, can be translated into the tactile domain. Participants were asked to rate these perceptual dimensions in response to sinusoidal and complex waveforms, including amplitude-modulated signals, sawtooth, and missing fundamental stimuli. Perceived pitch showed a systematic relationship with stimulus frequency for most participants, suggesting that tactile devices could effectively convey melodic patterns. The sawtooth waveform emerged as particularly effective for representing pitch changes, underscoring the role of rapid temporal transitions in tactile pitch encoding. Roughness ratings were negatively correlated with pleasantness, mirroring well-established findings in auditory perception. Waveforms with sudden temporal changes or rapid amplitude modulations were consistently judged as less pleasant. Taken together, these findings indicate that tactile systems can effectively convey melodic structure and emotional tone, laying the groundwork for musical touch interfaces. Importantly, our results highlight the crucial role of the fast temporal envelope rather than the temporal fine structure, in shaping vibrotactile perception. Consistent with this interpretation, our data provide evidence for a tactile analog of the auditory missing fundamental phenomenon, reinforcing the idea that tactile pitch perception primarily relies on envelope periodicity rather than the presence of specific frequency components.

Concept Learning Builds Behaviourally Relevant Attentional Templates
Attention optimizes learning by filtering relevant information to build conceptual knowledge. However, how learned concepts, once encoded in memory, subsequently guide attentional processes remains an intriguing question. We propose that concept learning leads to the emergence of attentional templates that store goal-relevant representations, thereby actively guiding attention allocation. Participants completed two separate learning tasks and a test, wherein each trial began with a cue, indicating which learning task should be employed. Random test trials included a probe instead of concept specific features: a small arrow appeared at a feature location that was relevant (i.e., valid) or irrelevant (i.e., invalid) for the cued task. Successful learners were faster at responding to valid probes than invalid, demonstrating the deployment of concept-specific attentional templates. Importantly, the efficiency of this attention allocation was tied to concept learning success, with higher learning performance yielding greater response time benefits at test. Thus, our results reveal that learning builds behaviourally relevant attentional templates, and subsequently, learned concepts in memory guide attention by deploying these templates, a phenomenon that we introduce as learning-guided attention. This work provides novel insights into the dynamic interplay between learning, memory, and attention.

Injured SSTR2+ nociceptor axons in neuromas drive chronic spontaneous neuropathic pain
Spontaneous pain is a very common but poorly understood consequence of peripheral nerve injury. We developed a system for measuring spontaneous pain-related behaviors in mice over months, which revealed that limb flicks--emerging predominantly 2 months post-injury--reflect spontaneous pain, and that neuromas are the drivers of this component of neuropathic pain. In vivo dorsal root ganglion imaging showed that small-diameter sensory neurons are the source of spontaneous ectopic neuroma activity and are different from the intact neurons that drive stimulus-evoked pain. Cell-specific optogenetic stimulation studies identified that injured SSTR2+ sensory axons in neuromas are the triggers of spontaneous limb flicks/neuropathic pain. These findings reveal the mechanisms of spontaneous neuropathic pain and open new therapeutic opportunities.

Machine learning behavioral analysis reveals cervical instability as an early biomarker of Amyotrophic Lateral Sclerosis
Early detection of neuromuscular disorders is a major clinical challenge, with most diagnoses only occurring after considerable motor neuron degeneration has already taken place. The central problem for early diagnosis of neuromuscular diseases is the subtlety of early symptoms and where to look for them. Without defined behavioral markers, the earliest stages of disease go undetected, delaying intervention and limiting neuroprotective therapeutic evaluation. Here, we present a machine learning (ML) based framework that identifies subtle postural alterations in freely behaving animals. Using longitudinal pose data from SOD1G93A mice, a widely used Amyotrophic Lateral Sclerosis (ALS) mouse model, we focused on postural states in idle periods, behavioral states usually overlooked in disease monitoring. Our analyses revealed consistent deviations in posture and a feature analysis pinpointed cervical instability during adolescence as a key distinguishing feature. We validated these findings through two independent behavioral assays engaging cervical musculature: rearing and wet-dog shakes, both of which showed significant impairments in male SOD1G93A mice as early as 3 weeks of age, many weeks earlier than conventional muscle function assays. This approach establishes an unbiased, non-invasive, scalable strategy for detecting early-stage neuromuscular dysfunction, and provides a foundation both for clinical behavioral biomarker development in ALS and related disorders and will enable evaluation of early neuroprotective interventions.

A gut-brain axis for aversive interoception drives innate and anticipatory emesis in Drosophila.
Signals from the gut are increasingly recognized as modulators of brain function and behavior. However, the pathways through which the gut conveys adverse or unpleasant information to the brain are still not well understood. In this study, we identify an aversive gut-brain axis in Drosophila melanogaster that detects toxin-induced gut damage and triggers both innate and learned anticipatory emesis (vomiting). After toxin ingestion, reactive oxygen species are produced by midgut enterocytes and detected by the transient receptor potential channel TrpA1 on nearby enteroendocrine cells. This sensing stimulates the release of neuropeptides from enteroendocrine cells, likely representing the gastric malaise flies experience after eating. We show that these neuropeptides act on specific serotonergic and dopaminergic neurons in the brain. These neurons interact with each other and signal to the downstream memory-related mushroom bodies to promote emesis. This circuit not only drives an immediate emetic response but also represents a malaise-driven aversive signal. The signal manifests as the persistent activity of dopaminergic neurons, which reinforces aversive valence to odor cues in the mushroom bodies. Thus, the flies learn that a specific odor predicts the presence of a toxin in food and exhibit anticipatory emesis upon re-exposure to the same odor. Taken together, we have identified an interoceptive signaling pathway that may be conserved for detecting harmful gut conditions and for remembering how to avoid them. Our work offers a mechanistic framework for studying aversive gut-brain communication involved in feeding, metabolism, depression, brain injury, and neurodegenerative diseases.

Functional Reorganization of the Somatomotor Network in Prodromal and Early Parkinson's Disease
In Parkinson's disease (PD), higher network attack tolerance (NAT) may contribute to compensation of motor deficits. However, it is unclear whether NAT is lost due to disease progression or actively increased as a compensatory response. We used cross-sectional resting state functional MRI data of 28 healthy controls (HC), 60 prodromal PD patients, 94 clinical PD patients to create graph theoretical networks. NAT was assessed at global and subnetwork level by calculating global efficiency upon iterative node removal. Using linear mixed-effects models we assessed how putaminal dopamine terminal (DaT) binding, or disease status affected NAT, controlling for density, age, sex and education. Finally, we compared the node degree distribution specifically for the somatomotor network (SMN) across groups. Lower putaminal DaT predicted higher SMN NAT. Patients with PD showed elevated SMN NAT versus controls. Neither global nor other networks showed an effect. Compared to HCs subcortical/cerebellar SMN nodes appeared more connected in PD and prodromal patients. Dopaminergic depletion appears to drive targeted reorganization of the SMN. This reorganization may involve additional recruitment of subcortical and cerebellar regions to sustain the information flow inside the SMN. Concomitantly, this active adaptation motivates further investigations regarding SMN NAT as potential compensation mechanism in early PD.

Adolescent alcohol exposure disrupts extinction learning and retrosplenial cortex physiology in adult males
Adolescent binge drinking can lead to a myriad of issues later in life, including co-occurring diagnoses of Alcohol Use Disorder (AUD) and affective disorders such as post-traumatic stress disorder (PTSD). Although efforts to understand the effects of adolescent alcohol exposure on later health outcomes have unveiled lasting, maladaptive behaviors in adulthood, questions remain about region and cell-type specific mechanisms that drive such effects. Here, we tested the hypothesis that adolescent alcohol exposure would produce lasting alterations in retrosplenial cortex (RSC) function and physiology. In support of this hypothesis, we found that adolescent intermittent ethanol (AIE) vapor exposure resulted in impaired extinction recall of a trace fear memory in adulthood, as well as lasting reductions in intrinsic excitability in adult RSC pyramidal cells. Importantly, these changes were sex-specific, occurring in males but not females. Together, this work suggests that the RSC may be a key, vulnerable locus for the detrimental effects of adolescent alcohol exposure.

Lower Bound Estimates for Electrophysiological Power Dissipation in Human Gray Matter
The human brain is popularly described as remarkably energy efficient, with its metabolic power consumption estimated at approximately 20 watts (W). Biophysical models have partitioned this power budget across distinct cellular processes, but these theoretical estimates have yet to be empirically constrained using whole-brain electrophysiological data. Here, we used magnetoencephalography (MEG) source imaging of resting-state human brain activity to derive empirical lower-bound estimates of electrical power dissipation in cortical gray matter. We found that the total power dissipated by currents, primarily associated with post-synaptic potentials, ranges between 10-9 and 10-10 W, several orders of magnitude lower than prevailing metabolic estimates. Using finite element modeling (FEM), we observed that electrophysiological power dissipation is predominantly confined to gray matter. Additionally, spatial variations in MEG-derived power dissipation partially correlated with regional oxygen metabolism measured by PET, yet notable discrepancies emerged across large-scale functional brain networks. These results underscore a critical divergence between electrophysiological and metabolic indices of brain energy use, and highlight the need for more integrated biophysical models to bridge this gap and better characterize the physiological underpinnings of regional brain energetics.

Retrograde mitochondrial transport regulates mitochondrial biogenesis in zebrafish neurons
To maintain a healthy mitochondrial population in a long-lived cell like a neuron, mitochondria must be continuously replenished through the process of mitochondrial biogenesis. Because the majority of mitochondrial proteins are nuclear encoded, mitochondrial biogenesis requires nuclear sensing of mitochondrial population health and function. This can be a challenge in a large, compartmentalized cell like a neuron in which a large portion of the mitochondrial population is in neuronal compartments far from the nucleus. Using in vivo assessments of mitochondrial biogenesis in zebrafish neurons, we determined that mitochondrial transport between distal axonal compartments and the cell body is required for sustained mitochondrial biogenesis. Estrogen-related receptor transcriptional activation links transport with mitochondrial gene expression. Together, our data support a role for retrograde feedback between axonal mitochondria and the nucleus for regulation of mitochondrial biogenesis in neurons.

Analyzing Gaze and Hand Movement Patterns in Leader-Follower Interactions During a Time-Continuous Cooperative Manipulation Task
In daily life, people often interact by taking on leader and follower roles. Unlike laboratory experiments, these interactions unfold naturally and continuously. Although it is well established that gaze typically precedes object manipulation, much less is known about how gaze-hand patterns evolve in interactive settings where one person must take the other's actions into account. Here we examine predictive, planning-related behavior in a two-player tabletop game called "do-undo". Participants alternated as Leader and Follower. The Leader performed simple pick-and-place actions to alter the arrangement of objects, while the Follower used other objects to restore the previous configuration. We recorded eye and hand movements, along with object trajectories, using a system that combined eye tracking with multi-camera motion capture. Touch sensors on the players' hands provided precise timing of contacts, allowing us to segment cooperative action into well-defined temporal intervals. As expected, eye fixations consistently preceded manipulation, but clear role differences emerged. Leaders looked more often and earlier at target objects. In many trials, their gaze anticipated not only their own actions but also those required of the Follower. Leaders also more frequently checked the outcome of the do-undo sequence. Both roles showed gaze patterns consistent with memorization, but alternating gazes between objects and destinations were much more common in Leaders. Some patterns suggested longer-term planning beyond the immediate action. These findings reveal distinct decision-making and planning strategies in Leaders and Followers. Leaders consider not only their own next moves but also the potential actions of their partners, shedding light on the complex cognitive processes that underly everyday human interaction.

Increased sensitivity to myopia and altered retinal ON/OFF balance in a mouse model lacking Dusp4
Myopia occurs as the eye fails to stop the emmetropization process, causing an overgrowth of the eyeball. Environmental factors like light and genetics play a key role in the development of myopia. Animal models of inherited retinal disorders lacking a functional ON-pathway and which develop high myopia identified several differentially expressed genes suggesting a possible involvement of these genes in myopia. Using a mouse model in which one of those genes, Dusp4, was deleted, we aim to better understand the mechanisms implicated in myopia development and the role of DUSP4 in the retina. We report here that mice lacking DUSP4 have a reduced basal level of retinal dopamine and a higher susceptibility to lens-induced myopia. Dusp4 is expressed in ON-bipolar cells and a subset of OFF-bipolar cells in a light dependent manner. The absence of DUSP4 causes a hyperactivation of the MAPK/ERK pathway. Dusp4-/- mice show a reduced optomotor response and an altered retinal response to light stimuli. We observed increased ON-bipolar cell responses and reduced oscillatory potentials together with altered OFF and ON-OFF RGC response to light flashes. Altogether, these data demonstrate a light-dependent role for DUSP4 in bipolar cell signaling and provide new insights into retina-driven mechanisms of myopia development, nuancing the impact of ON and OFF pathways upon emmetropization.

Neuroprotective Parkinson's Disease Therapeutic: Transition Metal Dichalcogenide Nanoflower Treatments Alleviate Pathological Cell Stress
Parkinson's disease (PD) is triggered by irreversible degeneration of dopaminergic neurons in the midbrain, hypothalamus, and thalamus. Although the underlying molecular etiology of these pathological processes remains unclear, progressive aggregation of alpha-synuclein (a-syn) and mitochondrial dysfunction are two expected mechanisms implicated in neuronal degeneration. Accumulating evidence indicates that transition metal dichalcogenide (TMD) nanoflowers (NFs), a novel class of nanomaterials, can restore mitochondrial health by the activation of mitochondrial biogenesis. However, therapeutic potential of TMD NFs in PD remains unclear. The current study investigates the neuroprotective properties of molybdenum disulfide (MoS2) and molybdenum diselenide (MoSe2) nanoflowers (NFs) in neurons and astrocytes exposed to a-syn aggregates. It was found that MoS2 and MoSe2 suppressed a-syn-induced unfolded protein response (UPR) in the endoplasmic reticulum, and upregulated autophagy and exocytosis of a-syn fibrils. TMD NFs also reversed a-syn-induced damage of cell mitochondria, simultaneously stimulating mitochondrial biogenesis. As a result, a drastic decrease in ROS levels in both neurons and astrocytes was observed. These results show that MoS2 or MoSe2 NFs could fully rescue neurons and astrocytes from the cytotoxic effects of a-syn fibrils. Neuroprotective properties of these novel nanomaterials were further explored in Caenorhabditis elegans that overexpress a-syn. Nematodes that received NFs experienced a drastic reduction in the amount of aggregated a-syn which resulted in a significant increase in C. elegans lifespan. These findings indicated that MoS2 or MoSe2 NFs could be used as novel therapeutic to decelerate the progression of PD.

Reward-reset interval timing drives patch foraging decisions through neural state transitions in dorsomedial striatum
Activities with diminishing returns pose a unique computational problem for the brain, requiring a combination of outcome evaluation and temporal tracking. Deciding the right time to stop one pursuit and move to alternatives is an important part of effective time management, yet it is unknown how the decision-making circuits of the brain determine the moment to switch. The dorsomedial striatum (DMS) mediates both goal-directed decision-making and interval timing, two functions that converge during patch foraging, where animals must time when to exit patches to maximize reward rates. We recorded extracellular activity from neurons in DMS while freely moving mice performed a patch-foraging task. Mice employed a 'reward-reset' strategy, primarily basing their exit decisions on the time since the last reward, but with the patch residence time and environmental reward-rate context also contributing to the intended time of departure. Individual neurons in DMS underwent discrete firing rate transitions at characteristic delays following each reward. These transition delays were distributed across the population, creating a cumulative signal that reached a threshold coinciding with patch exit. This population activity pattern spanned the intended reward-to-exit interval, compressing or expanding in accordance with patch residence time and changing environmental conditions. Fiber photometry recordings revealed phasic dopamine signals in DMS encoding reward prediction errors that reflected the declining reward probability over time. Our results provide insights into how DMS integrates its dual roles in timing and action selection to guide time investment strategies during foraging.

Data-driven burst shape analysis for functional phenotyping of neuronal cultures
Cultures of neurons in vitro are instrumental for studying network dynamics in normal and pathological conditions. Mature networks typically exhibit network bursting activity, which has traditionally been quantified by simplified features such as inter-burst intervals and burst durations. While these features advanced the understanding of development, disease phenotypes, and drug effects, they overlook the temporal structure of activity within bursts. Here, we developed a comprehensive framework to quantify burst shapes, the time course of network firing during bursts. Applying this approach to four datasets, including rodent- and human pluripotent stem cell-derived cultures, we show that burst shapes contain rich information about the underlying network dynamics. We quantify this information by using traditional and shape features to classify the recording conditions (types of genetic disorder, presence of pharmacological agents) and demonstrate that shapes significantly increase classification accuracy. We provide a pipeline for burst shape characterization, including simplified features that capture most of the shape information, establishing burst shape as a robust and biologically meaningful marker for functional phenotyping in disease modeling and drug screening.

Beyond seizure control: identifying deficits in cognitive networks in absence seizure.
Absence epilepsy is frequently associated with cognitive impairments, yet the direct or indirect involvement of cognitive circuits remains poorly understood, as spike-and-wave discharges are rarely reported in these regions. Here, we investigate the role of a thalamic-prefrontal pathway in a mouse model of absence epilepsy (Scn8a+/-). We find that Scn8a+/- mice exhibit deficits in reversal learning, along with impaired recruitment of medial prefrontal cortex (mPFC) neurons by the Reuniens nucleus of the thalamus. This deficit is accompanied by an altered excitation-inhibition balance and reduced excitability of layer I interneurons in the mPFC, which constitutes the main recipient zone of reuniens inputs to the mPFC. Remarkably, stimulation of Reuniens at 20 Hz significantly reduces seizure incidence and improves performance in reversal learning. Our findings reveal previously unrecognized cognitive circuit dysfunctions in absence epilepsy and highlight the thalamo-prefrontal axis as a promising target for both cognitive and seizure-related interventions.