bioRxiv Subject Collection: Neuroscience's Journal
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Saturday, July 5th, 2025
| Time |
Event |
| 12:04a |
Adaptive changes of cholinergic projections to the nucleus accumbens bidirectionally mediate cocaine reinforcing effects
The laterodorsal tegmentum (LDT) sends critical inputs to distinct reward circuit regions, including the nucleus accumbens (NAc), but their functional role in addiction-related behaviors remains underexplored. Here, we demonstrate that LDT-NAc cholinergic projections undergo cocaine-induced adaptations and modulate cocaine-related behaviors. Using cell type-specific tracing, we show that LDT neurons preferentially innervate NAc medium spiny neurons and cholinergic interneurons. Large-scale in vivo recordings reveal that cocaine pre-exposure induces persistent alterations in both LDT and NAc neuronal dynamics and modifies responses to subsequent cocaine challenge. Remarkably, pre-exposure to cocaine triggers population-specific adaptations in the LDT, selectively enhancing excitability of LDT-NAc-projecting cholinergic neurons while reducing that of non-projecting cholinergic cells. Behaviorally, optogenetic activation of LDT-NAc cholinergic projections enhances cocaine conditioning, whereas their inhibition diminishes reinforcing effects of cocaine. Our findings identify LDT-NAc cholinergic inputs as key substrates of cocaine-induced plasticity, and critical mediators of the rewarding properties of cocaine, introducing a novel component to addiction circuitry. | | 12:04a |
Low and high frequency signatures of impaired consciousness in temporal lobe seizures
Impaired consciousness is a debilitating and unpredictable outcome of mesial temporal lobe seizures whose mechanisms to date remain unclear. Moreover, questions about the relationship between impaired consciousness and lateralization, hemispheric spread and electrophysiological characteristics of seizures are yet to be answered. To address these gaps, we conducted in-depth investigation of behavioral and intracranial EEG data from 186 mesial temporal lobe seizures of 51 patients with intractable mesial temporal lobe epilepsy. We found that bilateral mesial temporal spread of seizures is not a necessary condition for impaired consciousness, although seizures with bilateral mesial temporal involvement were significantly more likely to have impaired consciousness than unilateral seizures. Contrary to prior belief, we found no relationship between the onset side (left vs. right temporal lobe or language dominant vs. non-dominant lobe) of seizures and the probability of impaired consciousness. Lastly, we established that widespread increases in slow-wave activity (delta band) in extratemporal cortical areas, as well as increases in fast activity (beta band) in the temporal lobes were both robust markers of seizures with impaired consciousness and could predict ictal impairment with up to 86% accuracy. Our findings shed new light on networks that underlie impaired consciousness in temporal lobe epilepsy and may help guide deep brain stimulation of such systems (e.g. via thalamic nuclei) as a potential intervention to improve consciousness during seizures. | | 12:04a |
Targeted ablation and regeneration of enteric nervous system neurons in zebrafish
The enteric nervous system (ENS) is the intrinsic nervous system of the gut and regulates essential gut functions, including motility, digestion, and immune response, ensuring gut homeostasis. ENS dysfunction or loss is associated with gastrointestinal disorders such as Hirschsprung disease (HSCR). Currently, surgery is the only treatment for HSCR, but it often has lifelong, severe complications. Restoring missing ENS neurons by stimulating endogenous neuronal regeneration presents a promising therapeutic approach for ENS disease. To study the cellular-molecular mechanisms of neuronal regeneration we first need to identify an animal model system with robust ENS regeneration. For this, we developed a chemical-genetic ablation model in zebrafish using the Gal4/UAS NTR 2.0 system for targeted ENS neuron ablation. Spatially and temporally controlled neuronal death was confirmed by morphological changes, complete neuronal loss, and TUNEL assays. Quantification of regenerated neurons demonstrated complete restoration of ENS neuron numbers to control levels by 9 days post treatment with recovery of gut motility. Among the regenerated neurons, nitrergic, cholinergic and vipergic subtypes showed full recovery, whereas serotonergic neurons only displayed partial recovery, indicating subtype-specific differences in the regenerative capacity and/or timing. Our study establishes a robust platform for dissecting the cellular molecular mechanisms of ENS regeneration to develop potential treatment approaches for ENS-related diseases. | | 12:04a |
Multimodal sensory overload in dopamine-deficient larval zebrafish leads to paradoxical kinesia
Paradoxical kinesia, the temporary alleviation of motor deficits by powerful, urgent stimuli in Parkinson's disease (PD), remains poorly understood at the neural circuit level. Through chemo-genetic ablation of tyrosine hydroxylase-expressing neurons in larval zebrafish and brain-wide calcium imaging under head-fixed, tail-free conditions, we uncovered a neural mechanism underlying this phenomenon. While catecholamine (CA)-deficient larvae exhibited severe locomotor deficits during free swimming, they showed paradoxical recovery of tail movements during whole-brain neural activity imaging. This locomotor recovery was accompanied by a significantly increased number of active neurons in the midbrain and hindbrain, but with reduced firing rates. Further analyses across 2158 anatomically defined regions allowed us to uncover a subset of regions, genes, and neurotransmitter types. GABAergic neurons were found to primarily account for the hyperactivity in the hindbrain, while glutamatergic neurons accounted for the hyperactivity in the midbrain. Hierarchical clustering of neuronal activity with tail movements revealed distinct motor- and non-motor-associated hyperactive clusters in the hindbrain and midbrain, respectively. We identified the Mesencephalic Locomotor Region (MLR) sandwiched between these domains, with enhanced glutamatergic firing rate and cholinergic activation. Furthermore, we found that Telencephalic corticotropin-releasing factor b (crhb) expressing neurons play a crucial role in mediating stress-response to the tectum, which in turn triggers a cascade of neuronal hyperactivity downstream via MLR. These findings reveal a neural mechanism that links stress-induced sensory processing with motor control systems in the absence of regulatory feedback from catecholaminergic neurons, suggesting a direct, unmodulated pathway that bypasses typical inhibitory controls. | | 12:04a |
TMC1 and TMC2 are cholesterol-dependent scramblases that regulate membrane homeostasis in auditory hair cells
TMC1 and TMC2, the pore-forming subunits of the mechanoelectrical transduction (MET) complex in inner ear sensory hair cells, are essential for auditory and vestibular function. Pathogenic mutations in TMC1 are a leading cause of genetic hearing loss, but their underlying cellular mechanisms remain poorly understood. Here, we reveal that TMC1 and TMC2 are cholesterol-regulated lipid scramblases whose activity modulates plasma membrane asymmetry. Using reconstituted proteoliposomes and molecular dynamics simulations, we demonstrate that both proteins facilitate phospholipid translocation across membrane bilayers, a process tuned by cholesterol and enhanced by deafness-causing TMC1 mutations. We show that this scramblase activity correlates with TMC1-dependent externalization of phosphatidylserine and membrane blebbing in murine auditory hair cells, linking TMC1-dependent membrane homeostasis dysregulation to auditory sensory cell pathology. These findings identify TMCs as a novel family of lipid scramblases, advancing our understanding of MET complex biology and offering mechanistic insight into membrane-driven forms of hereditary deafness. | | 12:04a |
Task-evoked functional connectivity exhibits novel and strengthened relationships with executive function relative to the resting state
Executive functioning in children has been linked to intrinsic brain network organization assessed during the resting state, as well as to brain network organization during the performance of cognitive tasks. Prior work has established that task-based brain networks are stronger predictors of behavior than resting state networks, yet it is unclear if tasks only strengthen relationships that exist weakly at rest or if tasks also evoke unique relationships. A lack of discernment regarding how tasks and the resting state commonly and uniquely support executive functions precludes a holistic understanding of the neurobiological basis of executive functions. This project investigated differences in brain network organization and relationships with executive function ability between the resting state and two executive function tasks, a stop signal task and an emotional n-back task, using the Adolescent Brain and Cognitive Development (ABCD) Study dataset. Both executive function tasks evoked a more integrated network organization than the resting state, and executive function ability was related to different aspects of brain network organization during the resting state and during the tasks. Further, task-related shifts in brain network organization evoked several new relationships with executive function that were not detectable during the resting state and strengthened a relationship with executive function that existed weakly during the resting state. Overall, this study establishes a distinction between common and unique features of intrinsic and task-evoked brain function that facilitate executive function in children. | | 12:04a |
Recognizing EEG responses to active TMS vs. sham stimulations in different TMS-EEG datasets: a machine learning approach
Background: Transcranial Magnetic Stimulation (TMS) with simultaneous Electroencephalogram (TMS-EEG) allows assessing the neurophysiological properties of cortical neurons. However, TMS-evoked EEG potentials (TEPs) can be affected by components unrelated to TMS direct neuronal activation. Accurate, automatic tools are therefore needed to establish the quality of TEPs. Objective: To assess the discriminability of EEG responses to TMS vs. EEG responses to sham stimulations using sequence-to-sequence machine learning (ML). Methods: Two indipendent TMS-EEG datasets including TMS and several sham stimulation conditions were obtained from the left motor area of healthy volunteers (N=33 across datasets). A Bi-directional Long Short-Term Memory (BiLSTM) ML network was used to label each time point of the EEG signals as pertaining to TMS or sham conditions. Main outcome measures included accuracy at single-trial level and after averaging five to twenty trials. Results: For TMS conditions, post-stimulus vs. baseline/pre-stimulus EEG comparisons yielded moderate (60%-75%) single-trial accuracy and high-accuracy (>75%) for 20 trials across datasets, while for sham conditions post- vs. baseline/pre-stimulus EEG comparisons yielded lower accuracy rates than for TMS conditions, except for unmasked auditory stimulation. Furthermore, baseline/pre-stimulus TMS vs. baseline/pre-stimulus sham EEG comparisons showed chance-level accuracy, whereas post-stimulus TMS vs. post-stimulus sham EEG comparisons had moderate (single trial) to high (20 trial) accuracy, except for TMS with and without the click noise masking. Single-subject findings were comparable to group-level results across datasets. Conclusions: TEPs after active TMS are discernible from various sham stimulations even after a handful of trials and at the single-subject level using a BiLSTM ML approach. | | 12:32a |
Parietal top-down projections balance flexibility and stability in adaptive learning
The ability to flexibly modify behavior in response to changing environmental contingencies is fundamental to adaptive decision-making, yet how distributed brain circuits coordinate such rapid adaptation remains unclear. Here, we show that the posterior parietal cortex (PPC) facilitates adaptive learning via parallel projections to the auditory cortex (AC) and inferior colliculus (IC). In a within-session auditory reversal task, AC neurons supported flexible stimulus updating following rule reversal, whereas IC neurons preserved stable auditory discrimination across rules. Dual retrograde tracing revealed anatomically segregated PPC neurons projecting to AC (PPCAC) and IC (PPCIC). PPCAC neurons flexibly encoded stimulus-outcome contingencies, while PPCIC neurons stably represented response outcomes. Circuit-specific optogenetic inactivation confirmed their distinct contributions to behavioral adaptation. This double dissociation reveals a circuit mechanism by which parallel PPC projections coordinate flexible rule updating and stable motor execution, enabling rapid behavioral adaptation and providing a mechanistic framework for cognitive flexibility. | | 12:32a |
A NEST-based framework unlocks massively parallel simulation of networks of multicompartment neurons with customizable subcellular dynamics.
While the implementation of learning and memory in the brain is governed in large part by subcellular mechanisms in the dendrites of neurons, large-scale network simulations featuring such processes remain challenging to achieve. This can be attributed to a lack of appropriate software tools, as neuroscientific simulation software focuses on the one hand on highly detailed models, and on the other hand on massive networks featuring point-neurons. Here, we fill this gap by implementing a framework for the massively parallel simulation of simplified dendrite models with customizable subcellular dynamics. To achieve this, we leverage the NEural Simulation Tool (NEST), the neuroscientific reference with respect to efficient massively parallel simulations of point neuron networks. By co-opting the already existing model descriptions language NESTML, we generate C++ code implementing user-configurable subcellular dynamics. Through benchmarking and profiling, we show that the generated models run efficiently, leading to scalable NEST network simulations. We demonstrate relevant functionalities by showing that a key sensory computation - the association of top-down context arriving at distal dendrites in layer 1 and feedforward sensory input arriving perisomatically - can be achieved in a single shot fashion through apical calcium dynamics. Our work thus unlocks the study of how dendritic processes shape learning, and in particular of how brain-wide communication through long-range, layer 1-targetting connections steers perisomatic plasticity. | | 1:49a |
Molecular Dynamics in the Ventral Tegmental Area during Chronic Pain-Induced Negative Affect
Chronic pain frequently coexists with negative affect, with about 60% of patients suffering from both. This dual condition complicates treatment and exacerbates both disorders, highlighting the urgent need for innovative therapeutic strategies. Chronic pain negative affect (CPNA) involves complex neurobiological changes, including increased hyperexcitability of the ventral tegmental area (VTA), a critical region involved in reward, mood, and pain processing. To elucidate CPNA's underlying mechanisms, we employed a multidisciplinary approach using immunohistochemistry, lipidomic analysis, and proteomic screening to investigate VTA molecular alterations in mice subjected to partial sciatic nerve ligation (pSNL) at one and four weeks post-injury. Our results revealed a significant, sex-dependent increase in Kv7.2 channel expression in dopamine neurons, alongside a notable reduction in endocannabinoid 2-arachidonoylglycerol (2-AG) levels, which plays a vital role in mood regulation. This neurochemical shift associated with an increase in negative affect-like behaviors, as determined by the forced swim test. Furthermore, pharmacological intervention utilizing either exogenous 2-AG or retigabine, a Kv7 channel opener, effectively alleviated pain-related negative affect symptoms. Proteomic profiling further uncovered alterations within the CaMKK2 pathway, involving crucial proteins such as PLC{gamma}2, AMPK{gamma}2, and AMPK{beta}1, and CaMK1, with changes in abundance and phosphorylation activity that could be reversed with the next-generation CaMK1 antagonist CS640. This research provides the first comprehensive analyses of VTA adaptations linked to CPNA, yielding significant insights into molecular changes impacting VTA neuronal integrity and signaling throughout CPNA progression. | | 1:49a |
Natural gradient Bayesian sampling: an innate algorithm emerges in canonical cortical circuits
Accumulating evidence suggests the canonical cortical circuit, consisting of excitatory (E) and diverse classes of inhibitory (I) interneurons, implement sampling-based Bayesian inference to compute stimulus posteriors. However, most of the identified sampling algorithms in the circuit are still simpler than the nonlinear circuit dynamics. Through comprehensive theoretical analyses of the nonlinear circuit dynamics, we discover the canonical circuit dynamics innately implements natural gradient Bayesian sampling, which is an advanced sampling algorithm that adaptively adjusts the sampling step size based on the local geometry of stimulus posteriors measured by Fisher information. Specifically, the nonlinear circuit dynamics can implement natural gradient Langevin and Hamiltonian sampling of uni- and multi-variate stimulus posteriors, and these algorithms can be switched by interneurons. We also find that the non-equilibrium circuit dynamics when transitioning from the resting to evoked state can further accelerate natural gradient sampling, and analytically identify the neural circuit's annealing strategy. Remarkably, we identify the approximated computational strategies employed in the circuit dynamics, which even resemble the ones widely used in machine learning. Our work provides an overarching connection between canonical circuit dynamics and advanced sampling algorithms, deepening our understanding of the circuit algorithms of Bayesian sampling. |
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