bioRxiv Subject Collection: Neuroscience's Journal
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Monday, October 13th, 2025
| Time |
Event |
| 12:17a |
A 'brain-first' mouse model of progressive alpha-synuclein pathology via intranasal rotenone administration
The precise aetiology of Parkinson's disease (PD) is still poorly understood, but it is thought to arise due to an intricate relationship between genes and the environment. Our study takes a unique approach to understanding the effect of environmental factors on the onset and progression of -synuclein (aSyn) pathology, a key feature of PD, from the olfactory bulb (OB) to other brain regions. In the present study, we evaluated the time-dependent progression of PD-like pathology by administering rotenone intranasally for 5.5 months in C57BL/6 male mice. We performed olfactory and motor tests and examined the aSyn accumulation, glial cell activation and dopaminergic neurodegeneration after 3, 4 and 5.5 months of rotenone exposure by immunoblotting and immunofluorescence techniques. We observed a time-dependent progression of aSyn accumulation from the OB to other brain regions, including the mid-brain and cortex. Consistently, we observed a time-dependent behavioural impairment, OB atrophy, progression of aSyn pathology, neuroinflammation and neurodegeneration. Our findings also established a link between distinct astrocyte activation and dopaminergic (DAergic) activity. In conclusion, this chronic and progressive mouse model mimics the brain-first type of progression of PD-like pathology in some PD patients, opening the possibility for testing potential disease-modifying interventions. | | 11:01a |
Transcriptional regulation of disease-relevant microglial activation programs
Microglia, the brain's innate immune cells, can adopt a wide variety of activation states relevant to health and disease. Dysregulation of microglial activation occurs in numerous brain disorders, and driving or inhibiting specific states could be therapeutic. To discover regulators of microglial activation states, we conducted CRISPR interference screens in iPSC-derived microglia for inhibitors and activators of six microglial states. We identified transcriptional regulators for each of these states and characterized 31 regulators at the single-cell transcriptomic and cell-surface proteome level in two distinct iPSC-derived microglia models. Finally, we functionally characterized several regulators. STAT2 knockdown inhibits interferon response and lysosomal function. PRDM1 knockdown drives disease-associated and lipid-rich signatures and enhanced phagocytosis. DNMT1 knockdown results in widespread loss of methylation, activating negative regulators of interferon signaling. These findings provide a framework to direct microglial activation to selectively enrich microglial activation states, define their functional outputs, and inform future therapies. | | 11:01a |
Tachykinin 1-expressing neurons in the lateral habenula signal negative reward prediction error
Evaluating outcomes to accurately predict which actions lead to reward is crucial for survival. Discrepancies between expected and realized outcomes, termed reward prediction errors, serve as a teaching signal to update subsequent predictions and promote adaptive behavior. Neural correlates of prediction errors have been identified in several brain regions, including the lateral habenula (LHb), which contains a subpopulation of neurons encoding negative RPEs (nRPEs) that are excited by worse-than-expected outcomes and inhibited by better-than-expected outcomes. LHb projections to the midbrain shape firing in dopaminergic neurons and play a well-established role in reward learning and decision-making. However, the LHb engages in a wide variety of behaviors beyond reward processing, and it remains unclear whether these distinct functions are mediated by specific transcriptionally defined cell types. Little is known about the transcriptomic identity of nRPE-encoding neurons, limiting our understanding of the specific role of these signals in outcome valuation. Using cell type-specific recording in mice performing reward-guided tasks, we demonstrate neurons expressing the neuropeptide gene Tachykinin-1 (Tac1) represent a subpopulation of LHb neurons encoding reward prediction errors. We found LHbTac1 reward outcome responses are sensitive to changes in both the expected value and realized value of rewards, and their activity scales with the magnitude of the difference. Further, LHbTac1 neurons show little modulation to other task-related events, or to innately aversive stimuli that engage a broader population of LHb cell types. Together, these data demonstrate that Tac1 marks a subpopulation of LHb neurons that preferentially encodes nRPE. Our results provide insight into cell type-specific contributions of habenular neurons in RPE signaling and open avenues for more targeted manipulations of nRPE-encoding neurons to understand their role in reward-guided behavior. | | 12:18p |
A compressed code for memory discrimination
The ability to discriminate similar visual stimuli has been used as an important index of memory function. This ability is widely thought to be supported by expanding the dimensionality of relevant neural codes, such that neural representations for the similar stimuli are maximally distinct, or "separated." An alternative hypothesis is that discrimination is supported by lossy compression of visual inputs, efficiently coding sensory information by discarding seemingly irrelevant details. A benefit of compression, relative to expansion, is that it allows the individual to efficiently retain fewer essential dimensions underlying stimulus variation---a process linked to higher-order visual processing---without hindering discrimination. Under the compression hypothesis, pattern separation is facilitated when more information from similar stimuli can be discarded, rather than preserving more information about distinct stimulus dimensions. We test the compression versus expansion hypotheses by predicting performance on the canonical mnemonic similarity task. First, we train neural networks to compress perceptual and semantic factors of stimuli, and measure lossiness of those representations using the mathematical framework underlying compression. Consistent with the compression hypothesis, and not the expansion hypothesis, we find that greater lossiness predicts the ease and performance of lure discrimination, particularly in later layers of convolutional neural networks shown to predict brain activity in the higher-order visual stream. We then empirically confirm these predictions across two sets of images, four behavioral datasets, and alternative metrics of lossiness. Finally, using task fMRI data, we identify signatures of lossy compression---neural dimensionality reduction and information loss---in the higher-order visual stream regions V4 and IT as well as hippocampal subregions dentate gyrus/CA3 and CA1 associated with lure discrimination performance. These results suggest lossy compression may support mnemonic discrimination behavior by discarding redundant and overlapping information. | | 12:18p |
Resolving Cellular Morphology in the Human Brain with Multiparametric Diffusion MR Spectroscopy
Diffusion-weighted magnetic resonance spectroscopy (dMRS) is a unique, non-invasive technique capable of probing cell-type specific morphology. However, conventional dMRS methods are limited in their ability to provide detailed morphological information. This study demonstrates the potential of a multi-parametric dMRS approach, combining diffusion-time dependent and double-diffusion encoding MR spectroscopy, to characterize soma and neurite morphology of neuronal and glial cells. This methodology holds promise for developing biomarkers for the diagnosis, monitoring, and phenotyping of neurological pathologies, like Alzheimer's Disease, Parkinson's Disease, or Multiple Sclerosis, where alterations in soma and neurite morphology are reported. | | 12:18p |
The neural correlates of novel versus familiar metaphors in healthy young adults: A functional near-infrared spectroscopy study
Despite extensive investigation, the neural correlates of metaphor processing remain debated. Poor theoretical and experimental control of variables that drive metaphor activation (particularly the constructs of novelty and familiarity) may be the reason for past discrepancies between studies. To address this issue, we used functional near-infrared spectroscopy (fNIRS) and a carefully designed paradigm modified from Cardillo et al. (2012) to investigate how neural activation varies by sentence type (metaphorical versus literal sentences) and novelty (completely novel versus familiarized phrases). Activity was significantly greater for metaphorical over literal sentences in the left inferior frontal gyrus, pars triangularis (LIFGtri), left inferior parietal cortex, right IFG, pars opercularis (RIFGop), and right angular gyrus (RAG). Novel metaphors to which participants had no prior exposure had significantly higher (albeit weak) effects within RIFGop, RAG, and right middle temporal gyrus (RMTG) compared to novel metaphors to which participants were exposed just prior to the fNIRS experiment. Pre-exposed, more familiar metaphors significantly activated a wider network of regions compared to novel metaphors, including bilateral middle frontal gyrus (MFG), bilateral IFGtri, and LMTG. A greater response time difference between conditions was associated with less LMFG activity for metaphors over literal sentences but higher LMTG activity for novel over more familiar metaphors. Taken together, these findings suggest that metaphors - particularly novel metaphors - do engage right hemisphere cortex more than other phrase types (literal sentences, more familiar metaphors) but that the effects are weaker than condition differences within canonical left language network and domain-general multiple demand network regions. | | 12:18p |
A comprehensive characterization of the phospholipid and cholesterol composition of the uncinate fasciculus in the human brain: evidence of age-related alterations
The uncinate fasciculus (UF) is a long-range association fiber tract that serves to connect the anterior temporal lobe with the orbitofrontal cortex. The UF has been implicated via neuroimaging studies in the neurobiological vulnerability to psychiatric disorders posed by a history of childhood abuse (CA), as well as in the psychopathology underlying depressive disorders. Since the myelin sheath is highly enriched in lipids, white matter (WM) dysfunction may reflect alterations in the myelin lipid profile. In fact, our previous work showed that in the anterior cingulate cortex WM, there was a specific effect of CA in the choline glycerophospholipid fatty acids (FA) involved in the synthesis of arachidonic acid. Given that the UF does not exist in rodents, its molecular properties are highly understudied and its lipid composition is virtually unknown. As such, we sought to quantify the phospholipid FA and cholesterol quantities of the human postmortem UF and measure whether we could detect lipid-related or myelin-constituent gene/protein changes associated with CA and/or depression. Fresh-frozen left hemisphere UF samples were analyzed from individuals with depression who died by suicide with a history of severe CA (DS-CA), individuals with depression who died by suicide without a history of CA (DS), and non-psychiatric control subjects who died naturally or accidentally (CTRL). Phospholipids were separated by thin-layer chromatography. FA and non-derivatized cholesterol were quantified using gas chromatography-flame ionization detection. Relative expression of myelin-constituent genes (PLP1, MAG, CNP, MOG, PLLP, MBP, and MOBP) was measured by RT-qPCR, and levels of myelin-constituent proteins (MAG, MOG, MBP, and PLP) were measured by immunoblotting. We found no robust relationships between depression or CA and any lipid measures, nor in myelin-constituent gene and protein levels. However, in the phospholipids, we observed striking age relationships that varied across fractions, with an overall pattern of increases in monounsaturates and decreases in long chain omega-6 polyunsaturates with age. In tandem, we observed that most myelin-constituent genes and proteins showed decreasing trends with age, with PLP1 and MAG showing significantly decreasing relationships. We hypothesize that the changes in lipid composition and lipid-protein interactions contribute to age-related myelin deficits and declines in cognition. The absence of group differences highlights the importance of regional specificity in molecular studies assessing neurobiological correlates of psychiatric disorders. | | 12:18p |
Role of the locus coeruleus noradrenergic system in susceptibility and resilience following early life stress in male and female mice
Background: Child adversity (CA), encompassing emotional, physical, and sexual maltreatment or abuse, affects a substantial number of children worldwide. Moreover, it is the leading predictor of psychiatric disorders such as major depressive disorder (MDD), anxiety, and suicidal behavior. Despite the robust link between CA and psychopathology, individual outcomes vary significantly, with some children demonstrating resilience. Resilience is an adaptive and dynamic process, which mitigates the long-term effects of CA, suggesting potential protective mechanisms that remain underexplored. This study investigates the role of the locus coeruleus-norepinephrine (LC-NE) system, a critical modulator of stress, cognition, and emotion, in mediating resilience and susceptibility following early life stress (ELS). Methods: Using a maternal deprivation model combined with limited nesting and bedding, we examined behavioral, physiological, and neurobiological markers associated with ELS outcomes in mice of both sex. Results: Behavioral clustering revealed distinct phenotypes: resilient, anxious, and depressive-like with sex-specific differences in distribution. Early markers, including body weight and ultrasonic vocalization (USV) patterns, predicted long-term susceptibility. Neuroanatomical analyses identified sex-specific LC-NE activation patterns associated with resilience and susceptibility, highlighting the caudal-dorsal LC as a critical region in males and females in different phenotypes, anxious in males and resilient in females. Conclusion: These findings highlight the impact of ELS on the LC-NE system and its role in shaping adaptive and maladaptive trajectories, offering insights into potential interventions targeting resilience mechanisms in children exposed to CA. | | 12:18p |
Asynchronous firing and off-states in working memory maintenance
Persistent spiking activity and activity-silent mechanisms have been proposed as neural correlates of working memory. To determine their relative contribution, we recorded neural activity from the lateral prefrontal and posterior parietal cortex of two male macaques using high-density microelectrode probes. We found that, when averaged across all neurons, persistent delay activity was observable throughout the duration of single trials in populations of prefrontal neurons with silent periods that did not deviate significantly from chance. However, temporal fluctuations in activity-dependent mnemonic information were present and weakly correlated between the prefrontal and posterior parietal cortices, suggesting at least partial, long-distance synchronization of off-states. Decoding accuracy of neurons recorded simultaneously was also reduced relatively to pseudo-populations constructed by splicing different trials together. Our results support an asynchronous state of working memory, maintained by the distributed pattern of persistent discharges across cortical neurons, which is subject to widely distributed fluctuations in information representation fidelity. | | 6:47p |
Axon Regeneration and Functional Recovery after Spinal Cord Injury is Enhanced by Allele-Specific ApoE Neuronal Action through LRP8
Adult CNS trauma frequently causes neuronal disconnection and persistent deficits due to failed axon regeneration. While model system screening has identified multiple candidate neural repair pathways, ApoE-LRP8 signaling is unique in being implicated clinically. Here, we show that cortical axon regeneration requires LRP8 and is modified by APOE variants. ApoE2-expressing mice show reparative corticospinal and raphespinal axon growth with greater motor function than controls after spinal cord injury. Distinct from ApoE in other settings, there is no change in inflammation or scarring. After axotomy, ApoE exerts allele-specific effects on LRP8 localization and signaling in cortical neurons. APOE alleles regulate synaptic organization gene expression by cortical neurons after injury, with little effect on glial gene expression. AAV-mediated overexpression of ApoE2 in mice after spinal trauma increases locomotor recovery and reparative axon growth. Thus, ApoE-LRP8 signaling for axon regrowth following CNS trauma provides a potential therapeutic intervention site. | | 8:46p |
A single session of mild intensity physical exercise modulates brain oscillations in healthy young adults: a pilot study.
An acute session of moderate or vigorous physical exercise (PE) induces a cascade of neurophysiological processes such as release of growth factors, which relate to increased electroencephalogram (EEG) activity. Studies using animal models of Alzheimer disease (AD) showed that these mechanisms are disrupted even at asymptomatic stages of the disease. Specifically, increased neural activity within Theta band observed in healthy mice was not evidenced in mice models of AD, suggesting that EEG could be a suitable non-invasive tool to detect preclinical AD. The present study aims investigating the possible neurophysiological effects after a session of mild intensity PE, which is feasible to carry out in most population, during an EEG recording. Thus, sixteen young humans cycled at a low intensity in a stationary bike to study PE effects on the EEG frequency bands. EEG was acquired before and after PE (immediately after performing the PE, or 20-25 minutes later). Results showed that PE increased Alpha activity in frontal and central electrodes for at least 25 minutes, which aligns with previous studies in humans. Trends to increased Theta activity were observed within the left hemisphere immediately after PE, but not 25 minutes after finishing PE. Studies using larger samples should assess whether mild intensity PE increases Alpha and Theta and induces effects of different duration in both frequency bands, suggesting sensitivity of EEG to detect diverse neurophysiological effects induced by PE. Another pending issue is whether increased Alpha after PE in humans is functionally equivalent to increased Theta observed in mice. | | 10:51p |
Sensorimotor adaptation of vocal pitch is severely impaired in cerebellar ataxia
Sensory errors, mismatches between predicted sensory outcomes of movement and reafferent sensory feedback, drive changes in the feedforward control of future motor behavior that correct for those errors. Across a wide variety of motor behaviors, individuals with cerebellar damage show impairments in these corrections, strongly suggesting a key role of the cerebellum in sensorimotor adaptation. However, the extent to which the cerebellum is involved in controlling vocal pitch is currently unknown. Crucially, vocal pitch differs in several ways from other systems that suggest it relies more on feedback than feedforward control. Adaptation itself also differs in vocal pitch: rather than the gradual build-up/decay of learning seen in other systems, pitch adaptation and de-adaptation are almost immediate. Together, this questions whether adaptation in vocal pitch relies on the same mechanism as other motor domains. Here, we test the hypothesis that the cerebellum underlies sensorimotor adaptation in vocal pitch, testing the domain-generality of this neurocomputational process. In both sustained vocalization and a more natural word production task, individuals with cerebellar ataxia fail to adapt to external auditory perturbation of vocal pitch. The complete lack of adaptation observed, compared to the impaired but present adaptation seen in other systems, suggest that the cerebellum plays an especially critical role in maintaining accurate control of vocal pitch. Conversely, we failed to detect a previously observed increase in online compensation to vocal pitch errors in ataxia, potentially suggesting this may be an idiosyncratic change in control rather than a common trait in this population. |
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