bioRxiv Subject Collection: Neuroscience's Journal
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Monday, March 17th, 2025
| Time |
Event |
| 3:47a |
Analyzing Neural Response to Visual Stimuli: Firing Rates, Frequency Band Dynamics, and Synchrony in Near and Far Flanker Conditions
This study examines neural responses to visual stimuli under Near and Far flanker conditions using EEG. Fifty participants (25 per condition) completed a visual task with closely or distantly positioned distractors. EEG data were analyzed using spectrograms, wavelet transformation, and neural firing rate estimation. Standard preprocessing techniques ensured data quality and statistical tests assessed differences between conditions. Findings provide insight into how spatial stimulus configurations affect neural processing and attention. | | 3:47a |
Two-Phase Coding Strategy by CA1 Pyramidal Neurons: Linking Spatiotemporal Integration to Predictive Behavior
Space and time are fundamental components of memory, yet how the brain encodes these dimensions to guide behavior remains unclear. Using virtual-reality environments, we uncovered a two-phase neural code in hippocampus CA1 that represents time or distance through two functional pyramidal subpopulations, PyrUp and PyrDown. In Phase I, PyrUp activity synchronously increases to mark the initiation of encoding; In Phase II, their activity decays at heterogeneous, neuron-specific rates, creating a gradual divergence in across-population firing rates that scales with elapsed time. Conversely, PyrDown activity initially decreases before gradually rising. The crossover point, where rising PyrDown activity surpasses declining PyrUp activity, precedes predictive licking behavior. Combining optogenetics and computational modeling, we provided circuit-level evidence that PyrUp neurons primarily process locomotion-related inputs regulated by somatostatin-positive interneurons, whereas PyrDown neurons mainly receive reward-related inputs gated by parvalbumin-positive interneurons. These findings advance our understanding of how hippocampal circuits compute spatiotemporal information to inform behavior. | | 3:47a |
Experimental change in personality: Overexpression of GDNF in the rat striatum converts the low exploratory phenotype into highly explorative
Major vulnerability factors for psychiatric disorders such as depression, that often prevent complete remission and lead to relapses, are temperamental. In a rat model of clustered persistent high anxiety/low motivation, we have found that overexpression of glial-cell-line-derived neurotrophic factor (GDNF) by intra-striatally administered adeno-associated virus vector strikingly converts the passive coping style of low exploratory rats into an active one, similar to high exploratory rats. This conversion of behavioural strategy developed gradually over repeated testing, and was associated with increased catecholamine metabolism in several brain regions and changes in the regulation of serotonin neurotransmission. An increase in in vivo dopamine transporter availability in the striatum was necessary for the phenotype conversion. Associated changes in striatal gene expression included key players in monoamine storage and epitranscriptomic regulation. The increase in GDNF signalling also caused alterations in levels and regional covariation of oxidative metabolism, indicative of persistent reorganization of neural activity throughout the brain. Thus, neurotrophic factors, GDNF in particular, may play a pivotal role in the development, persistence and alteration of personality traits, and therefore constitute a potential target for treatment of chronic, relapsing psychiatric disorders. | | 4:42a |
Progressively reduced cerebral oxygen metabolism and elevated plasma NfL levels in the zQ175DN mouse model of Huntington disease
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG-repeat expansion in exon-1 of the huntingtin gene. Currently, no disease-modifying therapies are available, with a significant challenge in evaluating therapeutic efficacy before clinical symptoms emerge. This highlights the need for early biomarkers and intervention strategies. Therefore, it is essential to develop and characterize accurate mouse models and identify early biomarkers for preclinical therapeutic development. In this study, we characterized the pathological progression of the heterozygous zQ175 neo-deleted knock in (zQ175DN) mouse model across four age groups: 3, 6, 10, and 16 months to identify human translatable outcome measures. T2-relaxation-under-spin-tagging (TRUST) MRI was used to assess global CMRO2, while T2-weighted MRI was used to analyze brain volumes. Significant brain volume loss was detected as early as 6 months of age, worsening progressively with age in the zQ175 DN mice, resembling HD brain volumetric changes. A decline in CMRO2 was observed in 6-month-old zQ175 DN mice, with significant and progressive reductions in 10- and 16- months old HD mice. Additionally, PHP1-positive mutant huntingtin (mHTT) aggregates were present in the striatum of zQ175 DN mice at all four age groups, with intranuclear localization prior to 6 months, transitioning to both intranuclear and neuropil aggregates in older zQ175 DN mice, suggesting that the localization of mHTT aggregates may reflect the severity of HD pathogenesis. Interestingly, plasma neurofilament light chain (NfL) protein concentrations were significantly elevated at 6 months of age and older zQ175DN mice. These findings provide valuable insights for selecting outcome measures in preclinical evaluations of HD therapies using the zQ175 DN mouse model. | | 4:42a |
Perimenopause promotes neuroinflammation in select hippocampal regions in a mouse model of Alzheimers disease
Alzheimers disease (AD) is the most common neurodegenerative disorder characterized by age-dependent amyloid beta (A{beta}) aggregation and accumulation, neuroinflammation, and cognitive deficits. Significantly, there are prominent sex differences in the risk, onset, progression, and severity of AD, as well as response to therapies, with disease burden disproportionally affecting women. Although menopause onset (i.e., perimenopause) may be a critical transition stage for AD susceptibility in women, the role of early ovarian decline in initial disease pathology, particularly key neuroinflammatory processes, is not well understood. To study this, we developed a unique mouse model of perimenopausal AD by combining an accelerated ovarian failure (AOF) model of menopause induced by 4-vinylcyclohexene diepoxide (VCD) with the 5xFAD transgenic AD mouse model. To target early stages of disease progression, 5xFAD females were studied at a young age (~4 months) and at the beginning stage of ovarian failure analogous to human perimenopause (termed peri-AOF), and compared to age-matched males. Assessment of neuropathology was performed by immunohistochemical labeling of A{beta} as well as markers of astrocyte and microglia activity in the hippocampus, a brain region involved in learning and memory that is deleteriously impacted during AD. Our results show that genotype, AOF, and sex contributed to AD-like pathology. Aggregation of A{beta} was heightened in female 5xFAD mice and further increased at peri-AOF, with hippocampal subregion specificity. Further, select increases in glial activation also paralleled A{beta} pathology in distinct hippocampal subregions. However, cognitive function was not affected by peri-AOF. These findings align with the hypothesis that perimenopause constitutes a period of susceptibility for AD pathogenesis in women. | | 4:42a |
Phase-synchronized 40 Hz transcranial electric and magnetic stimulation boosts gamma oscillations and working memory
Gamma oscillations play a crucial role in core cognitive functions such as memory processes. Enhancing gamma oscillatory activity, which is reduced in Alzheimers Disease (AD), may have therapeutic potential, but effective interventions remain to be determined. This study applies novel noninvasive brain stimulation techniques, namely phase-locked 40-Hz intermittent theta-burst stimulation (iTBS) and transcranial alternating current stimulation (tACS), and explores gamma oscillations and working memory changes. In 300 experimental sessions conducted on 30 participants, the effects of 40-Hz tACS, 40-Hz iTBS, two combined interventions (phase-locked iTBS to tACS peak sine wave or tACS trough sine wave), and a sham condition were explored. Gamma oscillatory activity (for 2 hours after intervention), working memory (3-back and 1-back load), and brain functional connectivity were monitored following each intervention. All stimulation protocols enhanced 40-Hz oscillatory power, with the iTBS-tACS Peak showing the most significant and stable increase, followed by 40-Hz tACS and 40-Hz iTBS. These stimulation protocols improved functional connectivity during the 30 minutes post-intervention while participants performed a memory task. Only the 40-Hz tACS and iTBS protocols enhanced high-load working memory speed. Concurrent, peak-synchronized 40 Hz iTBS combined with tACS and 40-Hz tACS may be a reliable protocol to induce long-lasting oscillatory activity in the gamma frequency range. These protocols may have therapeutic effects in patients with Alzheimers disease. | | 4:42a |
Rapid modulation of choice behavior by ultrasound on the human frontal eye fields
A fundamental challenge in neuroscience is establishing causal brain-function relationships with spatial and temporal precision. Transcranial ultrasonic stimulation (TUS) offers a unique opportunity to modulate deep brain structures non-invasively with high spatial resolution, but temporally precise effects and their neurophysiological foundations have yet to be demonstrated in humans. Here, we develop a temporally precise TUS protocol targeting the frontal eye fields (FEFs), a well-characterized circuit critical for saccadic eye movements. We demonstrate that TUS induces robust excitatory behavioral effects. Importantly, individual differences in baseline GABAergic inhibitory tone predict response magnitude. These findings establish TUS as a reliable tool for chronometric circuit interrogation and highlight the importance of neurophysiological state in neuromodulation. This work bridges human and animal research, advancing targeted TUS applications in neuroscience and clinical settings. | | 4:42a |
Subthreshold variability of neuronal populations driven by synchronous synaptic inputs
Even when driven by the same stimulus, neuronal responses are well-known to exhibit a striking level of spiking variability. In-vivo electrophysiological recordings also reveal a surprisingly large degree of variability at the subthreshold level. In prior work, we considered biophysically relevant neuronal models to account for the observed magnitude of membrane voltage fluctuations. We found that accounting for these fluctuations requires weak but nonzero synchrony in the spiking activity, in amount that are consistent with experimentally measured spiking correlations. Here we investigate whether such synchrony can explain additional statistical features of the measured neural activity, including neuronal voltage covariability and voltage skewness. Addressing this question involves conducting a generalized moment analysis of conductance-based neurons in response to input drives modeled as correlated jump processes. Technically, we perform such an analysis using fixed-point techniques from queuing theory that are applicable in the stationary regime of activity. We found that weak but nonzero synchrony can consistently explain the experimentally reported voltage covariance and skewness. This confirms the role of synchrony as a primary driver of cortical variability and supports that physiological neural activity emerges as a population-level phenomenon, especially in the spontaneous regime. | | 5:40a |
Deep-learning models of the ascending proprioceptive pathway are subject to illusions
Proprioception is essential for perception and action. Like any other sense, proprioception is also subject to illusions. In this study, we model classic proprioceptive illusions in which tendon vibrations lead to biases in estimating the state of the body. We investigate these illusions with task-driven models that have been trained to infer the state of the body from distributed sensory muscle spindle inputs (primary and secondary afferents). Recent work has shown that such models exhibit representations similar to the neural code along the ascending proprioceptive pathway. Importantly, we did not train the models on illusion experiments and simulated muscle-tendon vibrations by considering their effect on primary afferents. Our results demonstrate that task-driven models are indeed susceptible to proprioceptive illusions, with the magnitude of the illusion depending on the vibration frequency. This work illustrates that primary afferents alone are sufficient to account for these classic illusions and provides a foundation for future theory-driven experiments. | | 1:50p |
State-dependent relationship between lower and higher order networks in fMRI brain dynamics
Resting-state functional magnetic resonance imaging (fMRI) is a powerful tool for exploring the brain's functional organization. Functional connectivity (FC) is a commonly studied feature of fMRI data defined as the temporal correlation between activity patterns in pairs of brain regions. A major discovery of the past two decades of FC research has been the identification of consistent modular groupings in brain region time series correlations, commonly known as resting-state networks (RSNs). A second major discovery is the observation that RSNs in cortex are organized spatially along a functional/anatomical gradient. At one end of this gradient are 'lower order' networks (LONs), predominantly specialized for unimodal information processing. At the other end are 'higher order' networks (HONs), responsible for integrating multimodal information. Unlike the stable structural connectivity (SC) based on fixed anatomical links, FC fluctuates over time, and varies across brain regions. FC coordination within RSNs depends on SC, forming interconnected networks that regulate cognition, emotion, and behavior. The aim of the present study was to understand better how RSNs interact and communicate, based on their underlying SC. We used a whole-brain connectome-based neural mass modelling approach to study resting-state and task-based fMRI FC data. Following virtual SC lesions in the model, we characterized the FC changes within and between RSNs, and observed how these changes varied across different cognitive states. Our findings reveal how FC dynamics depend on underlying SC, highlighting the flexibility of these interactions across different brain states. LON lesions generally decrease FC within and between other LONs, and vice-versa for HON lesions. At rest, we observed a mutual antagonism between LONs and HONs, which was reversed during task conditions, with certain tasks increasing coordination between LONs and HONs. These results highlight the dynamic nature of brain network interactions, influenced by brain states and task demands. Our findings also have implications for clinical practice, offering insights into conditions such as brain tumors and stroke. | | 1:50p |
Registered Report: Replication and Extension of Nozaradan, Peretz, Missal and Mouraux (2011)
Cognitive neuroscience research has attempted to disentangle stimulus-driven processing from conscious perceptual processing for decades. Some prior evidence for neural processing of perceived musical beat (periodic pulse) may be confounded by stimulus-driven neural activity. However, one study used frequency tagging, which measures electrical brain activity at frequencies present in a stimulus, to show increased brain activity at imagery-related frequencies when listeners imagined a metrical pattern while listening to an isochronous auditory stimulus (Nozaradan et al., 2011) in a manner that controlled for stimulus factors. It is unclear though whether this represents repeatable evidence for conscious perception of beat and whether the effect is influenced by relevant music experience, such as music and dance training. This registered report details the results of 13 independent conceptual replications of Nozaradan et al. (2011), all using the same vetted protocol. Listeners performed the same imagery tasks as in Nozaradan et al. (2011), with the addition of a behavioral task on each trial to measure conscious perception. Meta-analyses examined the effect of imagery condition, revealing smaller raw effect sizes (Binary: 0.03 uV, Ternary: 0.03 uV) than in the original study (Binary: 0.12 uV, Ternary: 0.20 uV) with no moderating effects of music or dance training. The difference in estimated effects sizes (this study: n = 152, p2 =.03 - .04; 2011 study: n = 8, p2 =.62 - .76) suggests that large sample sizes may be required to reliably observe these effects, which challenges the use of frequency tagging as a method to study (neural correlates of) beat perception. Furthermore, a binary logistic regression on individual trials revealed that only neural activity at the stimulus frequency predicted performance on the imagery-related task; contrary to our hypothesis, the neural activity at the imagery-related frequency was not a significant predictor. We discuss possible explanations for discrepancies between these findings and the original study and implications of the extensions provided by this registered report. | | 3:46p |
Lifetime physical activity and network attack tolerance contribute to the preservation of motor function in Parkinson's disease
We tested whether network resilience, quantified by network attack tolerance (NAT), is associated with dopamine terminal (DaT) integrity, motor function and lifetime factors in Parkinson's disease (PD). Data from 22 PD patients and 39 healthy controls included information on lifetime physical activity (PA), cognitive/motor performance, putaminal DaT integrity, and resting-state fMRI. NAT was assessed at global and subnetwork level by calculating global efficiency upon iterative node removal. Generalized linear-mixed-effects models were used to test the effects of PA, education, and dopamine integrity on NAT. Next, the moderating effect of lifetime factors on the association between NAT and motor function were assessed, controlling for DaT integrity. Greater putaminal DaT integrity was linked to higher somatomotor NAT. Higher global and somatomotor NAT supported motor function, especially in patients with moderate lifetime PA. Lifestyle factors may thus serve network-specific attack tolerance, thereby promoting motor preservation in PD, independent of dopaminergic impairment. | | 8:46p |
17q21.31 locus regulates Parkinson's disease relevant pathways through KANSL1 activity
An inversion polymorphism at the 17q21.31 locus defines the H1 and H2 haplotypes, with the former linked to multiple neurodegenerative disorders, including an increased risk of Parkinson's disease (PD). Although the high linkage disequilibrium at this locus has made it difficult to decipher which gene(s) drive the PD association, there is increasing evidence to support the role of KANSL1 as a risk gene. KANSL1 has been shown to regulate the expression of some PD-associated genes and pathways, likely as part of the histone acetylating non-specific lethal (NSL) complex. Here for the first time, we studied the global effects of 17q21.31 haplotype variation using bulk and single-nuclear RNA-sequencing data from control and PD patient brain. We first analysed differential gene expression across haplotype groups, and then assessed the contribution of KANSL1 by comparing with the results of an siRNA knockdown in neuronal and glial human cell lines. We demonstrated that the PD risk-associated H1 haplotype downregulates autophagy, lysosomal and mitochondrial processes, all of which have already been implicated in PD aetiology. Furthermore, these effects were apparent in both neuronal and glial cell types, and in the case of the latter, appear to be associated with the modulation of innate and adaptive immune responses. Thus, we identify important links between NSL complex activity and PD pathophysiology that can be leveraged for novel therapeutic interventions. |
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