bioRxiv Subject Collection: Neuroscience's Journal
[Most Recent Entries]
[Calendar View]
Sunday, March 10th, 2024
| Time |
Event |
| 4:36a |
Engulfment of viable neurons by reactive microglia in prion diseases
Microglia are recognized as the main cells in the central nervous system responsible for phagocytosis. During brain development, microglia eliminate excessive synapses and neurons, whereas in normal aging and neurodegenerative diseases, microglia are responsible for clearing protein aggregates and cell debris. The current study demonstrates that in prion disease, microglia effectively phagocytose prions or PrPSc during early preclinical stages. However, during the late preclinical stage, a critical shift occurs in microglial activity from PrPSc uptake to the engulfment of neurons. This change occurs before the manifestation of clinical symptoms and is followed by a rapid accumulation of total PrPSc, suggesting a potential link to neuronal dysfunction and behavioral deficits. Surprisingly, the engulfed neurons do not show apoptotic markers, indicating that microglia are targeting viable neurons. Despite up to 40% of neurons being partially engulfed at the clinical stage, there is no significant neuronal loss, suggesting that many engulfment events are incomplete, terminated or protracted. This phenomenon of partial engulfment by reactive microglia is independent of the CD11b pathway, previously associated with phagocytosis of newborn neurons during neurodevelopment. The study establishes partial engulfment as a consistent occurrence across multiple prion-affected brain regions, various mouse-adapted strains, and different subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) in humans. The current work describes a new phenomenon of partial engulfment of neurons by reactive microglia, shedding light on a novel aspect of neuronal-microglia interactions. | | 6:17a |
Convolutional neural network models of the primate retina reveal adaptation to natural stimulus statistics
The diverse nature of visual environments demands that the retina, the first stage of the visual system, encodes a vast range of stimuli with various statistics. The retina adapts its computations to some specific features of the input, such as brightness, contrast or motion. However, it is less clear whether it also adapts to the statistics of natural scenes compared to white noise, the latter of which is often used to infer models of retinal computation. To address this question, we analyzed neural activity of retinal ganglion cells (RGCs) in response to both white noise and naturalistic movie stimuli. We performed a systematic comparative analysis of traditional linear-nonlinear (LN) and recent convolutional neural network (CNN) models and tested their generalization across stimulus domains. We found that no model type trained on one stimulus ensemble was able to accurately predict neural activity on the other, suggesting that retinal processing depends on the stimulus statistics. Under white noise stimulation, the receptive fields of the neurons were mostly lowpass, while under natural image statistics they exhibited a more pronounced surround resembling the whitening filters predicted by efficient coding. Together, hese results suggest that retinal processing dynamically adapts to the stimulus statistics. | | 8:16a |
An Entrainment Oscillator Mechanism underlies Human Beat Matching Performance
Humans possess an innate ability to effortlessly entrain to auditory rhythms, which previous theories have linked to the supplementary motor area (SMA). Yet, whether entrainment, as measured by electrophysiological (EEG) recordings reflects actual processing of rhythms or merely a reflection of their periodical nature, is unknown. Here we conducted tested human participants on a novel beat matching task, in which they listened to two simultaneous tempos and asked to modulate the rate of a variable tempo (1.67-2.34 Hz between trials) to match a constant target tempo (2 Hz). EEG recordings exhibited entrainment to both frequencies at frontocentral electrodes that shifted into alignment over the course of each trial Behaviorally, participants tended to anchor the matched tempo to the starting comparison frequency, such that they underestimated the tempo for slower initial conditions and overestimated for faster initial conditions; further, tempo judgments were shifted away from the variable tempo on the previous trial. A model of phase-coupled oscillators, in which both tempos were pulled towards one another, replicated both effects. This model further predicted that by strengthening the coupling strength of the constant tempo oscillator, both bias effects could be eliminated. To test this, a second group of subjects underwent transcranial alternating current stimulation (tACS) to the SMA phase-locked to the target tempo at 2 Hz. Consistent with model predictions, tACS attenuated both behavioral effects. Overall, these results provide causal support to the role of the SMA in entrainment during human beat matching. | | 11:46p |
Effects of age and dietary methionine restriction on cognitive and behavioural phenotypes in the rTg4510 model of frontotemporal dementia
Metabolic disorders such as diabetes and obesity are linked to neurodegenerative diseases, with evidence of decreased brain glucose metabolism and insulin resistance in patients with dementia. Given the rising prevalence of age-related diseases, lifestyle adjustments and nutritional interventions are gaining interest. Dietary methionine restriction (MR) is a nutritional intervention that enhances insulin sensitivity and delays ageing-associated metabolic alterations. Since the potential impact of MR on neurodegenerative diseases like dementia is not fully understood, we here examined the metabolic and behavioural phenotypes of a murine tauopathy model (rTg4510), which overexpresses human P301L mutated tau, and assessed the impact of an 8-week dietary MR. The rTg4510 mice and wild type (WT) littermates were assessed at 6 and 12 months of age. While rTg4510 mice displayed progressive behavioural and motor impairments at 6 and 12 months of age, MR led to significant benefits in the aged 12-month-old cohort, improving motor coordination and learning, short-term memory, and social recognition. These effects were accompanied by increased glycolysis in the hippocampus and higher FGF21 levels in the cortex. These benefits occurred in the absence of alterations in glucose metabolism/adiposity in this model. Overall, our results support the positive impact of MR on rTg4510 mice, suggesting this as a potential therapeutic intervention to delay and/or improve the progression in tau-related disease. | | 11:46p |
Microglia Depletion leads to Increased Susceptibility to Ocular Hypertension-Dependent Glaucoma
In recent years, microglia have been highlighted for playing integral roles in neurodegenerative diseases, like glaucoma. To better understand the role of microglia during chronic ocular hypertension, we depleted microglia from aged (9-12 months old) DBA/2J (D2) mice, which exhibit age-related increases in intraocular pressure, using a dietary CSF1R antagonist, PLX5622. Retinal ganglion cell (RGC) somas were counted, and optic nerve cross-sections stained and assessed for glaucomatous damage. Sustained administration of dietary PLX5622 significantly reduced the numbers of retinal microglia. Dietary PLX5622 did not lead to changes in intraocular pressure in D2 or normotensive DBA/2J-Gpnmb+ (D2-Gpnmb+) control mice. While PLX5622-treated D2-Gpnmb+ did not develop optic nerve damage, PLX5622-treated D2 mice showed a significant increase in moderate-to-severe optic nerve damage compared to D2 mice fed a control diet. In conclusion, global reduction of microglia exacerbated glaucomatous neurodegeneration in D2 mice suggesting microglia play an overall beneficial role in protecting from ocular hypertension associated RGC loss. | | 11:46p |
Modeling spatial contrast sensitivity in responses of primate retinal ganglion cells to natural movies
Retinal ganglion cells, the output neurons of the vertebrate retina, often display nonlinear summation of visual signals over their receptive fields. This creates sensitivity to spatial contrast, letting the cells respond to spatially structured visual stimuli, such as a contrast-reversing grating, even when no net change in overall illumination of the receptive field occurs. Yet, computational models of ganglion cell responses are often based on linear receptive fields. Nonlinear extensions, on the other hand, such as subunit models, which separate receptive fields into smaller, nonlinearly combined subfields, are often cumbersome to fit to experimental data, in particular when natural stimuli are considered. Previous work in the salamander retina has shown that sensitivity to spatial contrast in response to flashed images can be partly captured by a model that combines signals from the mean and variance of luminance signals inside the receptive field. Here, we extend this spatial contrast model for application to spatiotemporal stimulation and explore its performance on spiking responses that we recorded from retinas of marmosets under artificial and natural movies. We show how the model can be fitted to experimental data and that it outperforms common models with linear spatial integration, in particular for parasol ganglion cells. Finally, we use the model framework to infer the cells' spatial scale of nonlinear spatial integration and contrast sensitivity. Our work shows that the spatial contrast model provides a simple approach to capturing aspects of nonlinear spatial integration with only few free parameters, which can be used to assess the cells' functional properties under natural stimulation and which provides a simple-to-obtain benchmark for comparison with more detailed nonlinear encoding models. | | 11:46p |
Cannabinoid CB2 receptors in primary sensory neurons are implicated in CB2 agonist-mediated suppression of paclitaxel-induced neuropathic nociception and sexually-dimorphic sparing of morphine tolerance
Cannabinoid CB2 agonists show therapeutic efficacy without the unwanted side effects commonly associated with direct activation of CB1 receptors. The G protein-biased CB2 receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks the development of morphine tolerance in this model. However, the specific cell types involved in this phenomenon have never been investigated and whether this therapeutic profile is observed in female mice remains poorly understood. We used conditional deletion of CB2 receptors from specific cell populations to determine the population(s) mediating the anti-allodynic and morphine-sparing effects of CB2 agonists. Anti-allodynic effects of structurally distinct CB2 agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB2f/f mice of either sex. The anti-allodynic effect of the CB2 agonists were absent in conditional knockout (KO) mice lacking CB2 receptors in peripheral sensory neurons (AdvillinCRE/+; CB2f/f) but preserved in mice lacking CB2 receptors in CX3CR1 expressing microglia/macrophages (CX3CR1CRE/+; CB2f/f). The morphine-sparing effect of LY28282360 occurred in a sexually-dimorphic manner, being present in male mice but absent in female mice of any genotype. In mice with established paclitaxel-induced neuropathy, prior LY2828360 treatment (3 mg/kg per day i.p. x 12 days) blocked the subsequent development of morphine tolerance in male CB2f/f mice but was absent in male (or female) AdvillinCRE/+; CB2f/f mice. LY2828360-induced sparing of morphine tolerance was preserved in male CX3CR1CRE/+; CB2f/f mice, but this effect was not observed in female CX3CR1CRE/+; CB2f/f mice. Similarly, co-administration of morphine with a low dose of LY2828360 (0.1 mg/kg per day i.p. x 6 days) reversed tolerance to the anti-allodynic efficacy of morphine in paclitaxel-treated male CB2f/f mice, but this effect was absent in female CB2f/f mice and AdvillinCRE/+; CB2f/f mice of either sex. Additionally, LY2828360 (3 mg/kg per day i.p. x 8 days) delayed, but did not prevent, the development of paclitaxel-induced mechanical and cold allodynia in either CB2f/f or CX3CR1CRE/+; CB2f/f mice of either sex. Our studies reveal that CB2 receptors in primary sensory neurons are required for the anti-allodynic effects of CB2 agonists in a mouse model of paclitaxel-induced neuropathic nociception. We also find that CB2 agonists acting on primary sensory neurons produce a sexually-dimorphic sparing of morphine tolerance in males, but not female, paclitaxel-treated mice. | | 11:46p |
Sexual Dimorphism in Age-Dependent Neurodegeneration After Mild Head Trauma in Drosophila: Unveiling the Adverse Impact of Female Reproduction
Environmental insults, including mild head trauma, significantly increase the risk of neurodegeneration. However, it remains challenging to establish a causative connection between early-life exposure to mild head trauma and late-life emergence of neurodegenerative deficits, nor do we know how sex and age compound the outcome. Using a Drosophila model, we demonstrate that exposure to mild head trauma causes neurodegenerative conditions that emerge late in life and disproportionately affect females. Age-at-injury further exacerbates this effect in a sexually dimorphic manner. We further identify Sex Peptide (SP) signaling as a key factor in female susceptibility to post-injury brain deficits. RNA sequencing highlights changes in innate immune defense transcripts specifically in mated females during late life. Our findings establish a causal relationship between early head trauma and late-life neurodegeneration, emphasizing sex differences in injury response and the impact of age-at-injury. Finally, our findings reveal that reproductive signaling adversely impacts female response to mild head insults and elevates vulnerability to late-life neurodegeneration. |
|