Biology subjects

Pedrosa, R.

Publications and source records attributed to Pedrosa, R..

7 recordsLinked to original sources

bioRxiv2025

Multi-modal choroid plexus pathology in aging and Alzheimer's disease

Brain barriers, cerebrospinal fluid (CSF) dynamics, and peripheral factors are implicated as significant contributors to Alzheimers disease (AD). The choroid plexus (ChP) is a blood-brain interface that produces CSF and forms the blood-CSF barrier. However, how ChP pathology develops across the lifespan and contributes to AD has not been systematically characterized. Here, we report a multi-modal ChP atlas integrating single-nucleus transcriptomics from 49 individuals, AI-assisted quantitative histopathology across >500 postmortem samples age 16 to 105, spatial transcriptomics, and functional studies in 5xFAD mice. We identify fibrosis, calcification, and macrophage abnormalities as hallmarks of ChP aging, with AD pathology conferring additional effects, including expansion of a pro-inflammatory fibroblast-macrophage signaling niche. In 5xFAD mice, macrophage dysfunction is associated with impaired epithelial barrier maintenance and repair. Together, these data provide a foundational resource for understanding ChP dysfunction in aging and AD and propose the macrophage-fibroblast-epithelial barrier axis as a driver of ChP pathology.

neuroscience↗

bioRxiv2025

Auditory regulation of hippocampal locomotion circuits by a non-canonical reticular-limbic pathway

The ability to rapidly detect and respond to unexpected auditory stimuli is critical for adaptive behavior, especially during locomotion. Since movement suppresses auditory cortical activity, it remains unclear how salient auditory information influences locomotor circuits. In this work, using in vivo calcium imaging, electrophysiology, chemo- and optogenetics, we investigate the path that relays loud broadband sounds to the dorsal hippocampus (dHPC) and modulates theta oscillations. We demonstrate that noise accelerates theta frequency and decreases its power, effects mediated by entorhinal cortex (EC) and medial septum (MS) inputs while independent of the primary auditory cortex. Activation of dorsal cochlear nucleus (DCN) neurons projecting to the pontine reticular nucleus (PRN) mimics noise-driven hippocampal responses, supporting a brainstem-limbic auditory processing route. Furthermore, noise selectively modulates CA1 pyramidal neuron and interneuron activity, reflecting diverse circuit dynamics. Finally, loud broadband noise stimulus increased theta coherence between the dHPC and the medial prefrontal cortex (mPFC), enhancing interregional synchronization. These results highlight the mechanisms in which the DCN filters behaviorally relevant sounds promoting acoustic motor integration in the hippocampus during locomotion, without direct influence of the auditory cortex.

neuroscience↗

bioRxiv2022

Hippocampal ripples coincide with ''up-state'' and cortical spindles in Retrosplenial Cortex

During NREM sleep hippocampal Sharp-wave ripples (SWR) events are thought to stabilize memory traces for long-term storage in downstream neocortical structures. Within the neocortex, Default Mode Network (DMN) areas interact preferentially with the hippocampus purportedly to consolidate those traces. Transient bouts of slow oscillations and sleep spindles in DMN areas are often observed around SWRs, suggesting that these two activities are related and that their interplay possibly contributes to memory consolidation. To investigate how SWRs interact with the DMN and spindles, we combined cortical wide-field voltage imaging, ECoG, and hippocampal LFP recordings in anesthetized and sleeping mice. Here we show that, during SWR, "up-states" and spindles reliably co-occur in a cortical subnetwork centered around the Retrosplenial cortex. Furthermore, Retrosplenial transient activations and spindles predict Slow Gamma oscillations in CA1 during SWRs. Together, our results suggest that Retrosplenial-hippocampal interaction may be a central source of information exchange between cortex and hippocampus.

neuroscience↗

bioRxiv2022

Hippocampal gamma and sharp wave/ripples mediate bidirectional interactions with cortical networks during sleep

Hippocampus-neocortex interactions during sleep are critical for memory processes: hippocampally-initiated replay contributes to memory consolidation in the neocortex and hippocampal sharp wave/ripples are linked to generalized increases in neocortical cell activity and DOWN-UP state transitions. Yet, the spatial and temporal patterns of this exchange are unknown. With voltage imaging, electrocorticography, and laminarly-resolved hippocampal potentials, we characterized cortico-hippocampal interactions during anesthesia and NREM sleep. We observed neocortical activation transients spanning multiple spatial scales hinting at a quasi-critical regime. Transients were organized in a small number of functional networks matching known anatomical connectivity. A network overlapping with the default mode network and centered on retrosplenial cortex was the most associated with the hippocampus. Interestingly, hippocampal slow gamma was the oscillation that best correlated with this neocortical network, outpacing ripples. In fact, neocortical activity predicted hippocampal slow gamma and followed ripples, suggesting that consolidation processes rely on bi-directional exchanges between hippocampus and neocortex.

neuroscience↗

bioRxiv2022

Hippocampal delta oscillations entrain neuronal activity, modulate gamma amplitude and convey information about running speed on a treadmill

Locomotion has long been associated with rhythmic oscillations in the rat hippocampus. Running speed and acceleration affect the spectral density at the theta (6-10 Hz) and gamma (30-150 Hz) bands and the rhythmic entrainment of neuronal activity. However, less is known about other oscillatory rhythms. Recent studies have shown that oscillatory activity in the delta (1-4 Hz) band also relates to locomotion in stationary conditions, such as running on a treadmill or in a running wheel. To further investigate the effects of stationary running on hippocampal oscillations, we recorded CA1 local field potentials and neuronal activity while rats ran at different speed protocols on a treadmill. We found a remarkable oscillatory activity at 2 Hz that was strongly modulated by running speed. Delta power and peak frequency were highest at the fastest running speed, both in constant and progressively increasing speed protocols. Delta and theta oscillations co-occurred and showed independent relationships in their instantaneous power and frequency. Moreover, the delta phase modulated the amplitude of low-gamma (20-50 Hz) oscillations and the spiking activity of putative pyramidal neurons in a speed-dependent manner. Finally, spectral components in the delta frequency range, but not theta, predicted running speed using a naive Bayes classifier. In summary, our study shows that locomotion-related delta oscillations convey information about stationary running speed and coordinate hippocampal rhythmic activity in a speed-dependent manner. Statement of significanceTheta and gamma oscillations are hallmarks of rhythmic activity in the rat hippocampus during locomotion and exploratory behaviors, but less is known about other oscillatory rhythms. This study shows the emergence of delta ([~]2 Hz) oscillations in the dorsal CA1 of rats running on a treadmill. Locomotion-related delta oscillations are independent of the concomitant theta activity and convey information about running speed. Delta waves modulate low-gamma oscillations and the spiking activity of pyramidal neurons in a speed-dependent way. These results suggest that oscillatory activity in the delta band aids rhythmic coordination during stationary locomotor behaviors.

neuroscience↗

bioRxiv2021

The Hybrid Drive: a chronic implant device combining tetrode arrays with silicon probes for layer-resolved ensemble electrophysiology in freely moving mice

Understanding the function of brain cortices requires simultaneous investigation at multiple spatial and temporal scales and to link neural activity to an animals behavior. A major challenge is to measure within- and across-layer information in actively behaving animals, in particular in mice that have become a major species in neuroscience due to an extensive genetic toolkit. Here we describe the Hybrid Drive, a new chronic implant for mice that combines tetrode arrays to record within-layer information with silicon probes to simultaneously measure across-layer information. The design of our device combines up to 14 tetrodes and 2 silicon probes, that can be arranged in custom arrays to generate unique areas-specific (and multi-area) layouts. We show that large numbers of neurons and layer-resolved local field potentials can be recorded from the same brain region across weeks without loss in electrophysiological signal quality. The drives lightweight structure ({approx} 3.5 g) leaves animal behavior largely unchanged during a variety of experimental paradigms. We demonstrate how the data collected with the Hybrid Drive allow state-of-the-art analysis in a series of experiments linking the spiking activity of CA1 pyramidal layer neurons to the oscillatory activity across hippocampal layers. Our new device fits a gap in the existing technology and increases the range and precision of questions that can be addressed about neural computations in freely behaving mice.

neuroscience↗

bioRxiv2020

Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed in many cancer types and in vivo studies have shown that vascular endothelial cell FAK expression and FAK-phosphorylation at tyrosine (Y) 397, and subsequently FAK-Y861, are important in tumour angiogenesis. Pericytes also play a vital role in regulating tumour blood vessel stabilisation, but the involvement of pericyte FAK-Y397 and FAK-Y861 phosphorylation in tumour blood vessels is unknown. Using Pdgfr{beta}Cre+;FAKWT/WT, Pdgfr{beta}Cre+;FAKY397F/Y397F and Pdgfr{beta}Cre+;FAKY861F/Y861F mice, our data demonstrate that tumour growth, tumour blood vessel density, blood vessel perfusion and pericyte coverage were affected only in late stage tumours in Pdgfr{beta}Cre+;FAKY861F/Y861F but not Pdgfr{beta}Cre+;FAKY397F/Y397F mice. Further examination indicates a dual role for pericyte FAK-Y861 phosphorylation in the regulation of tumour vessel regression and also in the control of a pericyte derived pericrine signals that influence apoptosis in cancer cells. Overall this study identifies the role of pericyte FAK-Y861 in the regulation of tumour vessel regression and tumour growth control and that non-phosphorylatable FAK-Y861F in pericytes reduces tumour growth and blood vessel density.

cancer biology↗