Biology subjects

Belo, J. A.

Publications and source records attributed to Belo, J. A..

3 recordsLinked to original sources

bioRxiv2026

Nasal inhalations and exhalations evoke distinct prefrontal-cortex responses with constant latency

Neuronal activity synchronous to breathing is salient across the mammalian brain. These modulations are typically characterized as oscillating signals phase-locked to the ongoing breathing rhythm and treated as evidence for respiratory entrainment of cortical and subcortical oscillations. Since activation of the olfactory circuitry has been identified as their preponderant source, we wondered whether respiratory brain signals could be better understood as sequences of evoked sensory potentials. To help distinguish between these scenarios, we set out to quantify the detailed alignment of prefrontal cortex local field potentials (LFPs) to the nasal airflow cycle across the natural repertoire of rat breathing. We found that, while LFP and breathing show salient synchrony for all breathing modes, the phase of their locking is a strict linear function of respiratory rate. We explain this by showing that LFPs align to nasal airflow with a constant time lag of 100 ms, irrespective of breathing rate. Segmenting by breathing cycles revealed that LFP peaks and fast-gamma bursts are time-locked to inhalations, while LFP troughs and slow-gamma activity time-lock to exhalations. Our results support the view that respiratory signals across the frontal brain of rodents are sensory potentials evoked by cyclic ortho- and retronasal airflow.

neuroscience↗

bioRxiv2025

ALDH1L1 links folic acid and retinoic acid to prevent neural tube defects

Folic acid (FA) supplementation during pregnancy is the commonly accepted treatment to prevent neurodevelopmental defects. The mechanism by which FA prevents neural tube defects (NTDs) remains unclear. FA also prevents other developmental malformations, including the alcohol-induced malformations in Fetal Alcohol Syndrome models. We show that FA acts through a metabolic link to retinoic acid (RA) signaling. Using a pax3-knockdown Xenopus model of FA-rescueable NTDs, we show that RA or its precursors equally rescue these defects. Similarly, FA rescues alcohol-induced NTDs in a model previously shown to be rescued by RA. We identify the FA-metabolizing enzyme, formyl tetrahydrofolate dehydrogenase (ALDH1L1, FTHFD), encoded by the aldh1l1 gene, as essential for this rescue. Mechanistically, FA upregulates aldh1l1 expression, leading to increased RA biosynthesis. Knockdown of the ALDH1L1 activity using CRISPR/Cas9 abolishes the FA protective effect. To support these observations, we show that the human ALDH1L1 enzyme converts retinaldehyde to RA, and its overexpression restores neural tube closure in aldh1l1-knockdown embryos when retinaldehyde is provided. At the cellular level, reduced RA signaling induces an overproliferation of neural plate precursors and a pathological expansion of the neural tube. ALDH1L1 enables FA to restore normal neural plate proliferation, thereby preventing NTDs. These findings establish ALDH1L1 as a previously unrecognized enzymatic link between FA (vitamin B9) and RA signaling, revealing how FA supplementation safeguards neural development and suggesting opportunities to refine strategies for NTD prevention. Significance StatementDespite the global success of folic acid (FA) supplementation in preventing neural tube defects (NTDs), the medical community continues to debate its exact mechanism, optimal dosage, and why it fails in some cases. This study provides a breakthrough by providing a mechanistic explanation linking FA supplementation and retinoic acid (RA) signaling. We identify the enzyme ALDH1L1 as the molecular bridge between FA and RA and demonstrate that FA protection is indirect, requiring ALDH1L1 to convert Vitamin A into RA. This discovery reframes the debate surrounding FA in the prevention of NTDs. Clinically, our findings suggest that integrating FA supplementation with optimized Vitamin A levels could improve current preventive practices and maximize neurodevelopmental safeguards during early pregnancy.

developmental biology↗

bioRxiv2024

Breathing modulates network activity in frontal brain regions during anxiety

Anxiety elicits various physiological responses, including changes in respiratory rate and neuronal activity within specific brain regions such as the medial prefrontal cortex (mPFC). Previous research suggests that the olfactory bulb (OB) modulates the mPFC through respiration-coupled neuronal oscillations (RCOs), which have been linked to fear-related freezing behavior. Nevertheless, the impact of breathing on frontal brain networks during other negative emotional responses, such as anxiety-related states characterized by higher breathing rates, remains unclear. To address this, we subjected rats to the elevated plus maze (EPM) paradigm while simultaneously recording respiration and local field potentials in the OB and mPFC. Our findings demonstrate distinct respiratory patterns during EPM exploration: slower breathing frequencies prevailed in the closed arms, whereas faster frequencies were observed in the open arms, independent of locomotor activity, indicating that anxiety-like states are associated with increased respiratory rates. Additionally, we identified RCOs at different frequencies, mirroring the bimodal distribution of respiratory frequencies. RCOs exhibited higher power during open arm exploration, when they showed greater coherence with breathing at faster frequencies. Furthermore, we confirmed that nasal respiration drives RCOs in frontal brain regions, and found a stronger effect during faster breathing. Interestingly, we observed that the frequency of prefrontal gamma oscillations modulated by respiration increased with heightened anxiety levels and breathing frequency. Overall, our study provides evidence for a significant influence of breathing on prefrontal cortex networks during anxious states, shedding light on the complex interplay between respiratory physiology and emotional processing. Significance StatementUnderstanding how breathing influences brain activity during anxious states could pave the way for novel therapeutic interventions targeting respiratory control to alleviate anxiety symptoms. Our study uncovers a crucial link between respiratory patterns and anxiety-related neural activity in the brain. By investigating the interplay between breathing, neuronal oscillations, and emotional states, we reveal that anxiety induces distinct respiratory patterns, with higher breathing rates correlating with anxious behavior. Importantly, we demonstrate that respiration drives oscillatory activity in the prefrontal cortex, and this effect is potentiated during the fast breathing associated with anxiety. Furthermore, the breathing cycle modulates the emergence of prefrontal gamma oscillations differentially across anxiety levels. This discovery sheds new light on the intricate relationship between respiratory physiology and emotional processing.

neuroscience↗