Biology subjects

Huerta, P. T.

Publications and source records attributed to Huerta, P. T..

7 recordsLinked to original sources

bioRxiv2026

Cholinergic impairment in the dorsal motor nucleus of the vagus during experimental Alzheimer's disease

Cholinergic neurons in the dorsal motor nucleus of the vagus (DMN) in the brainstem are a key source of efferent vagus nerve fibers that regulate vital functions, including heart rate and inflammation. Whether the integrity of DMN cholinergic neurons is affected during Alzheimer's disease (AD) remains unknown. Here, in female and male mice with experimental AD (5xFAD), which exhibit age-dependent memory impairment, basal forebrain cholinergic neurodegeneration, and microglial alterations, we observe a reduction in cholinergic neuron density in the DMN at 6 and 10 months of age. Furthermore, while an important physiological function of DMN cholinergic signaling, such as suppression of heart rate, is preserved in control mice upon electrical DMN stimulation, the extent of suppression diminishes with age in both female and male 5xFAD mice. In addition, while electrical DMN stimulation lowers pro-inflammatory cytokine levels in control mice subjected to endotoxemia, this anti-inflammatory effect is diminished with age in 5xFAD mice, with females showing earlier dysfunction at 6 months. These results reveal previously unrecognized age-dependent cholinergic deficits in the DMN and disrupted brain - to - periphery vagus nerve circuits in experimental AD. These findings advance our understanding of AD mechanisms and are of interest for the development of conceptually novel therapies.

physiology↗

bioRxiv2025

Butyrate preserves entorhinal-hippocampal spatial coding and blood brain barrier integrity in mice with depleted gut microbiome

Given the widespread and increasing consumption of oral antibiotics globally, understanding their impact on cognition through the gut-brain axis is crucial. We investigated whether broad-spectrum antibiotics disrupt spatial cognition by altering behavior, neural dynamics, brain metabolism, and blood- brain barrier integrity. Here we show that male mice receiving antibiotic-treated water display significant impairments in spatial memory tasks and abnormal encoding of space by entorhinal grid cells and hippocampal place cells. These cognitive deficits are accompanied by altered brain metabolism and blood-brain barrier permeability in the hippocampal formation. Remarkably, supplementation with butyrate, a key microbiome-derived metabolite, preserves spatial cognition, neural dynamics, and blood-brain barrier function despite antibiotic treatment. These findings reveal that gut microbiome depletion disrupts the hippocampal-entorhinal network underlying spatial cognition, while suggesting butyrate supplementation as a potential therapeutic approach to mitigate antibiotic-induced cognitive impairments.

neuroscience↗

bioRxiv2025

AAV-mediated peripheral single chain variable fragments administration to reduce cerebral tau in adult P301S transgenic mice: mono- vs combination therapy

Tau is a primary target for immunotherapy in Alzheimers disease. Recent studies have shown the potential of anti-tau fragment antibodies in lowering pathological tau levels in vitro and in vivo. Here, we compared the effects of single-chain variable fragments (scFv) derived from the well-characterized monoclonal antibodies PHF1 and MC1. We used adeno-associated virus 1 (AAV1) to deliver scFvs to skeletal muscle cells in eight-week-old P301S tau transgenic mice. We evaluated motor and behavioral functions at 16 and 23 weeks of age and measured misfolded, soluble, oligomeric and insoluble brain tau species. Monotherapy with scFv-MC1 improved motor and behavioral functions more effectively than scFv-PHF1 or combination therapy. Brain glucose metabolism also benefited from scFv-MC1 treatment. Surprisingly, combining scFvs targeting early (MC1) and late (PHF1) tau modifications did not produce additive or synergistic effects. These results confirm that intramuscular AAV1-mediated scFv-MC1 gene therapy holds promise as a potential treatment for Alzheimers disease. Our findings also suggest that combining scFvs targeting different tau epitopes may not necessarily enhance efficacy if administered together in a prevention paradigm. Further research is needed to explore whether other antibodies combinations and/or administration schedules could improve the efficacy of scFv-MC1 alone. Graphical abstract/eTOC synopsisKatel and colleagues show that peripheral vectorized scFvMC1 (in monotherapy) reduces pathological tau species in tau transgenic mice more efficiently than in combination with scFv-PHF1. The authors observed improved motor and behavioral functions together with increased brain glucose metabolism in scFv-MC1-treated mice. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/638144v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@7edcccorg.highwire.dtl.DTLVardef@d1fc50org.highwire.dtl.DTLVardef@bf6f8org.highwire.dtl.DTLVardef@1832331_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Heterogeneity of anti-Caspr2 antibodies: specificity and pathogenicity

Maternal anti-Caspr2 (Contactin-associated protein-like 2) antibodies have been associated with increased risk for autism spectrum disorder (ASD). Previous studies have shown that in utero exposure to anti-Caspr2 antibodies results in a phenotype with ASD-like features in male mice. Here we ask whether four newly generated antibodies against Caspr2 are pathogenic to the developing fetal brain and whether they function through similar means. Our results show that the novel anti-Caspr2 antibodies recognize different epitopes of Caspr2. In utero exposure to these antibodies elicits differential ASD-like phenotypes in male offspring, tested in the social interaction, open field, and light-dark tasks. These results demonstrate variability in the antigenic specificity and pathogenicity of anti-Caspr2 antibodies which may have clinical implications.

immunology↗

bioRxiv2024

Intrinsic diving reflex induces potent antioxidative response by activation of NRF2 signaling

AimsThis study aims to elucidate the underlying mechanisms of diving reflex, a powerful endogenous mechanism supporting underwater mammalian survival. Antioxidative responses, observed in marine mammals, may be contributing factors. Using a multi-organ approach, this study assesses whether acute and chronic diving reflex activate nuclear factor-erythroid-2-related factor 2 (NRF2) signaling pathways, which regulate cellular antioxidant responses. MethodsMale Sprague-Dawley rats (n=38) underwent either a single diving session to elicit acute diving reflex, or daily diving sessions for 4-weeks to produce chronic diving reflex. NRF2 (total, nuclear, phosphorylated), NRF2-downstream genes, and malondialdehyde were assessed via Western blot, immunofluorescence, RT-PCR, and ELISA in brain, lung, kidney, and serum. ResultsDiving reflex increased nuclear NRF2, phosphorylated NRF2, and antioxidative gene expression, in an organ-specific and exposure time-specific manner. Comparing organs, the brain had the highest increase of phosphorylated NRF2 expression, while kidney had the highest degree of nuclear NRF2 expression. Comparing acute and chronic sessions, phosphorylated NRF2 increased the most with chronic diving reflex, but acute diving reflex had the highest antioxidative gene expression. Notably, calcitonin gene-related peptide appears to mediate diving reflex effects on NRF2 activation. ConclusionsAcute and chronic diving reflex activate potent NRF2 signaling in the brain and peripheral organs. Interestingly, acute diving reflex induces higher expression of downstream antioxidative genes compared to chronic diving reflex. This result contradicts previous assumptions requiring chronic exposure to diving for induction of antioxidative effects and implies that the diving reflex has a strong translational potential during preconditioning and postconditioning therapies. Key PointsO_LIDiving reflex activates potent NRF2 signaling via multiple mechanisms, including phosphorylation, nuclear translocation, and KEAP1 downregulation with both acute and chronic exposure. C_LIO_LIDiving reflex activates NRF2 via differential pathways in the brain and other organs; phosphorylated NRF2 increases more in the brain, while nuclear NRF2 increases more in the peripheral organs. C_LIO_LIAcute diving reflex exposure induces a more pronounced antioxidative effect than chronic diving reflex exposure, indicating that the antioxidative response activated by diving reflex is not dependent upon chronic adaptive responses and supports diving reflex as both a preconditioning and postconditioning treatment. C_LI

physiology↗

bioRxiv2020

Cortical dynamics underlying social behavior in dominance hierarchy and spatial navigation

Rodents establish dominance hierarchy as a social ranking system in which one subject acts as dominant over all the other subordinate individuals. Dominance hierarchy regulates food access and mating opportunities, but little is known of its significance in collective behavior, for instance during navigation for foraging or migration. Here, we implemented a simplified goal-directed spatial navigation task in mice and found that the social context exerts significant influence on individual decision-making, even when efficient navigation rules leading to reward had been previously learned. Thus, decision-making and consequent task performance were strongly dependent on contingent social interactions arising during collective navigation, yet their influence on individual behavior was outlined by dominance hierarchy. Dominant animals did not behave as leaders during navigation; conversely, they were most sensitive to social context. Social ranking in turn was reflected in the neural activity and connectivity patterns of the prefrontal cortex and hippocampus, both in anesthetized and behaving mice. These results suggest that the interplay between contingent social interactions and dominance hierarchy can regulate behavioral performance, supported by the intrinsic matrix of coordinated activity in the hippocampal-prefrontal circuit. Significance StatementDecision-making is shaped by intrinsic features, such as memory-stored information, and external influences, such as social interactions, yet their interplay is not well understood. We studied decision-making during collective behavior and found that instead of prioritizing memory-based pertinent information, mice shifted their individual decisions according to contingent social interactions arising in the social context. Conversely, constitutive social interactions, such as dominance hierarchy, were relevant to outline the effect of the social environment on individual behavior. Our results suggest that intrinsic hippocampal-cortical activity and connectivity patterns define social interactions. Hence, intrinsic cortical dynamics underlie behavioral performance during social decision-making.

neuroscience↗

bioRxiv2019

Lupus auto-antibodies act as positive allosteric modulators at NMDA receptors and induce spatial memory deficits

Patients with Systemic lupus erythematosus (SLE) experience various peripheral and central nervous system manifestations including spatial memory impairment. A subset of auto-antibodies (DNRAbs) cross-react with the GluN2A and GluN2B subunits of the NMDA receptor (NMDAR). We find that these DNRAbs act as positive allosteric modulators on NMDARs with GluN2A-containing NMDARs, even those containing a single GluN2A subunit, exhibiting a much greater sensitivity to DNRAbs than those with exclusively GluN2B. Accordingly, GluN2A-specific antagonists provide greater protection from DNRAb-mediated neuronal cell death than GluN2B antagonists. Using transgenic mice to perturb expression of either GluN2A or GluN2B in vivo, we find that DNRAb-mediated disruption of spatial memory characterized by early neuronal cell death and subsequent microglia-dependent pathologies requires GluN2A-containing NMDARs. Our results indicate that GluN2A-specific antagonists or negative allosteric modulators are strong candidates to treat SLE patients with nervous system dysfunction.

neuroscience↗