Biology subjects

Espinoza, D.

Publications and source records attributed to Espinoza, D..

4 recordsLinked to original sources

bioRxiv2026

Disruption of Pre-Bötzinger Complex neuropeptidergic tonality controls fear and metabolic response

Stress profoundly impacts systemic metabolism, yet the central circuits linking stress responses to peripheral metabolic regulation remain poorly defined. Here, we identify the preBotzinger complex (preBotC), a brainstem breathing rhythm generator, as a key stress-responsive hub coordinating metabolic adaptations. Using viral tracing, we show that preBotC neurons project to brown adipose tissue and liver, and that a subset of these projection neurons expresses the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor PAC1R, positioning PACAP signaling as a critical modulator of this circuit. Whole-brain c-Fos mapping revealed robust preBotC activation under stress, while spatial transcriptomics demonstrated altered neuronal metabolic circuitry in preBotC following PAC1R ablation. PAC1R knockdown in preBotC combined with stress resulted in blunted respiratory rhythmicity, reduced sympathetic innervation, and suppression of energy expenditure and lipid metabolic pathways in brown fat, while reprogramming hepatic transcriptional networks toward amino acid metabolism and gluconeogenesis. These findings define a unique neuropeptidergic brainstem-periphery circuit integrating stress, respiration, and metabolism. HighlightsO_LIPAC1R deletion in preBotC amplifies PTSD-like fear--greater generalization and freezing despite equal stress. C_LIO_LIPreBotC-PAC1R neurons send projections to BAT and liver, forming a respiratory-metabolic hub. C_LIO_LILoss of PAC1R lifts the preBotC "brake," raising resting breathing rate and magnifying stress-induced heart-rate spikes. C_LIO_LILoss of PAC1R show systemic metabolic failures--glucose intolerance, lower VO2 input, reduced energy expenditure, and weaker BAT sympathetic tone. C_LIO_LISpatial transcriptomics reveal marked shifts in preBotC neuronal subpopulations after PAC1R ablation. C_LI

neuroscience↗

bioRxiv2025

Nutrient excess remodels islet autonomic innervation via pancreatic schwann cells

Nutrient excess results in short- and long-term adaptations in the structure and function of metabolic organs, such as pancreatic islets. Pancreatic innervation contributes to islet architecture and function in many species, including humans, but little is known about its adaptation to over-nutrition. Here, we use 3D imaging to show that short-term high fat diet rapidly remodels islet sympathetic innervation while long-term high fat diet results in islet-specific cholinergic neuropathy. Using highly targeted, organ- and circuit-specific approaches, we demonstrate that remodeling of pancreatic innervation contributes to impaired glycemic control with short- and long-term nutrient excess. Counteracting the nutrient-induced changes in sympathetic and parasympathetic inputs to the pancreas using neuromodulation and repurposed FDA-approved approaches, we can significantly improve glycemic control even with long-term high fat diet. Finally, we identify islet Schwann cells as a source of the neurotrophic factor, S100b, contributing to rapid sympathetic hyperinnervation with short-term overnutrition. Our findings reveal novel adaptations in islet innervation contributing to nutrition-mediated metabolic dysfunction that can be ameliorated by targeting pancreatic neural circuits.

physiology↗

bioRxiv2021

Gene regulatory networks controlling temporal patterning, neurogenesis and cell fate specification in the mammalian retina.

Gene regulatory networks (GRNs), consisting of transcription factors and their target cis- regulatory sequences, control neurogenesis and cell fate specification in the developing central nervous system, but their organization is poorly characterized. In this study, we performed integrated single-cell RNA- and scATAC-seq analysis in both mouse and human retina to profile dynamic changes in gene expression, chromatin accessibility and transcription factor footprinting during retinal neurogenesis. We identified multiple interconnected, evolutionarily-conserved GRNs consisting of cell type-specific transcription factors that both activate expression of genes within their own network and often inhibit expression of genes in other networks. These GRNs control state transitions within primary retinal progenitors that underlie temporal patterning, regulate the transition from primary to neurogenic progenitors, and drive specification of each major retinal cell type. We confirmed the prediction of this analysis that the NFI transcription factors Nfia, Nfib, and Nfix selectively activate expression of genes that promote late-stage temporal identity in primary retinal progenitors. We also used GRNs to identify additional transcription factors that promote (Insm1/2) and inhibit (Tbx3, Tcf7l1/2) rod photoreceptor specification in postnatal retina. This study provides an inventory of cis- and trans-acting factors that control retinal development, identifies transcription factors that control the temporal identity of retinal progenitors and cell fate specification, and will potentially guide cell-based therapies aimed at replacing retinal neurons lost due to disease.

neuroscience↗

bioRxiv2019

Neuropilin 2 signaling mediates corticostriatal transmission, spine maintenance, and goal-directed learning in mice

The striatum represents the main input structure of the basal ganglia, receiving massive excitatory input from the cortex and the thalamus. The development and maintenance of cortical input to the striatum is crucial for all striatal function including many forms of sensorimotor integration, learning and action control. The molecular mechanisms regulating the development and maintenance of corticostriatal synaptic transmission are unclear. Here we show that the guidance cue, Semaphorin 3F and its receptor Neuropilin 2 (Nrp2), influence dendritic spine maintenance, corticostriatal short-term plasticity, and learning in adult male and female mice. We found that Nrp2 is enriched in adult layer V pyramidal neurons, corticostriatal terminals, and in developing and adult striatal spiny projection neurons (SPNs). Loss of Nrp2 increases SPN excitability and spine number, reduces short-term facilitation at corticostriatal synapses, and impairs goal-directed learning in an instrumental task. Acute deletion of Nrp2 selectively in adult layer V cortical neurons produces a similar increase in the number of dendritic spines and presynaptic modifications at the corticostriatal synapse in the Nrp2-/- mouse, but does not affect the intrinsic excitability of SPNs. Furthermore conditional loss of Nrp2 impairs sensorimotor learning on the accelerating rotarod without affecting goal-directed instrumental learning. Collectively, our results identify Nrp2 signaling as essential for the development and maintenance of the corticostriatal pathway and may shed novel insights on neurodevelopmental disorders linked to the corticostriatal pathway and semaphorin signaling.\n\nSignificance StatementThe corticostriatal pathway controls sensorimotor, learning and action control behaviors and its dysregulation is linked to neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here we demonstrate that neuropilin 2 (Nrp2), a receptor for the axon-guidance cue semaphorin 3F, has important and previously unappreciated functions in the development and adult maintenance of dendritic spines on striatal spiny projection neurons (SPNs), corticostriatal short-term plasticity, intrinsic physiological properties of SPNs and learning in mice. Our findings, coupled with Nrp2s association with ASD in human populations, suggest that Nrp2 may play an important role in ASD pathophysiology. Overall, our work demonstrates Nrp2 as a key regulator of corticostriatal development, maintenance and function, and may lead to better understanding of neurodevelopmental disease mechanisms.

neuroscience↗