Biology subjects

Malacon, K.

Publications and source records attributed to Malacon, K..

5 recordsLinked to original sources

bioRxiv2026

Juvenile influenza can impair myelin development and adult behavior through chemokine signaling in mice

Brain development, especially developmental myelination, continues through young adulthood. Concordantly, children may be particularly vulnerable to neural-immune challenges. To investigate the consequences of major childhood immune challenges, juvenile mice were exposed to respiratory influenza (H1N1) infection. White matter-specific microglial reactivity accompanied by oligodendrocyte loss was evident until two months following infection. Mice exhibited hyperlocomotion and impaired attention, but not anxiety-like behavior, at one month following infection. Linking the oligodendroglial and behavioral deficits, genetic disruption of oligodendrocyte development at the same juvenile timepoint recapitulated this behavioral phenotype. Microglial reactivity and oligodendrocyte numbers normalized by young adulthood. However, myelin development was disrupted, with persistently decreased myelinated axon density and reduced myelin sheath thickness. Hyperlocomotion resolved, but anxiety-related behaviors emerged at two months after infection. At 6 months, anxiety resolved but cognitive deficits persisted. Elevated CSF chemokines and microglial chemokine expression prompted testing the role of the multi-chemokine receptor CCR3. CCR3 inhibition rescued these cellular and behavioral aberrations after juvenile H1N1 infection. Together, these findings underscore the potential for disruption of myelin development and lasting cognitive and neuropsychiatric sequelae following major immune challenges during the juvenile period and highlight chemokine signaling as an important therapeutic target.

neuroscience↗

bioRxiv2025

Dysregulated Microglial Synaptic Engulfment in Diffuse Midline Glioma

Diffuse midline glioma (DMG) is a near-universally lethal form of pediatric high-grade glioma, driven by neuronal activity-regulated paracrine signaling and synaptic integration of malignant cells into neural circuits. In turn, DMG increases neuronal excitability, augmenting neuron-to-glioma signaling. In the healthy brain, microglia, the resident immune cells of the central nervous system (CNS), regulate neuronal excitability and synaptic connectivity. However, the role of microglia in promoting tumor-associated hyperexcitable neural networks in glioma remains unknown. Here, we investigate the activity-regulated engulfment of neuronal synapses by microglia in both healthy and glioma-bearing mice, and further explore how glioma cells alter microglia-mediated circuit refinement, contributing to pathogenic neuronal hyperexcitability. Microglia-mediated circuit refinement in the glioma microenvironment was characterized through synaptic engulfment analysis of both excitatory and inhibitory synapses by microglia in healthy mice and patient-derived DMG xenograft models, paired with optogenetic stimulation in the neocortex. We found that glutamatergic neuronal activity in the healthy brain increased excitatory synaptic engulfment by microglia in a previously unappreciated negative feedback mechanism that may guard against hyperexcitability. In contrast, this activity-regulated increase in excitatory synaptic engulfment was abrogated in DMG-infiltrated brains. Instead, inhibitory synaptic engulfment was significantly increased in DMG in response to glutamatergic neuronal activity. Together, these dysregulated synaptic engulfment mechanisms may create imbalance in the excitatory to inhibitory (E:I) synapse ratio predicted to increase neuronal excitability. Complementary single-nuclei sequencing studies revealed concordant tumor-specific, activity-regulated changes in microglia-neuron signaling showing reduced expression of excitatory synaptic refinement gene programs in microglia, potentially mediating the aberrant synaptic engulfment observed in DMG. These findings reveal novel cancer-neuron-immune interactions in DMG and provide an opportunity to potentially modulate tumor-associated neuronal hyperexcitability by targeting aberrant microglial synaptic engulfment. HIGHLIGHTSO_LIExcitatory synaptic engulfment by microglia increases in a glutamatergic neuronal activity-dependent manner in the healthy brain. C_LIO_LIIn the glioma-infiltrated brain, this feedback regulatory mechanism is inverted, with loss of activity-regulated excitatory synaptic engulfment and aberrant increased inhibitory synaptic engulfment. C_LIO_LITranscriptomic changes in glioma-associated microglia contribute to differential excitatory and inhibitory synaptic engulfment, with reduced excitatory synaptic refinement gene programs in tumor-associated microglia. C_LIO_LIActivity-regulated soluble factors drive this imbalanced excitatory-inhibitory postsynaptic engulfment by glioma-associated microglia. C_LI

neuroscience↗

bioRxiv2025

Neuroligin-3 interaction with CSPG4 regulates normal and malignant glial precursors through PIEZO1

Glioma pathophysiology is robustly regulated by interactions with neurons. Key to these interactions is the role of neuroligin-3 (NLGN3), a synaptic adhesion molecule shed in response to neuronal activity1-5 that functions as a paracrine factor crucial for glioma growth. Here, we elucidate the mechanistic pathway whereby shed NLGN3 interacts with glioma and their normal glial counterpart. NLGN3 interacts with Chondroitin Sulfate Proteoglycan 4 (CSPG4) on both glioma and healthy oligodendrocyte precursor cells (OPCs)6-9, facilitating CSPG4 shedding by ADAM10. NLGN3-CSPG4 interactions and consequent shedding alter membrane tension, thereby activating PIEZO1 mechanosensitive channels and causing membrane depolarization. The NLGN3-CSPG4-PIEZO1 axis maintains OPCs in an undifferentiated, stem-like state and promotes glioma proliferation, underscoring important functional roles for the NLGN3-CSPG4-PIEZO1 axis in both healthy and malignant glial precursors.

neuroscience↗

bioRxiv2022

Myelin plasticity in ventral tegmental area is required for opioid reward

All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance use disorders. Here, we demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by either optogenetic stimulation or by morphine administration specifically within the reward center ventral tegmental area (VTA), but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens (NAc). Genetic blockade of oligodendrogenesis dampens NAc dopamine release dynamics, which is critical for reward learning, and impairs behavioral conditioning to morphine. Our findings identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward. One-Sentence SummaryActivity-dependent myelin plasticity in the ventral tegmental area modulates dopaminergic circuit function and opioid reward

neuroscience↗

bioRxiv2020

Internal state configures olfactory behavior and early sensory processing in Drosophila larva

Animals exhibit different behavioral responses to the same sensory cue depending on their state at a given moment in time. How and where in the brain are sensory inputs combined with internal state information to select an appropriate behavior? Here we investigate how food deprivation affects olfactory behavior in Drosophila larvae. We find that certain odors reliably repel well-fed animals but attract food-deprived animals. We show that feeding state flexibly alters neural processing in the first olfactory center, the antennal lobe. Food deprivation differentially modulates two separate output pathways that are required for opposing behavioral responses. Uniglomerular projection neurons mediate odor attraction and show elevated odor-evoked activity in the food-deprived state. A multiglomerular projection neuron mediates odor aversion and receives odor-evoked inhibition in the food-deprived state. The switch between these two pathways is regulated by the lone serotonergic neuron in the antennal lobe, CSD. Our findings demonstrate how flexible behaviors can arise from state-dependent circuit dynamics in an early sensory processing center.

neuroscience↗