Biology subjects

Snaidero, N.

Publications and source records attributed to Snaidero, N..

6 recordsLinked to original sources

bioRxiv2026

Deep Phenotyping with Global Brain Activity and Plasticity Mapping Identify the Dorsal Raphe-Basolateral Amygdala Circuit as a Mediator of Adaptive Stress Responses

Exposure to chronic environmental challenges triggers divergent behavioral trajectories across individuals. At the core, these different trajectories can be classified as individuals actively adapting to the challenges ("responders") and those displaying a rigid, non-responsive phenotype ("non-responders"). The brain system-wide network configurations that dictate why individuals diverge along these differential coping strategies, which can also lead to disease vulnerability or resilience, remain poorly understood. Here, we paired machine-learning-based deep behavioral phenotyping with multi-modal whole-brain imaging, integrating longitudinal Manganese-Enhanced MRI (MEMRI) and post-challenge cFOS mapping, to chart the functional landscape of individual stress trajectories in mice subjected to chronic social defeat stress. High-dimensional behavioral phenotyping revealed that active stress adaptation is a complex trajectory marked by latent, pre-stress kinetic signatures in vigilance-like and locomotive behaviors. At the neural level, longitudinal MEMRI captured distinct, consolidated activity reconfigurations across canonical valence and stress-regulatory circuits that segregated responders from non-responders. Complementary whole-brain cellular cFOS network analysis after an additional acute challenge revealed that non-responders exhibited marked hyper-modularity and network fragmentation, whereas responders feature a tightly integrated functional module co-clustering the periaqueductal gray, ventral tegmental area, basolateral amygdala (BLA), and dorsal raphe (DR). Notably, functional network connectivity along the DR-BLA axis was completely lost in non-responsive animals. Finally, pathway-specific chemogenetic inhibition of BLA-projecting DR neurons during a social challenge significantly attenuated social avoidance and reversed anxiety-like behavioral deficits, effectively shifting active behavioral adaptation toward a non-responsive phenotype. Together, these findings demonstrate that individual stress-coping strategies are driven by coordinated, system-wide reconfigurations of activity and plasticity, identifying the DR-BLA circuit as a critical gatekeeper of adaptive stress responses. Graphical AbstractGlobal neural functional alterations defining responding vs non-responding populations following chronic stress are understudied, yet crucial. Deep phenotyping followed by mapping brain-wide activity and plasticity changes identified these underlying divergent functional networks. Acute manipulation of a dorsal raphe - basolateral amygdala pathway ameliorated adaptive stress responses, highlighting the significance of this network-based approach. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/740522v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1850a04org.highwire.dtl.DTLVardef@1549284org.highwire.dtl.DTLVardef@15f3ebforg.highwire.dtl.DTLVardef@107ca9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Selective Cortical Myelination Reflects Axon-Driven Progression of the BCAS1-positive Oligodendrocyte Lineage

Myelination in the cerebral cortex is sparse, discontinuous, showing marked heterogeneity across cortical areas and along individual axons, yet the mechanisms that establish this complex and selective architecture remain unclear. Using histological mapping of oligodendrocyte lineage cells across cortical areas combined with longitudinal in vivo imaging, we find that initial myelination is highly targeted: up to 80 percent of the earliest segments arise consecutively along the same subset of axons. We observed that oligodendrocyte precursor cells enter a premyelinating BCAS1-positive state even within cortical regions that remain poorly myelinated or unmyelinated. However, the progression beyond early premyelinating morphologies correlates with local myelin levels and with interactions with specific neuronal partners. BCAS1-positive ensheathments show a preferential stabilisation and elongation along parvalbumin interneurons compared with somatostatin interneurons, linking regional neuronal composition to differential myelin levels. These findings indicate that cortical myelination emerges from intrinsic lineage programs that are refined through selective interactions with axons, thereby linking neuronal diversity to cortical myelin distribution and providing a framework to understand why remyelination may fail in regions where myelination supportive neuronal populations are reduced.

neuroscience↗

bioRxiv2026

Local demyelination rekindles oligodendrocyte precursor dynamics and remyelination in old age

Cortical myelination is critical for circuit function, plasticity, and long-term stability in the adult brain. With age and disease, the capacity to restore myelin after oligodendrocyte (OL) loss declines, and this failure is thought to reflect intrinsic limitations of OL precursor cells (OPCs) and a loss of permissive cues within the cortical environment. Here, using single-OL ablations and intravital imaging in mice, we show that as cortical remyelination efficiency declines, OPC motility declines, a phenomenon that can be mimicked by blocking CXCL12/CXCR4 signaling. Counter to prevailing notions, however, we find that even in aging, OPCs retain the capacity to generate new OLs and sheath axons, which can be rekindled by a graded demyelinating stimulus, inducing a more juvenile OPC motile state. This reveals an unrecognized remyelination potential in aging and identifies OPC dynamics as a key determinant of cortical remyelination, a property that could be targeted to improve myelin repair.

neuroscience↗

bioRxiv2019

Precision in a sea of profusion: Myelin replacement triggered by single-cell cortical demyelination

Myelin--rather than being a static insulator of axons--is emerging as an active participant in circuit plasticity. This requires precise regulation of oligodendrocyte numbers and myelination patterns. Here, by devising a laser ablation approach of single oligodendrocytes, followed by in vivo imaging and correlated ultrastructural reconstruction, we show that in mouse cortex demyelination as subtle as loss of a single oligodendrocyte can trigger robust cell replacement and remyelination timed by myelin breakdown. This results in reliable reestablishment of the original myelin pattern along continuously myelinated axons, while in parallel profuse isolated internodes emerge on previously unmyelinated axons. Thus, in mammalian cortex, internodes along partially myelinated cortical axons are typically not re-established, suggesting that the cues that guide patchy myelination are not preserved through cycles of de- and remyelination. In contrast, continuous obligatory myelin shows remarkable homeostatic resilience with single axon precision.

neuroscience↗

bioRxiv2019

Localized calcium accumulations prime synapses for phagocyte removal in cortical neuroinflammation

Cortical pathology contributes to chronic cognitive impairment of patients suffering from the neuroinflammatory disease multiple sclerosis (MS). How such gray matter inflammation affects neuronal structure and function is not well understood. Here we use functional and structural in vivo imaging in a mouse model of cortical MS to demonstrate that bouts of cortical inflammation disrupt cortical circuit activity coincident with a widespread but transient loss of dendritic spines. Spines destined for removal show a local calcium accumulation and are subsequently removed by invading macrophages and activated microglia. Targeting phagocyte activation with a new antagonist of the colony-stimulating factor 1 receptor prevents cortical synapse loss. Overall, our study identifies synapse loss as a key pathological feature of inflammatory gray matter lesions that is amenable to immunomodulatory therapy.\n\nHIGHLIGHTSO_LIWidespread, but transient loss of synapses in inflammatory lesions and beyond\nC_LIO_LIReversible impairment of neuronal firing and circuit function in the inflamed cortex\nC_LIO_LICalcium dyshomeostasis of single spines precedes swift synapse loss\nC_LIO_LIPhagocyte-mediated spine pruning as targetable mechanism of synapse loss\nC_LI

neuroscience↗

bioRxiv2018

Profound functional and molecular diversity of mitochondria revealed by cell type-specific profiling in vivo

Mitochondria vary in morphology and function in different tissues, however little is known about their molecular diversity among cell types. To investigate mitochondrial diversity in vivo, we developed an efficient protocol to isolate cell type-specific mitochondria based on a new MitoTag mouse. We profiled the mitochondrial proteome of three major neural cell types in cerebellum and identified a substantial number of differential mitochondrial markers for these cell types in mice and humans. Based on predictions from these proteomes, we demonstrate that astrocytic mitochondria metabolize long-chain fatty acids more efficiently than neurons. Moreover, we identified Rmdn3 as a major determinant of ER-mitochondria proximity in Purkinje cells. Our novel approach enables exploring mitochondrial diversity on the functional and molecular level in many in vivo contexts.

cell biology↗