Biology subjects

Silva, B. A.

Publications and source records attributed to Silva, B. A..

5 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

The phosphodiesterase-5 inhibitor vardenafil reverses sleep deprivation-induced amnesia in mice

Sleep deprivation (SD) disrupts memory processes, particularly those dependent on the hippocampus. Six hours of SD after training in a hippocampus-dependent task typically induces amnesia in mice and impairs performance upon memory testing later. However, we previously demonstrated that object-location memories (OLMs) encoded under SD conditions can be recovered several days later, suggesting that these memories were not lost but suboptimally stored. Given that engrams of a specific memory are distributed across multiple functionally connected brain regions, we hypothesized that SD-induced amnesia arises from disrupted network alterations extending beyond the hippocampus. Consistent with this, brain-wide cFos mapping revealed a widespread reduction in cFos in memory associated regions during recall in SD mice and connectivity analysis identified the hippocampus as a central hub in this network. Since cGMP signaling modulates memory processes, we next tested whether the cGMP-specific PDE5 inhibitor vardenafil could restore access to these latent memories. One day after training, vardenafil reversed SD-induced OLM impairment when administered 30 minutes before testing, but this effect was lost when testing occurred several days later. To achieve persistent access to OLMs formed under SD conditions, we combined vardenafil treatment with optogenetic engram stimulation. This combined approach successfully maintained OLM retrievability for several days post-manipulation. Crucially, successful retrieval in these mice was associated with a significant increase in engram cell reactivation within the dorsal dentate gyrus compared to mice that failed to recall. Collectively, these findings provide novel insight into the molecular and network mechanisms underlying SD-induced amnesia and offer a strong rationale for developing targeted PDE5-mediated therapies to reverse SD-related memory deficits. HighlightsO_LISD-induced amnesia is associated with reduced cFos expression within memory-associative circuitry C_LIO_LIThe phosphodiestarase-5-inhibitor vardenafil can be used to restore memory access C_LIO_LICombining optogenetics with vardenafil treatment sustains memory retrieval over several days C_LIO_LISuccessful retrieval reflects increased reactivation of engram cells in the dentate gyrus C_LI

neuroscience↗

bioRxiv2024

ABBA, a novel tool for whole-brain mapping, reveals brain-wide differences in immediate early genes induction following learning

Unbiased characterization of whole-brain cytoarchitecture represents an invaluable tool for understanding brain function. For this, precise mapping of histological markers from 2D sections onto 3D brain atlases is pivotal. Here, we present two novel software tools facilitating this process: Aligning Big Brains and Atlases (ABBA), designed to streamline the precise and efficient registration of 2D sections to 3D reference atlases, and BraiAn, an integrated suite for multi-marker automated segmentation, whole-brain statistical analysis, and data visualisation. Combining these tools, we performed a comprehensive comparative study of the whole-brain expression of three of the most widely used immediate early genes (IEGs). Thanks to their neural activity-dependent expression, IEGs have been used for decades as a proxy of neural activity to generate unbiased mapping of activity following behaviour, but their respective induction in response to neuronal activation across the entire brain remains unclear. To address this question, we systematically compared the brain-wide expression cFos, Arc and NPAS4, three abundantly used IEGs, across three different behavioural conditions related to memory. Our results highlight major differences in both their distribution and induction patterns, indicating that they do not represent equivalent markers across brain areas or activity states, but can provide instead complementary information.

neuroscience↗

bioRxiv2019

Plasma Membrane Calcium Atpase downregulation in dopaminergic neurons alters cellular physiology and behavior in Drosophila melanogaster

Accumulation of calcium is proposed to account for selective dopaminergic neuron (DN) dysfunctionality, a characteristic of Parkinsons Disease (PD). To test the in vivo impact of calcium increment in DN physiology we downregulated the Plasma Membrane Calcium ATPase (PMCA), a bomb that extrudes cytosolic calcium, in those neurons in Drosophila melanogaster. Using th-GAL4>PMCARNAi, PMCA was selectively reduced, leading to increased cytosolic calcium and mitochondrial oxidative stress with no neurodegeneration. In the eye, PMCARNAi expression provoked a subtle disorganization, suggesting scarce toxicity. Interestingly, we observed several locomotor alterations and a higher level of dopamine in brains. Finally, flies presented a reduction of lifespan and a perimortem non-motor phenotype characterized by abdominal swelling, possibly due to constipation. We conclude that elevated cytosolic calcium in DN could trigger cellular dysfunction generating mitochondrial oxidative stress and motor and non-motor symptoms, typical of PD.

neuroscience↗

bioRxiv2018

Differential encoding of predator fear in the ventromedial hypothalamus and periaqueductal grey

The ventromedial hypothalamus is a central node of the mammalian predator defense network. Stimulation of this structure in rodents and primates elicits abrupt defensive responses, including flight, freezing, sympathetic activation, and panic, while inhibition reduces defensive responses to predators. The major efferent target of the ventromedial hypothalamus is the dorsal periaqueductal grey, and stimulation of this structure also elicits flight, freezing, and sympathetic activation. However, reversible inhibition experiments suggest that the ventromedial hypothalamus and periaqueductal grey play distinct roles in the control of defensive behavior, with the former proposed to encode an internal state necessary for the motivation of defensive responses, while the latter serves as a motor pattern initiator. Here we used electrophysiological recordings of single units in behaving mice exposed to a rat to investigate the encoding of predator fear in the dorsomedial division of the ventromedial hypothalamus and the dorsal periaqueductal grey. Distinct correlates of threat intensity and motor responses were found in both structures, suggesting a distributed encoding of sensory and motor features in the medial hypothalamic-brainstem instinctive network.

neuroscience↗