Biology subjects

Soria, G.

Publications and source records attributed to Soria, G..

10 recordsLinked to original sources

bioRxiv2025

Pre-amyloid cognitive intervention preserves brain function in aged TgF344-AD rats, maintaining connectivity and enhancing plasticity in a sex-specific manner

BackgroundAlzheimers disease is characterized by progressive cognitive decline and neurodegeneration, with cognitive reserve playing a key role in mitigating disease impact. Cognitive stimulation has been suggested as a non-pharmacological approach to enhance cognitive reserve and delay cognitive deterioration, but its underlying mechanism remains to be fully understood. This study investigates the effects of pre-amyloid cognitive intervention on brain connectivity, memory, synaptic plasticity and neuroinflammation in aged TgF344-AD rats, considering sex-specific differences. MethodsMale and female TgF344-AD and wild-type rats were assigned to trained and untrained groups, with cognitive stimulation administered through repetitive delayed nonmatch-to-sample tasks. Longitudinal magnetic resonance imaging acquisitions assessed training-induced changes in whole-brain functional connectomics and in particular entorhinal cortex connectivity. Memory was evaluated using the novel object recognition test. Cellular analysis of neurons (NeuN+, Parvalbumin+) and microglial cells, as well as molecular (PSD95, TrkB, p-RPS6, and VGLUT) analyses were conducted to determine the role of cognitive stimulation in modulating neuronal density, neuroinflammation and neuroplasticity. ResultsMale TgF344-AD rats undergoing prolonged cognitive stimulation had preserved global functional connectivity and exhibited improved recognition memory, compared to untrained animals, while TgF344-AD females did not follow this pattern. Entorhinal cortex connectivity was significantly loss in 19-month-old rats compared to wild-type rats and this was completely prevented by training. At a cellular level, cognitive stimulation significantly decreased the number of PV+ neurons in the dentate gyrus of trained rats. Moreover, a greater microglial density around A{beta} plaques and a less reactive phenotype was clearly observed at 11 in trained rats. These protective effects diminished by 19 months, coinciding with increased neuroinflammation and microglial dysfunction. At a molecular level, cognitive stimulation preserved PSD95 expression in male TgF344-AD and p-RPS6 in both sexes. ConclusionsPre-amyloid cognitive stimulation enhances synaptic plasticity, sustains brain network integrity, and modulates neuroinflammation, contributing to increased resilience against Alzheimers disease-related cognitive decline. In general, cognitive stimulation exerted a more protective effect in male TgF344-AD rats showing sex-dependent differences in pathology and cognitive reserve mechanisms. These findings highlight the importance of early cognitive engagement as a potential strategy to delay disease onset and underscore sex-specific differences in cognitive resilience mechanisms.

neuroscience↗

bioRxiv2024

Differential contribution of direct and indirect pathways from dorsolateral and dorsomedial striatum to motor symptoms in Huntington's disease mice

The alterations in the basal ganglia circuitry associated with motor symptoms in Huntingtons Disease (HD) have been extensively investigated. Yet, the specific contribution of the direct and indirect striatal output pathways from the dorsolateral (DLS) and dorsomedial striatum (DMS) to the motor dysfunction is still not fully understood. Here, using the symptomatic R6/1 male mouse model of HD, strong functional connectivity alterations between DMS and DLS regions with the rest of brain were observed by fMRI, particularly pronounced in the DLS. Then, we systematically evaluated how the selective optogenetic stimulation of the direct and indirect pathways from DLS and DMS influences locomotion, exploratory behavior, and motor learning. In wild type (WT) mice, optogenetic stimulation of the direct pathway from DLS and the indirect pathway from DMS elicited subtle locomotor enhancements, while exploratory behavior remained unaltered. Additionally, stimulation of the indirect pathway from DLS improved the performance in the accelerated rotarod task. In contrast, in HD mice, optogenetic stimulation of the distinct striatal pathways did not modulate these behaviors. Overall, this study points to deficits in the integration of neuronal activity in HD mice, while it contributes to deeper understanding of the complexity of motor control by the diverse striatal subcircuits.

neuroscience↗

bioRxiv2022

Inhibitors of ROCK kinases induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells

BRCA2-deficient cells are highly sensitive to poly-ADP-ribose polymerase inhibitors (PARPi) due to their impaired homologous recombination repair. This increased cytotoxicity is triggered by DNA replication stress induced by PARP trapping on DNA. Thus, it is broadly assumed that DNA damage is a prerequisite for BRCA2 synthetic lethality (SL). Here we show that inhibiting ROCK kinases in BRCA2 deficient cells, triggers SL independently from acute replication stress. In contrast, such SL is preceded by enhanced M-phase defects such as anaphase bridges, and abnormal mitotic figures, which were associated with multipolar spindles, supernumerary centrosomes and multinucleation. SL was also triggered by inhibiting Citron Rho-interacting kinase, another enzyme which, similarly to ROCK kinases, regulates cytokinesis. Together, these observations suggest cytokinesis failure as trigger of mitotic abnormalities and SL in BRCA2 cells. Furthermore, preventing mitotic entry by Early mitotic inhibitor 1 (EMI1) depletion promoted survival of BRCA2 deficient cells treated with inhibitors of ROCK kinases, thus reinforcing the association between M-phase and the cell death in BRCA2 deficient cells. This novel mechanism of SL induction is in contrast to the one triggered by PARPi and uncovers mitosis as an Achilles heel of BRCA2 deficient cells.

cancer biology↗

bioRxiv2022

Altered M2 Cortex - Superior Colliculus visual perception circuit in Huntington's Disease

The premotor cortical area -M2 cortex in rodents- connection to the striatum is involved in movement and prominently affected in Huntingtons Disease (HD). M2 cortex also projects to the superior colliculus (SC), implicated in oculomotor functions (i.e. saccades) and visual perception. Here, we investigated the contribution of M2 cortex - SC circuit to HD physiopathology in male mice. Using fMRI, we observed that M2 cortex functional connectivity with the SC was the most prominently affected circuit in the symptomatic R6/1 HD mouse model. Structural alterations were also detected by tractography and viral tracing. HD mice showed decreased defensive behavioral responses towards an unexpected visual stimuli, such as a moving robo-beetle, and decreased locomotion upon unexpected flash of light. Additionally, optogenetic M2 cortex - SC stimulation promoted avoidance responses towards the robo-beetle in WT, but not HD mice. Though, DWI measurements in vivo and ex vivo electrophysiological responses to optogenetic and electrical stimuli in the SC suggested preserved brain structure. Finally, GCamp6f fluorescence recordings with fiber photometry indicated that aberrant M2 cortex engagement might be the underlying mechanism of visual perception alterations in HD. Collectively, our findings point to a key role of M2 cortex - SC circuit alterations in HD pathophysiology.

neuroscience↗

bioRxiv2021

Auricular transcutaneous vagus nerve stimulation acutely modulates brain connectivity in mice

BackgroundBrain electrical stimulation techniques take advantage of the intrinsic plasticity of the nervous system, opening a wide range of therapeutic applications. Vagus nerve stimulation (VNS) is an approved adjuvant for drug-resistant epilepsy and depression. Its non-invasive form, auricular transcutaneous VNS (atVNS), is under investigation for applications, including cognitive improvement. ObjectiveWe aimed to study the effects of atVNS on brain connectivity, under conditions that improved memory persistence in CD-1 male mice. MethodsAcute atVNS in the cymba conchae of the left ear was performed using a standard stimulation protocol under light isoflurane anesthesia, immediately or 3 h after the training/familiarization phase of the novel object-recognition memory test (NORT). Another cohort of mice was used for bilateral c-Fos analysis after atVNS administration. Spearman correlation of c-Fos density between each pair of the thirty brain regions analyzed allowed obtaining the network of significant functional connections in stimulated and non-stimulated control brains. ResultsNORT performance was enhanced when atVNS was delivered just after, but not 3 h after, the familiarization phase of the task. No alterations in c-Fos density were associated to electrostimulation, but a significant effect of atVNS was observed on c-Fos-based functional connectivity. atVNS induced a clear reorganization of the network, increasing the inter-hemisphere connections and the connectivity of locus coeruleus. ConclusionOur results provide new insights in the effects of atVNS on memory performance and brain connectivity extending our knowledge of the biological mechanisms of bioelectronics in medicine. HighlightsO_LIatVNS, delivered immediately after NORT training phase, improves memory persistence C_LIO_LIatVNS did not promote significant changes in brain c-Fos density C_LIO_LIatVNS induced a significant reorganization of c-Fos-based functional brain network C_LIO_LIatVNS produced an enhancement in correlated activity between hemispheres C_LIO_LIatVNS did not engage the prefrontal-retrosplenial axis, characteristic of the DMN C_LI

neuroscience↗

bioRxiv2021

Shell shape as an indicator of phenotypic stocks of Tehuelche scallop (Aequipecten tehuelchus) in Northern Patagonia, Argentina

Tehuelche scallop, Aequipecten tehuelchus, is a commercially exploited species in Northern Patagonia, Argentina. Without genetic differentiation at the species level, A. tehuelchus presents three morphotypes: tehuelchus, madrynensis, and a non-common variant felipponei. The main goal of this study was to analyze the shell shape variation of Tehuelche scallop to differentiate and identify the phenotypic stocks. The shape differences between and within the two main morphotypes (tehuelchus and madrynensis) were assessed using geometric morphometrics in nine localities. The shell shape presented variability at geographic scale, with the morphologic traits that maximized the differentiation among localities between the tehuelchus and madrynensis morphotypes. Scallops from madrynensis morphotype presented higher and circular shell discs with smaller auricles than those from tehuelchus morphotype. Morphometric differentiation was also detected among localities of each morphotype, wherein most of the variability was related to the disc circularity and the symmetry of the auricles. The presence of morphologic variation in San Matias and San Jose gulfs, wherein a single genetic pool is shared, evidenced the plastic nature of the species. Given the distribution of this resource in distinct provincial jurisdictions, the differentiation of phenotypic stocks has relevance in the context of fishery management, especially if zoning and rotational strategies are implemented.

ecology↗

bioRxiv2021

Peripheral CB1 receptor blockade acts as a memory enhancer through an adrenergic-dependent mechanism

Peripheral inputs to the brain continuously shape its function and can influence the formation of non-emotional memory, but the underlying mechanisms have not been fully understood. Cannabinoid type-1 receptors (CB1R), widely distributed in the organism, is a well-recognized player in memory performance, and its systemic modulation significantly influences memory function. By assessing non-emotional memory in mice, we have now found a relevant role of peripheral CB1R in the formation of persistent memory. Indeed, peripherally restricted CB1R antagonism by using AM6545 showed a mnemonic effect that was occluded in adrenalectomized mice, after peripheral adrenergic blockade, or when vagus nerve was chemogenetically inhibited. Genetic CB1R deletion in dopamine {beta}-hydroxylase-expressing cells enhanced the formation of persistent memory, supporting a role of peripheral CB1R modulating the adrenergic tone. Notably, brain connectivity was affected by peripheral CB1R inhibition, and locus coeruleus activity and extracellular hippocampal norepinephrine, were increased. In agreement, intra-hippocampal {beta}-adrenergic blockade prevented AM6545 mnemonic effects. Together, we disclose a novel peripheral mechanism relevant for the modulation of the formation of persistent non-emotional memory.

neuroscience↗

bioRxiv2020

Loss of the RNA helicase Dhx15 impairs endothelial energy metabolism, lymphatic drainage and tumor metastasis in mice

DHX15 is an ATP-dependent RNA helicase involved in pre-mRNA splicing and a downstream substrate for Akt1, which plays a significant role in vascular biology. The aim of this study was to explore the regulatory function of DHX15 over the vasculature and endothelial cell biology. Results: DHX15-/- was lethal in mouse and zebrafish embryos. DHX15-/- zebrafish also showed an undeveloped parachordal line, which leads to the formation of lymphatic structures. DHX15+/- mice triggered lower vascular network density and impaired lymphatic function postnatally. Transcriptome and proteome analysis of DHX15 silenced LEC revealed alterations in the glycolysis and gluconeogenesis pathways. The validation of these results demonstrated an uncoupling of the glycolysis with the oxidation of pyruvate in the mitochondria and a lower activity of the Complex I, resulting in lower cellular ATP production. Noteworthy, DHX15+/- mice partially inhibited primary tumor growth and reduced lung metastasis after injection of LLC1 tumor cells.

cell biology↗

bioRxiv2020

M2 Cortex-Dorsolateral striatum stimulation reverses motor symptoms and synaptic deficits in Huntington's Disease

Huntingtons disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of basal ganglia. The cortex is the main striatal afference and progressive cortico-striatal disconnection characterizes HD. We mapped cortico-striatal dysfunction in HD mice to ultimately modulate the activity of selected cortico-striatal circuits to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo suggested prominent functional network deficits in fronto-striatal compared to motor-striatal pathways, which were accompanied by reduced glutamate levels in the striatum of HD mice. Moreover, optogenetically-stimulated glutamate release from fronto-striatal terminals was reduced in HD mice and electrophysiological responses in striatal neurons were blunted. Remarkably, repeated M2 Cortex-dorsolateral striatum optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that the selective stimulation of fronto-striatal pathways can become an effective therapeutic strategy in HD.

neuroscience↗

bioRxiv2019

Brain connectivity during Alzheimer’s disease progression and its cognitive impact in a transgenic rat model

The research of Alzheimers disease (AD) in their early stages and its progression till symptomatic onset is essential to understand the pathology and investigate new treatments. Animal models provide a helpful approach to this research, since they allow for controlled follow-up during the disease evolution. In this work, transgenic TgF344-AD rats were longitudinally evaluated starting at 6 months of age. Every 3 months, cognitive abilities were assessed by a memory-related task and magnetic resonance imaging (MRI) was acquired. Structural and functional brain networks were estimated and characterized by graph metrics to identify differences between the groups in connectivity, its evolution with age, and its influence on cognition. Structural networks of transgenic animals were altered since the earliest stage. Likewise, aging significantly affected network metrics in TgF344-AD, but not in the control group. In addition, while the structural brain network influenced cognitive outcome in transgenic animals, functional network impacted how control subjects performed. TgF344-AD brain network alterations were present from very early stages, difficult to identify in clinical research. Likewise, the characterization of aging in these animals, involving structural network reorganization and its effects on cognition, opens a window to evaluate new treatments for the disease. AUTHOR SUMMARYWe have applied magnetic resonance image based connectomics to characterize TgF344-AD rats, a transgenic model of Alzheimers disease (AD). This represents a highly translational approach, what is essential to investigate potential treatments. TgF344-AD animals were evaluated from early to advanced ages to describe alterations in brain connectivity and how brain networks are affected by age. Results showed that aging had a bigger impact in the structural connectivity of the TgF344-AD than in control animals, and that changes in the structural network, already observed at early ages, significantly influenced cognitive outcome of transgenic animals. Alterations in connectivity were similar to the described in AD human studies, and complement them providing insights into earlier stages and a plot of AD effects throughout the whole life span.

neuroscience↗