Biology subjects

Vila, M.

Publications and source records attributed to Vila, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Alpha-synuclein and neuromelanin converge to promote Parkinsons disease pathology

Parkinsons disease (PD) is defined by the preferential degeneration of neuromelanin (NM)-containing dopamine-producing neurons in the substantia nigra (SN), accompanied by intraneuronal inclusions rich in alpha-synuclein (aSYN). However, the mechanistic relationship between NM accumulation and aSYN pathology remains unclear. Here, we reveal a bidirectional pathogenic relationship between aSYN and NM. In human post-mortem midbrain tissue, ventral nigral neurons with high NM content display increased aSYN mRNA expression and are preferentially lost in PD. In a rat model that recapitulates age-dependent, human-like NM accumulation via targeted tyrosinase (TYR) expression, co-expression of aSYN accelerates NM buildup, enhances aSYN oligomerization, and aggravates nigrostriatal degeneration. Mechanistically, aSYN oligomerization in NM-producing rats decreases vesicular dopamine storage and impairs vesicle fusion with the plasma membrane, increasing cytosolic dopamine availability for oxidation into NM. Together, these findings support a pathogenic feedback loop in which elevated aSYN accelerates NM synthesis through disrupted dopamine compartmentalization, while NM accumulation further promotes aSYN aggregation and neuronal loss. This aSYN-NM axis may underlie the preferential vulnerability of pigmented nigral neurons in PD and provide a mechanistic framework for the development of future targeted therapeutics.

neuroscience↗

bioRxiv2026

Age-dependent brain pigmentation drives early neuroinflammatory molecular signatures linked to neurodegeneration

BackgroundNeuromelanin (NM) is a pigment that progressively accumulates with age in catecholaminergic neurons, particularly in the substantia nigra, ventral tegmental area, and locus coeruleus. These neuronal populations are especially vulnerable to degeneration in Parkinsons disease (PD). Elevated intracellular NM levels have been linked to neurodegeneration and PD-like phenotypes in experimental models. However, the molecular mechanisms underlying NM-induced pathology remain poorly understood, as human studies cannot disentangle the specific effects of NM accumulation from those of normal aging. MethodsWe performed transcriptomic microarray analysis on laser-captured catecholaminergic neurons and regions (substantia nigra, ventral tegmental area, locus coeruleus) from NM-producing transgenic mice (tgNM) and NM-free wild-type controls across different ages, and compared them to data from postmortem human brain tissue. One of the molecular targets identified, GPNMB, was validated in mouse and human tissue, and functionally tested in vivo. ResultsWe identified region- and age-dependent transcriptional changes associated with progressive NM accumulation. NM consistently upregulated neuroinflammatory pathways with enrichment of disease-associated microglial genes, while downregulating transcription, translation, and mitochondrial functions. Locus coeruleus exhibited the earliest and strongest transcriptional alterations, whereas substantia nigra and ventral tegmental area showed a later-onset, age-progressive transcriptional dysfunction. Neuron-specific analyses revealed that many changes originated within NM-containing neurons rather than being solely glial-driven. NM-driven transcriptional profiles in mice strongly correlated with postmortem data from PD patients, underscoring their translational relevance. Among molecular targets, the glycoprotein GPNMB was consistently upregulated in NM-containing neurons and validated at RNA and protein levels in both NM-producing transgenic mice and human PD brains. Functional experiments demonstrated that GPNMB overexpression attenuated NM-linked dopaminergic neurodegeneration and improved motor performance in mice. ConclusionThis study provides a comprehensive in vivo characterization of NM-specific transcriptomic changes in catecholaminergic neurons, showing that NM accumulation drives neuroinflammatory and neurodegenerative programs. Our results support that the neuroinflammatory changes observed in tgNM mice and in human PD represent early pathological events that precede overt neurodegeneration. The disease-associated gene GPNMB emerged as a conserved NM-induced factor with protective properties, highlighting its potential as a therapeutic target in PD and aging-related neurodegeneration.

neuroscience↗

bioRxiv2026

Repertoire-wide contextual mapping reveals signal functions in cooperatively breeding crows

Communication structures society, and is likewise shaped by relationships and shared tasks; yet, for most socially complex species, we know little of their full vocal repertoire and its functions. We investigated how communication structures the who, what, and when of social interactions in cooperative carrion crows - group-living birds who rely on coordinated behaviors, as in chick care. Leveraging machine learning to integrate large-scale data from crow-borne audio-loggers and nest cameras, we charted the vocal repertoire across 24 cooperative groups and mapped all discovered call types to behaviors and social context. We found that crows used a rich repertoire across three domains of joint behavior - flocking, chick care, and territorial display. Relatively quiet call types were abundant and included close-range calls that may coordinate chick care by announcing nest visits. Our study demonstrates how combining continuous-capture data and machine learning can reveal a holistic understanding of how vocalizations function across contexts.

animal behavior and cognition↗

bioRxiv2026

Genetic erosion and projected habitat loss in the protected Alpine moth Actias isabellae galliaegloria (Lepidoptera: Saturniidae)

O_LIMontane and specialist insects are particularly vulnerable to habitat loss and climate change. The Spanish Moon Moth (Actias isabellae), a rare and protected species, hosts an isolated Alpine population (subspecies galliaegloria) whose conservation status remains unclear. C_LIO_LIWe combined Restriction-site Associated DNA sequencing (RADseq) and Ecological Niche Modelling (ENM) to assess its genetic diversity, population structure, and environmental vulnerability. C_LIO_LIGenomic analyses revealed extremely low genetic diversity and inbreeding in the Alpine subspecies, consistent with a historical bottleneck, reducing adaptive potential. C_LIO_LISpecies distribution models predict a major contraction of suitable habitat by 2050 due to rising temperatures and declines in its primary host, Scots pine (Pinus sylvestris). C_LIO_LIThese findings highlight the compounded risks posed by genetic impoverishment and habitat loss, emphasizing the urgent need for targeted conservation measures. C_LIO_LIOur study demonstrates the value of integrating genomic and ecological approaches to evaluate extinction risk and guide management strategies for montane specialist insects under rapid environmental change. C_LI

evolutionary biology↗

bioRxiv2026

A VTA-pontine GABA pathway biases backward locomotion via local and distal inhibition

Locomotor direction in mammals is implemented by descending circuits, yet how midbrain selection systems bias directional motor output remains unclear. Here we define a projection-defined inhibitory pathway from the ventral tegmental area to the oral pontine reticular nucleus (VTAPnO) whose activation is sufficient to drive backward locomotion. These TH- VTA neurons form monosynaptic GABAA synapses locally while projecting to PnO, establishing a dual local-projection inhibitory architecture. Somatic activation reliably induced backward locomotion, and selective stimulation of VTAPnO terminals reproduced the effect. Pathway recruitment produced a rapid transient increase in dopaminergic single-unit activity and frequency-dependent increases in dopaminergic population calcium signals in awake mice. During forced locomotion, chronically recorded VTAPnO neurons were preferentially engaged during reverse compared to forward rotations. Together, these findings reveal a projection-defined midbrain pathway that biases locomotor direction through coordinated local inhibition and distal engagement of a brainstem premotor node.

neuroscience↗

bioRxiv2025

Introducing PIGMO, a novel PIGmented MOuse model of Parkinson's disease (V1)

There is a pressing need for the development, characterization, and standardization of animal models of Parkinsons disease (PD) that properly mimic the cardinal features of this disorder, comprising both the motor phenotype and neuropathological signatures. In the past few years, animal modeling has moved from neurotoxin-based approaches toward viral vectors carrying a given genetic payload of interest. Here, to induce pigmentation of the mouse brain upon systemic delivery, we took advantage of a modified adeno-associated viral vector capsid engineered to bypass the blood-brain barrier and coding for the human tyrosinase gene (AAV9-P31-hTyr). Obtained results revealed an ongoing pigmentation of catecholaminergic centers related to the pathophysiology of PD, such as the substantia nigra pars compacta, ventral tegmental area, and locus coeruleus. Moreover, pigmented dopaminergic neurons exhibited Lewy body-like intracytoplasmic inclusions, a progressive nigrostriatal degeneration, and a time-dependent PD motor phenotype. The bilateral pigmented mouse model of PD generated this way is highly reproducible, does not require stereotaxic surgery for viral vector deliveries, and opens unprecedented possibilities for preclinical testing of therapeutic candidates designed to reduce disease progression rates.

neuroscience↗

bioRxiv2025

Sex-dimorphic effects of neuromelanin buildup in rodent nigral dopamine neurons: implications for sex-biased vulnerability in Parkinson's disease

Neuromelanin (NM) is a dark pigment accumulating with age in human substantia nigra pars compacta (SNpc) dopamine (DA) neurons, conferring the dark look that inspired nigral areas name. Despite NM has long been associated with Parkinsons disease (PD), as melanized neurons favorably degenerate during disease development, NM functions within SNpc DA neurons are still mostly elusive. Here, by exploiting an NM-producing rat model generated by viral vector-induced expression of human Tyrosinase (hTyr), we inspected NM impact on nigral DA neurons survival and activity, on mitochondrial functionality of SNpc, and behaviors resembling non-motor and motor PD symptoms. Our data reveal sex dimorphism in NM effects on nigrostriatal dopamine circuit, with sex-biased alterations in neuronal firing activity and underlying intrinsic currents, nigral mitochondrial functions, and non-motor PD symptoms (anxiety). In conclusion, this study discloses unrealized NM effects within nigral DA neurons, advancing our comprehension of sex-specific features shaping sex-biased vulnerability to PD.

neuroscience↗

bioRxiv2025

Standardised TruAI automated quantification of intracellular neuromelanin granules in human brain tissue sections

AimsTo standardise and automate the quantitation of human-unique neuromelanin granules in catecholamine neurons in post-mortem tissue sections from healthy individuals at different ages to understand any changes in these granules with age. Methods5-6 {micro}m-thick fixed and paraffin-embedded transverse midbrain tissue sections were supplied from 47 cases from three brain banks following ethical approvals. Sections were prepared and automated digital images acquired. Standardisation and automation of the quantification of neuromelanin granules was performed using the TruAI feature of the Olympus VS200 desktop platform. Comparisons between stained and unstained sections as well as correlations with age were performed. ResultsThe automated platform reliably identified both stained and unstained intracellular neuromelanin granules and extracellular pigments, showing high reproducibility in measurements across laboratories using different tissue processing methods. Extraneuronal pigments were significantly smaller than intracellular neuromelanin granules. Sections processed for haematoxylin and eosin staining impacted the size and colour of both neuromelanin and the neurons containing neuromelanin. Haematoxylin made neuromelanin bluer, and the increased tissue processing made the intracellular area occupied by neuromelanin smaller in younger people. There was an increase in neuromelanin optical density and colour change (browner) with age. ConclusionsThe TruAI automated platform reliably quantifies individual neuromelanin granules in catecholamine neurons. Extraneuronal pigments are considerably smaller in size than intracellular neuromelanin, and intracellular neuromelanin changes its properties with age. The darkening and colour change of intracellular neuromelanin suggests an increase in eumelanin over time in healthy individuals. These changes can be reliably identified using the automated platform. Key pointsO_LIStandardised, reliable TruAI automated quantitation of intracellular neuromelanin granules in human brain sections gives novel insights into their structure and function C_LIO_LIExtraneuronal pigments, including neuromelanin granules released from dying pigmented neurons, are significantly smaller than intracellular neuromelanin granules C_LIO_LIIntracellular neuromelanin granules change their properties with healthy ageing becoming darker, consistent with more antioxidant eumelanin C_LI

neuroscience↗

bioRxiv2025

ERGA-BGE genome of Erebia palarica Chapman, 1905: a montane butterfly endemic to North-West Iberia

The reference genome of Erebia palarica will provide valuable insights into evolutionary and conservation genomics. On one hand, the reference genome paves the way to unravel the speciation process, reproductive barriers, and putative hybridisation of E. palarica with its closely related sister species: Erebica meolans. On the other hand, the reference genome will play an important role in the genetic monitoring of this endemic species, facilitating the use of genomics to estimate population genomics parameters. The genome was assembled into 14 contiguous chromosomal pseudomolecules (Z chromosome included). This chromosome-level assembly encompasses 0.49 Gb, composed of 38 contigs and 17 scaffolds, with contig and scaffold N50 values of 34.2 Mb and 38.4 Mb, respectively.

genomics↗

bioRxiv2025

ERGA-BGE genome of the Spanish Moon Moth Graellsia isabellae Graells, 1849: a nocturnal lepidopteran protected by the Habitats Directive

The reference genome of the Spanish Moon Moth, Graellsia isabellae, will be of great importance for evolutionary and conservation genomics. Firstly, this reference genome, alongside phylogenomic analyses, may finally resolve the longstanding debate regarding the scientific name of this iconic species--whether it should be Graellsia isabellae (Graells, 1849) or Actias isabellae (Graells, 1849). Secondly, the reference genome will be instrumental in the genetic monitoring of this protected species, enabling advanced methods to calculate contemporary population genomics estimates. The genome was assembled into 31 contiguous chromosomal pseudomolecules (Z chromosome included). The mitochondrial genome has also been assembled and is 15,247 bp in length. This chromosome-level assembly encompasses 0.56 Gb, composed of 38 contigs and 32 scaffolds, with contig and scaffold N50 values of 18.9 Mb and 20.4 Mb, respectively.

genomics↗

bioRxiv2024

Longitudinal neuromelanin changes in prodromal and early Parkinson's disease in humans and rat model

Studies in animal models of Parkinsons disease (PD) suggested that the accumulation of the neuromelanin (NM), a pigment contained in nigral dopaminergic neurons, could trigger neurodegeneration above a pathogenic threshold. Here we investigated this hypothesis using NM-sensitive MRI in rodents and in patients with isolated rapid eye movement sleep disorders (iRBD) subjects, a prodromal phase of parkinsonism, and early PD. We first combined NM-sensitive MRI and histology to study NM accumulation and neurodegeneration in a humanized rat model of PD. NM-MRI signal changes were biphasic with an initial increase due to the accumulation of NM in dopaminergic neurons, followed signal decrease due to neurodegeneration. In healthy subjects and patients with iRBD, NM-MRI signal increased initially and then decreased similarly as in rodents after reaching a similar maximum signal intensity in both groups. In early PD and converted iRBD patients, NM-MRI signal drop was greater than in healthy individuals. Results in animals and humans show that NM-sensitive MRI is a marker of the intracellular NM accumulation up to a threshold then of neuronal degeneration beyond this threshold and agree with the hypothesis of a pathogenic threshold of NM triggering neurodegeneration.

neuroscience↗

bioRxiv2024

LRRK2-mutant microglia trigger dopaminergic neurodegeneration when activated by neuromelanin

Parkinsons disease (PD) is a progressive, incurable neurodegenerative disorder characterized by the loss of neuromelanin (NM)-containing dopamine neurons (DAn) in the substantia nigra of the midbrain. Non-neuronal cells are increasingly recognized as contributors to PD. We generated human microglia-like cells (hMG) from induced pluripotent stem cells (iPSC) derived from patients with LRRK2 PD-causing mutations, gene-corrected isogenic controls, and healthy donors. While neither genotype induced neurodegeneration in healthy DAn, LRRK2 hMG become hyperreactive to LPS stimulation, exhibiting increased cytokine expression, reactive oxygen species, and phagocytosis. When exposed to NM-containing particles, but not -synuclein fibrils, LRRK2 hMG trigger DAn degeneration, in a process that is prevented by pre-treatment with the immunomodulatory drug ivermectin. Finally, post-mortem analysis of midbrain tissue of LRRK2-PD patients show increased microglia activation around NM-containing neurons, confirming our in vitro findings. Overall, our work highlights NM-activated microglias role in PD progression, and provides a model for testing therapeutic targets.

cell biology↗

bioRxiv2024

Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh Syndrome

Deficits in the mitochondrial energy-generating machinery cause mitochondrial disease (MD), a group of untreatable and usually fatal disorders. Among many severe symptoms, refractory epileptic events are a common neurological presentation of MD. However, the neuronal substrates and circuits for MD-induced epilepsy remain unclear. Here, using mouse models of mitochondrial epilepsy that lack mitochondrial complex I subunit NDUFS4 in a constitutive or conditional manner, we demonstrate that mitochondrial dysfunction leads to a reduction in the number of GABAergic neurons in the rostral external globus pallidus (GPe) and identify a specific affectation of pallidal Lhx6-expressing inhibitory neurons. Our findings further reveal that viral vector-mediated Ndufs4 re-expression in the GPe effectively prevents seizures and improves the survival in the models. Additionally, we highlight the subthalamic nucleus (STN) as a critical structure in the neural circuit involved in mitochondrial epilepsy, as its inhibition effectively reduces epileptic events. Thus, we have identified a novel role for pallido-subthalamic projections in the development of epilepsy in the context of mitochondrial dysfunction. Our results suggest STN inhibition as a potential therapeutic intervention for refractory epilepsy in patients with MD providing new leads in the quest to identify novel and effective treatments.

neuroscience↗

bioRxiv2023

Non-ablative disease-modifying effects of magnetic resonance-guided focused ultrasound in neuromelanin-producing parkinsonian rodents

Age-dependent accumulation of the brain pigment neuromelanin has been implicated in the pathogenesis of Parkinsons disease (PD). In humans, intracellular and extracellular neuromelanin levels are increased in PD postmortem brains and boosting neuromelanin production in rodents compromises neuronal function and viability and triggers a PD-like phenotype. Focused ultrasound has been shown to reduce ultraviolet light-induced skin hyperpigmentation in guinea pig and to remove brain extracellular {beta}-amyloid plaques in Alzheimers mouse models. Here we show that repeated application of transcranial focused ultrasound (tFUS) is able to decrease intracellular and extracellular neuromelanin levels in neuromelanin-producing parkinsonian rats, compared to sham-treated animals, without the need for any additional therapeutic agent or intervention. Reduced neuromelanin levels in tFUS-treated animals were associated with decreased Lewy-like pathology, preserved dopaminergic phenotype, attenuated nigrostriatal degeneration, reduced glial activation, and long-term recovery of motor function. Our findings indicate that tFUS treatment applied at prodromal/early disease stages provides by itself extended structural and functional preservation of the nigrostriatal pathway in neuromelanin-producing parkinsonian rats without causing overt neuronal damage. This FDA-approved technology should thus be explored further as a noninvasive method with neuroprotective potential in PD and to maintain neuromelanin to levels below its pathogenic threshold within the aging population. One Sentence SummaryTranscranial focused ultrasound reduces age-dependent neuromelanin accumulation and provides therapeutic benefit in parkinsonian rats

neuroscience↗

bioRxiv2023

Modelling human brain-wide pigmentation in rodents recapitulates age-related multisystem neurodegenerative deficits

One key limitation in developing effective treatments for neurodegenerative diseases is the lack of models accurately mimicking the complex physiopathology of the human disease. Humans accumulate with age the pigment neuromelanin inside neurons that synthesize catecholamines. Neurons reaching the highest neuromelanin levels preferentially degenerate in Parkinsons, Alzheimers and apparently healthy aging individuals. However, this brain pigment is not taken into consideration in current animal models because common laboratory species, such as rodents, do not produce neuromelanin. Here we generate a tissue-specific transgenic mouse, termed tgNM, that mimics the human age-dependent brain-wide distribution of neuromelanin within catecholaminergic regions, based on the constitutive catecholamine-specific expression of human melanin-producing enzyme tyrosinase. We show that, in parallel to progressive human-like neuromelanin pigmentation, these animals display age-related neuronal dysfunction and degeneration affecting numerous brain circuits and body tissues, linked to motor and non-motor deficits, reminiscent of early neurodegenerative stages. This model may open new research avenues in brain aging and neurodegeneration.

neuroscience↗

bioRxiv2023

Adult-specific Reelin expression alters striatal neuronal organization. Implications for neuropsychiatric disorders.

In addition to neuronal migration, brain development and adult plasticity, the extracellular matrix protein Reelin has been extensively implicated in human psychiatric disorders such as schizophrenia, bipolar disorder and autistic spectrum disorder. Moreover, heterozygous reeler mice exhibit features reminiscent of these disorders, while overexpression of Reelin protects against its manifestation. However, how Reelin influences the structure and circuits of the striatal complex, a key region for the above-mentioned disorders, is far from being understood, especially when altered Reelin expression levels are found at adult stages. In the present study, we took advantage of complementary conditional gain- and loss-of-function mouse models to investigate how Reelin levels may modify adult brains striatal structure and neuronal composition. Using immunohistochemical techniques, we determined that Reelin does not seem to influence the striatal patch and matrix organization (studied by -opioid receptor immunohistochemistry) nor the density of medium spiny neurons (MSNs, studied with DARPP-32). We show that overexpression of Reelin leads to increased numbers of striatal Parvalbumin- and Cholinergic-interneurons, and to a slight increase in the tyrosine hydroxylase-positive projections. We conclude that increased Reelin levels might modulate the numbers of striatal interneurons and the density of the nigrostriatal dopaminergic projections, suggesting that these changes may be involved in the protection of Reelin against neuropsychiatric disorders.

neuroscience↗

bioRxiv2022

European scenarios for future biological invasions

O_LIInvasive alien species are one of the major threats to global biodiversity, ecosystem integrity, natures contribution to people and human health. While scenarios about potential future developments have been available for other global change drivers for quite some time, we largely lack an understanding of how biological invasions might unfold in the future across spatial scales. C_LIO_LIBased on previous work on global invasion scenarios, we developed a workflow to downscale global scenarios to a regional and policy-relevant context. We applied this workflow at the European scale to create four European scenarios of biological invasions until 2050 that consider different environmental, socio-economic and socio-cultural trajectories, namely the European Alien Species Narratives (Eur-ASNs). C_LIO_LIWe compared the Eur-ASNs with their previously published global counterparts (Global-ASNs), assessing changes in 26 scenario variables. This assessment showed a high consistency between global and European scenarios in the logic and assumptions of the scenario variables. However, several discrepancies in scenario variable trends were detected that could be attributed to scale differences. This suggests that the workflow is able to capture scale-dependent differences across scenarios. C_LIO_LIWe also compared the Global- and Eur-ASNs with the widely used Global and European Shared Socioeconomic Pathways (SSPs), a set of scenarios developed in the context of climate change to capture different future socio-economic trends. Our comparison showed considerable divergences in the scenario space occupied by the different scenarios, with overall larger differences between the ASNs and SSPs than across scales (global vs. European) within the scenario initiatives. C_LIO_LIGiven the differences between the ASNs and SSPs, it seems that the SSPs do not adequately capture the scenario space relevant to understanding the complex future of biological invasions. This underlines the importance of developing independent, but complementary, scenarios focused on biological invasions. The downscaling workflow we presented and implemented here provides a tool to develop such scenarios across different regions and contexts. This is a major step towards an improved understanding of all major drivers of global change including biological invasions. C_LI

ecology↗

bioRxiv2022

A scenario-guided strategy for the future management of biological invasions

Future dynamics of biological invasions are highly uncertain because they depend on multiple environmental, societal and socio-economic drivers. We adopted a qualitative scenario approach to explore the future of invasive alien species (IAS) in Europe and created an overall strategy for their management that considers different plausible future developments. The scenarios and strategy were developed during two online workshops with a multidisciplinary team of experts. First, we downscaled four global scenarios of biological invasions to the European level. Second, we developed a management strategy structured into 19 goals that cover a broad array of IAS-related topics (i.e. policy, research, public awareness and biosecurity), and provided solutions for achieving these goals considering the European scenarios. Third, we identified four interrelated recommendations around which any long-term strategy for managing IAS in Europe can be structured: (i) a European biosecurity regime, (ii) a dedicated communication strategy, (iii) data standardization and management tools, and (iv) a monitoring and assessment system. Finally, we identified the feasibility of the IAS management strategy, finding strong differences among the four scenarios. High levels of technological development, public environmental awareness, and effectiveness of IAS policies facilitated the implementation of the overall management strategy. Together, our results indicate that it is time for a new management of biological invasions in Europe based on a more integrative perspective across sectors and countries to be better prepared for future challenges.

ecology↗