Biology subjects

Ferreira-Marques, M.

Publications and source records attributed to Ferreira-Marques, M..

4 recordsLinked to original sources

bioRxiv2026

ARTIFICIAL SELECTION DIVERSIFIES BIRDSONG THROUGH POLYGENIC CHANGES ACROSS SENSORY AND MOTOR SYSTEMS

Vocal learning, or the ability to acquire and produce contextualized sounds through social interaction, underlies human speech yet has evolved in a few animal lineages, including songbirds. In songbirds, learned song is produced by a dedicated neural circuit and depends on auditory feedback for its acquisition and maintenance. Roughly four centuries of artificial selection on the domestic canary (Serinus canaria) have produced song breeds whose vocalizations diverge as much as those of distinct species, offering a rare intraspecific system in which to identify the genetic and neural changes underlying vocal divergence. Here we show that selection for song reshaped the canary song control system. Compared with breeds selected for plumage or body form, song breeds show increased neural progenitor proliferation and breed-specific changes in neuronal recruitment, sensorimotor brain region volume, and auditory sensitivity. Genome-wide analyses reveal a polygenic architecture underlying song divergence, enriched for transcriptional regulation and synaptic transmission genes. Among these, we find a coding variant in ADGRV1, the gene mutated in human Usher syndrome type 2C, associated with low-frequency singing and elevated auditory thresholds in canary. Disrupting ADGRV1 in zebrafish alters hair cell dynamics, linking adgrv1 mutation to a peripheral sensory mechanism. These findings demonstrate that learned vocal behavior can diversify rapidly through changes spanning sensory, neurogenic, and motor systems, with hearing itself as a substrate for selection.

evolutionary biology↗

bioRxiv2026

Hypothalamic CYP46A1 cholesterol metabolism regulates diet-induced obesity

Obesity is a growing global health challenge which affects over 38% of the population and increases the risk of developing metabolic disorders. Effective long-term treatment options remain limited and often lead to significant side effects. The hypothalamus plays a central role in metabolic regulation by integrating peripheral and central signals to maintain energy homeostasis. While the hypothalamus regulates peripheral lipid metabolism, the role of lipid metabolic pathways within the hypothalamus itself remains unclear. Therefore, the molecular mechanisms linking hypothalamic activity to the development of obesity remain poorly understood. Given that cholesterol is the most abundant brain lipid, we investigated molecular players involved in its local regulation. Here, we identify the rate-limiting enzyme for brain cholesterol degradation, Cyp46a1, as a critical regulator of diet-induced obesity. We show that Cyp46a1 expression is significantly reduced in the hypothalamus of C57BL/6J mice exposed to a high-fat diet, suggesting a role in metabolic dysregulation. We used recombinant Adeno-Associated Viruses (AAV) to modulate Cyp46a1 expression in the arcuate nucleus, a key hypothalamic region regulating energy balance. We evaluated longitudinal changes in body weight, adipocyte size, PPAR-{gamma} expression, and hepatic lipid accumulation and pancreatic histopathology in mice undergoing chow or high fat diets. These experiments demonstrated that hypothalamic Cyp46a1 regulates body weight, adipocyte size, and hepatic and pancreatic histopathology. Conversely, CYP46A1 overexpression protects against high-fat diet-induced obesity and improves glucose homeostasis and insulin sensitivity, likely via crosstalk with hepatic and pancreatic function. Moreover, we found that hypothalamic CYP46A1 expression selectively modulates gut microbiota composition, linking this enzyme to the microbiota-gut-brain axis. Finally, we found that Cyp46a1 levels influence cognitive and motor performance, suggesting broader physiological relevance. Collectively, our findings reveal a previously unrecognized role of hypothalamic Cyp46a1 and cholesterol pathway control in obesity pathophysiology and metabolic homeostasis. These findings identify hypothalamic Cyp46a1 as a promising therapeutic target for obesity and its related comorbidities.

neuroscience↗

bioRxiv2025

Circadian Rhythms are Disrupted in Patients and Preclinical Models of Machado-Joseph Disease

Machado-Joseph disease (MJD) is caused by an abnormal CAG repeat expansion in the ATXN3 gene, leading to the expression of a mutant ataxin-3 (mutATXN3) protein. MJD patients exhibit a wide range of clinical symptoms, including motor incoordination. Emerging evidence highlights circadian rhythm disruptions as early indicators and potential risk factors for the progression of neurodegenerative conditions. Circadian rhythms are regulated by internal clocks, with the suprachiasmatic nucleus (SCN) acting as the master pacemaker to synchronize timing across the bodys behavioural and physiological functions. While sleep disturbances have been observed in MJD, the role of clock regulation in its pathophysiology remains largely unexplored in spinocerebellar ataxias. This study aimed to investigate circadian rhythms, characterize associated disruptions, and uncover the mechanisms underlying clock dysregulation in patients and preclinical models of MJD. Circadian activity in MJD patients was assessed over two weeks using actigraphy, while in a YAC-MJD transgenic mouse model, circadian rhythms were examined through: (a) wheel-running experiments; (b) telemetry-based monitoring of core body temperature; (c) immunohistochemical analysis of the neuropeptides arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP) in the SCN and paraventricular nucleus (PVN); and (d) RT-qPCR evaluation of clock gene expression in the cerebellum. The impact of mutATXN3 on clock mechanisms was further investigated using Bmal1/Per2-luciferase reporters. MJD patients exhibited a progressive decline in robustness of behavioural rhythms, demonstrated by negative correlations between the circadian function index, rest-activity fragmentation, and sleep efficiency with MJD clinical scales. YAC-MJD mice exhibited reduced activity levels, increased behavioural fragmentation, and required three additional days to re-entrain after a jet lag protocol, compared to controls. Disrupted core body temperature rhythms were observed, including a phase advance and elevated temperature ([~]1 {degrees}C) at the onset of the active period. Furthermore, transgenic mice showed reduced levels of VIP and AVP in the SCN and PVN, and decreased clock gene expression in the cerebellum. Lastly, we found new mechanistic evidence that WT ATXN3 activates the promoters of Bmal1 and Per2, whereas mutATXN3 loses the capacity to drive Per2 upon polyglutamine expansion. Overall, our findings indicate that central clock dysfunction in MJD is associated with impaired clock gene expression and disruptions in activity and temperature rhythms. This study provides the first robust evidence of circadian rhythm dysregulation and underlying mechanisms in MJD, paving the way for the identification of new biomarkers and the development of novel circadian-based interventions to tackle MJD and possibly other spinocerebellar ataxias. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/631212v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@25078dorg.highwire.dtl.DTLVardef@112e523org.highwire.dtl.DTLVardef@1818356org.highwire.dtl.DTLVardef@1d5a6c0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Ghrelin delays premature aging in Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal genetic condition arising from a single nucleotide alteration in the LMNA gene, which leads to the production of a defective lamin A protein known as progerin. The buildup of progerin hastens the onset of premature and expedited aging. Patients with HGPS exhibit short stature, low body weight, lipodystrophy, metabolic dysfunction, and skin and musculoskeletal abnormalities and, in most cases, die of cardiovascular disease by their early teenage years. Currently, no effective cure or treatment for the disease highlights the importance of discovering new therapeutic strategies. Herein, we present evidence that the hormone ghrelin, besides promoting autophagy and progerin clearance, rescued several cellular hallmarks of premature aging of human HGPS fibroblasts. Using an HGPS mouse model, LmnaG609G/G609G mice, we also show that ghrelin administration rescued the short-lived mice molecular and histopathological progeroid features, prevented progressive weight loss at later stages, reverted the lipodystrophic phenotype, and extended lifespan. Thus, we disclose that modulation of ghrelin signaling may give rise to new treatment targets and translational approaches that may improve outcomes and the health quality of HGPS patients and natural aging pathologies.

physiology↗