Biology subjects

Vilasboas-Campos, D.

Publications and source records attributed to Vilasboas-Campos, D..

5 recordsLinked to original sources

bioRxiv2026

Valence-specific ensembles in the laterodorsal tegmentum encode salient stimuli and modulate motivated behavior

The laterodorsal tegmentum (LDT) is a brainstem hub that integrates sensory and motivational signals to regulate adaptive behavior. While LDT neurons are known to modulate reward and aversion, whether salient stimuli recruit distinct neuronal ensembles within this structure remains unknown. Here, combined cell-type-specific calcium imaging, activity-dependent genetic tagging (TRAP2), and optogenetic reactivation to investigate how rewarding and aversive stimuli recruit and functionally define LDT neurons. Notably, single exposures to cocaine or shock in TRAP2;Ai14 mice labeled spatially and neurochemically distinct ensembles, with minimal overlap. We used fiber photometry and TRAP2 system to tag active neuronal ensembles in the LDT during cocaine (coca-LDT) and foot shock (shock-LDT) exposure, expressing GCaMP8m (green) in these neurons and, simultaneously, sRGECO (red) in the whole LDT. Our results demonstrate coca-LDT activation by physical aversive events and valenced odours, with reduced activity in response to rewarding liquids. Shock-LDT showed activation by physical aversive events, odours, and shock-predictive cues. Additionally, optogenetic reactivation of cocaine-TRAPed ensembles in a two-choice operant task biased action selection toward stimulation-paired responses, whereas shock-TRAPed ensemble activation did not drive avoidance. These findings identify functionally segregated LDT ensembles recruited by opposing motivational stimuli and reveal a causal role for reward-activated brainstem ensembles in shaping behavior. This functional segregation may contribute to the brains ability to differentiate stimulus types and, to some extent, valence experiences. Our results may provide evidence on how the LDT influences decision-making processes in addiction and anxiety disorders, potentially paving the way for novel therapeutic approaches.

neuroscience↗

bioRxiv2026

Dissociable neuronal substrates for positive and negative valence stimuli in the nucleus accumbens

The nucleus accumbens (NAc) responds to both natural and artificial rewards and to aversive stimuli; however, it remains unclear whether these opposing valence signals engage distinct neuronal ensembles. Here we used Fos-CreERT2-based activity-dependent tagging to label NAc neuronal ensembles activated by cocaine or foot shock. We found that cocaine ensemble consisted predominantly of dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs), whereas foot shock ensemble similarly recruited D1- and D2-MSNs. One-photon calcium imaging in freely moving mice revealed that acute cocaine primarily excited D1-MSNs while inhibiting the majority of D2-MSNs, whereas foot shock induced excitatory responses in both types of MSNs. Optogenetic reactivation of the cocaine-ensemble elicited a strong behavioural preference, whereas reactivation of the shock-ensemble produced no significant behavioural effect. Together, these findings demonstrate that cocaine recruits a functionally specific NAc ensemble distinct from that recruited by shock, providing mechanistic insight into the valence-specific neuronal substrates underlying reward and aversion processing.

neuroscience↗

bioRxiv2026

PRO-FitS: a novel phenotypic assay to identify enhancers of proteostasis in C. elegans

The prevalence of neurodegenerative diseases (NDs) continues to rise with the aging of populations worldwide, representing a pressing need for the establishment of therapeutic strategies. Maintaining proteostasis is crucial for healthy aging, as the accumulation of misfolded and aggregated proteins is a key contributor to age-related cellular dysfunction and disease. This study introduces a novel phenotypic assay using Caenorhabditis elegans to screen for small molecule enhancers of proteostasis, aiming at mitigating the proteotoxic stress associated with NDs. This new methodology- PRO-FitS- uses C. elegans motor activity as a proxy for the PROteome Fitness State upon a noxious protein-denaturating stimulus, while allowing a fast and experimenter-free readout. We demonstrate the efficacy of the assay by validating the role of pharmacological mTOR inhibition and serotonergic signaling activation in reducing heat shock-induced proteotoxic damage at the whole-organism level. PRO-FitS will allow the identification of novel compounds that alleviate protein aggregation disorders, potentially revealing new pathways and cellular targets not previously implicated in proteotoxicity. Significance StatementNeurodegenerative diseases remain without effective cures, in part due to the lack of scalable methods to identify compounds that improve proteostasis. We developed PRO-FitS, a whole-organism, automated phenotypic assay in C. elegans that uses motor activity recovery as a proxy for proteome fitness after proteotoxic stress. This platform enables rapid, unbiased screening of small molecules and genetic modifiers, bridging the gap between cellular assays and complex animal models. By demonstrating the assays robustness in both wild-type and disease-relevant contexts, we establish PRO-FitS as a versatile tool for discovering therapeutic candidates and uncovering novel pathways relevant to protein aggregation disorders.

neuroscience↗

bioRxiv2025

Efficacy of chronic 5-HT1A receptor agonism by NLX-112 in a mouse model of Spinocerebellar Ataxia type 3

BackgroundSpinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by an elongated polyglutamine (polyQ) sequence in the ataxin-3 protein. This expansion triggers neuropathological events, leading to progressive motor disturbances. Currently, no approved therapy exists for this debilitating condition, but compelling evidence suggests that targeting the serotonergic system can significantly attenuate SCA3 disease progression in animal models. ObjectiveThis study aimed to assess the effects of NLX-112, a highly selective serotonin 1A receptor (5-HT1AR) full agonist, in the CMVMJD135 transgenic mouse model of SCA3. MethodsNLX-112 (0.625 and 5 mg/kg/day) and tandospirone (a 5-HT1AR partial agonist used as a comparator; 20 and 80 mg/kg/day) were administered chronically in drinking water for 34 weeks, starting prior to symptom onset. To evaluate the effects of the drugs on SCA3 mice, motor-related behavioral tests and neuropathological techniques were employed. ResultsTreatment with the higher dose of NLX-112 led to improvements in motor coordination and balance, and slowing of symptom deterioration as the disease progressed. These beneficial effects were not achieved with tandospirone. NLX-112 treatment also elicited neuroprotective effects, reducing dopaminergic (tyrosine hydroxylase-positive) cell loss and astrocyte reactivity in the substantia nigra. ConclusionsNLX-112 treatment, started pre-symptomatically, enhanced motor function, slowed disease progression and elicited neuroprotective effects in SCA3 mice, supporting its further development as a drug candidate for treatment of ataxia and related movement disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/671624v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@548b2corg.highwire.dtl.DTLVardef@7d2f51org.highwire.dtl.DTLVardef@ad8ee4org.highwire.dtl.DTLVardef@80213c_HPS_FORMAT_FIGEXP M_FIG C_FIG Key findingsO_LINLX-112 attenuated motor deficits of SCA3 mice, when administered chronically prior to disease onset. C_LIO_LINLX-112 reduced neuropathological biomarkers in SCA3 mice, namely by restoring dopaminergic neuron loss and decreasing astrocyte reactivity. C_LIO_LINLX-112 is a potential candidate for addressing ataxia-related deficits in SCA3 patients. C_LI

neuroscience↗

bioRxiv2025

Allosteric Modulation of Pathological Ataxin-3 Aggregation: A Path to Spinocerebellar Ataxia Type-3 Therapies

Spinocerebellar ataxia type 3 (SCA3) is a rare inherited neurodegenerative disease caused by the expansion of a polyglutamine repeat in the protease ataxin-3 (Atx3). Despite extensive knowledge of the downstream pathophysiology, no disease-modifying therapies are currently available to halt disease progression. The accumulation of protein inclusions enriched in the polyQ-expanded Atx3 in neurons suggests that inhibiting its self-assembly may yield targeted therapeutic approaches. Here it is shown that a supramolecular tweezer, CLR01, binds to a lysine residue on a positively charged surface patch of the Atx3 catalytic Josephin domain. At this site, the binding of CLR01 decreases the conformational fluctuations of the distal flexible hairpin. This results in reduced exposure of the nearby aggregation-prone region, which overlaps with the substrate ubiquitin binding site and primes Atx3 self-assembly, ultimately delaying Atx3 amyloid fibril formation and reducing the secondary nucleation rate, a process linked to fibril proliferation and toxicity. These effects translate into the reversal of synapse loss in a SCA3 cultured cortical neuron model, an improved locomotor function in a C. elegans SCA3 model, and a delay in disease onset, accompanied by reduced severity of motor symptoms in a SCA3 mouse model. This study provides critical insights into Atx3 self-assembly, revealing a novel allosteric site for designing CLR01-inspired therapies targeting pathological aggregation pathways while sparing essential functional sites. These findings emphasize that targeting allosteric sites in amyloid-forming proteins may offer unique opportunities to develop safe therapeutic strategies for various protein misfolding disorders.

biophysics↗