Biology subjects

Perez, J.

Publications and source records attributed to Perez, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Gene model for the ortholog of tgo in Drosophila persimilis

Gene model for the ortholog of tango (tgo) in the May 2011 (Broad dper_caf1/DperCAF1) Genome Assembly (GenBank Accession: GCA_000005195.1) of Drosophila persimilis. This ortholog was characterized as part of a developing dataset to study the evolution of the Insulin/insulin-like growth factor signaling pathway (IIS) across the genus Drosophila using the Genomics Education Partnership gene annotation protocol for Course-based Undergraduate Research Experiences.

genomics↗

bioRxiv2026

PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain

BackgroundPhospholipase C gamma-2 (PLC{gamma}2) catalyzes the hydrolysis of the membrane phosphatidylinositol-4,5-bisphosphate (PIP2) to form diacylglycerol (DAG) and inositol trisphosphate (IP3), feeding into diverse downstream signaling pathways. PLCG2 polymorphisms have been associated with reduced and/or increased risk of Alzheimers disease (AD) and related dementias, longevity, autoinflammation, and immune disorders. In the brain, PLC{gamma}2 is expressed in microglia, and other neuroimmune and vascular interface populations, yet its role in brain homeostasis remains incompletely defined. MethodsWe analyzed the brains of three-month-old Plcg2 wild-type (WT), heterozygous (Het KO) and homozygous knockout (Homo KO) littermate mice modeling human PLCG2 loss-of-function risk alleles linked to AD risk using a multiomic approach that included lipidomics, metabolomics, proteomics, and transcriptomics, together with immunofluorescence, as well as flow-cytometric profiling of peripheral and brain-draining immune compartments. ResultsPlcg2 deficiency substantially impaired early survival and produced splenomegaly without increasing total spleen cellularity, instead shifting spleen composition toward myeloid/innate-enriched cells and away from B cells, with expansion of age-associated B-cell (ABC-like) subsets and parallel reductions in CD4 and CD8 regulatory T cells in spleen and cervical lymph nodes. Brain lipidomics revealed selective depletion of PIP2, despite very low bulk PLC{gamma}2 protein abundance relative to other PLC family members. PLC{gamma}2 loss led to significant reductions in myelin-enriched lipid classes and myelin/paranode-associated proteins, accompanied by compensatory upregulation of oligodendrocyte/myelin genes, and modest shifts in microglial, lysosomal, complement, and oxidative metabolism pathways by NanoString and DIA-MS. Targeted acylcarnitine profiling demonstrated reprogramming of brain oxidative metabolism, with increased short-, medium-, and long-chain acylcarnitines and enrichment of mitochondrial matrix fatty-acid and amino-acid catabolic enzymes in Homo KO brains. ConclusionsLoss of PLC{gamma}2 installs a coordinated program that compromises systemic immune tolerance and subtly erodes central myelin and phosphoinositide homeostasis while enhancing brain oxidative metabolism, effects that extend beyond microglial phagocytic signaling and may underlie increased vulnerability to AD pathology and aging, providing a mechanistic framework for how PLCG2 variation may link systemic immune regulation, white-matter integrity, and neurodegenerative risk. LimitationsBecause constitutive Plcg2 Homo KO mice display high early mortality and intestinal vascular abnormalities, observed phenotypes may reflect developmental compensation and may not fully recapitulate protective human PLCG2 variants.

neuroscience↗

bioRxiv2026

Gene model for the ortholog of tgo in Drosophila busckii

Gene model for the ortholog of tango (tgo) in the Sep. 2015 (UC Berkeley ASM127793v1/DbusGB1) Genome Assembly (GenBank Accession: GCA_001277935.1) of Drosophila busckii. This ortholog was characterized as part of a developing dataset to study the evolution of the Insulin/insulin-like growth factor signaling pathway (IIS) across the genus Drosophila using the Genomics Education Partnership gene annotation protocol for Course-based Undergraduate Research Experiences.

genomics↗

bioRxiv2026

PROTAC internalization and target degradation require clathrin-mediatedendocytosis

Proteolysis-targeting chimeras (PROTACs) are emerging as potent tools for targeted protein degradation that overcome many of the limitations of traditional small molecule inhibitors. Yet how these hetero-bifunctional therapeutics enter cells remains a mystery. While passive diffusion is conventionally assumed, the bulky structure of PROTACs suggests that active transport may be required. Recently, the fatty acid transporter CD36 was identified as a key receptor for PROTACs. However, because the uptake mechanism of CD36 is itself unknown, how PROTACs enter cells remains a mystery. Here we show that PROTAC uptake and function require clathrin-mediated endocytosis. We uncover previously unrecognized clathrin adaptor-binding motifs in the CD36 C-terminus and use live-cell imaging to visualize the recruitment of both CD36 and PROTACs to sites of clathrin-mediated endocytosis on the cellular plasma membrane. Strikingly, disruption of clathrin assembly through either genetic or pharmacological means abolishes all detectable PROTAC-induced protein degradation, demonstrating that the clathrin pathway is required for the function of PROTACs that utilize diverse E3 enzymes against multiple targets. These results elucidate the molecular mechanism of PROTAC entry into cells, providing critical information for optimizing cellular uptake and response to targeted degraders.

pharmacology and toxicology↗

bioRxiv2026

Early ingestive experience with a high-fat diet tunes satiation and nutrient-specific appetitive behaviors

Overconsumption of foods rich in fats, sugars, and calories is a major contributing factor to increased risk for cardiometabolic disease. Ingestive experience with these foods can begin early in children, yet there is limited understanding of the impact of early life nutrition on the development of vagal afferent neurons necessary for coordinating appetitive and satiating behaviors. To address this gap, mice reared on a chow diet (control) were compared to those reared on a high-fat diet (HFDEARLY). We demonstrate that the vagally-mediated satiation response to cholecystokinin (CCK) does not mature until adolescence in chow-reared mice. However, HFDEARLY exposure triggers a precocious maturation of this response, accompanied by transcriptomic changes in the nodose ganglion. Durable changes in appetitive behaviors were also evident in adult HFDEARLY mice, which consumed more lipid than control mice. Behavioral analyses point to alterations in orosensory processing and enhanced appetition in adult HFDEARLY mice. Furthermore, female HFDEARLY mice showed a selective increase in consumption of a calorie-dense liquid diet in adulthood, accompanied by changes in body composition, suggesting a lasting, sex-specific vulnerability to overconsumption of palatable, energy-dense foods. Together, these results establish nutrient exposure as a significant contributor to vagal circuit maturation and function.

animal behavior and cognition↗

bioRxiv2025

Identification of non-coding elements associated with the evolutionary loss of digit 1.

Evolutionary loss of digits and limbs occurred many times during the diversification of tetrapods. The limbs of the earliest tetrapods were polydactylous, bearing as many 8 digits, but after the pentadactyly (five digits) was stabilized, no lineage evolved more than five digits per limb but many underwent digit loss. Within mammals, digit 1 (thumb on the forelimb or hallux on the hindlimb) is lost most frequently and is typically the first digit to disappear. Evidence from numerous studies of limb development shows that digit 1 development is controlled by mechanisms that are at least partially independent of the posterior 4 digits. In addition, evolutionary loss of digit 1 occurred independently in forelimbs and hindlimbs. Despite the frequency of digit loss in mammals, the underlying genetic mechanisms have not been uncovered. We used comparative genomics and bioinformatics to reconstruct the evolutionary history of genomic changes associated with digit 1 loss in the forelimbs and/or hindlimbs of 65 mammalian species. We identified a set of conserved non-coding elements that evolved in concert with independent (parallel) losses of digit 1. These elements, which are frequently near genes with known roles in digit development, underwent accelerated evolution in digit-reduced lineages. Furthermore, we find that elements with accelerated rates of evolution show significant loss of binding sites for transcription factors that are crucial for anterior digit development. The results suggest that cis-regulatory elements important for the development of digit 1 are evolutionarily accelerated in mammalian lineages that underwent reduction and loss of digit 1.

evolutionary biology↗

bioRxiv2025

Brain-wide synaptosome profiling reveals localized mRNAs that diversify synapses

Chemical synapses are the principal communication nodes of the brain, defined by their specialization and plasticity. Their diversity spans multiple levels, from the polarity and magnitude of electrophysiological responses to the proteins driving these differences. Here, we describe another layer of synapse diversity - synaptic transcriptome diversity. Using transgenic mice to fluorescently label presynapses in Camk2a-, Gad2-, DAT-, PV-, SST-, and VIP-expressing neurons, combined with fluorescence-activated synaptosome sorting, we profiled synaptic transcriptomes across five brain regions. We identified [~]4000 mRNAs enriched at synapses - some type-specific, others shared - and highlight region-specific enrichments of mRNAs encoding protein subunits or family members. We found that the abundance of synaptic mRNAs is not a passive reflection of their abundance in cellular somata, indicating active trafficking and sorting mechanisms. Integrating transcriptomic and proteomic data, we identified [~]90 genes with significantly correlated mRNA-protein ratios across regions, mainly involved in synaptic vesicle dynamics, receptor signaling, and calcium regulation, suggesting a key role for local translation in maintaining protein copy number. Although synaptic mRNAs represent only a fraction of the templates for the synaptic proteome, the synaptic transcriptome reflects the synapse diversity captured by the proteome equally well. Together, this dataset (https://syndive.org/) provides a resource for exploring how synaptic mRNA localization and local translation shape synaptic identity and function.

neuroscience↗

bioRxiv2025

Evaluating the roles of testosterone and sex-linked genes in territorial aggression of sex-reversed XY females in the African pygmy mouse

Sex differences in social aggression are widespread across the animal kingdom, with males typically displaying greater territoriality. While this dimorphism has traditionally been attributed to sex hormones, sex chromosomes can also contribute to it independently of hormonal influence. In the African pygmy mouse Mus minutoides, naturally occurring sex-reversed XY females (named X*Y due to a mutation on the X chromosome) are highly territorial in comparison to the other female genotypes present in the population (XX and XX*). However, the molecular basis of this phenotype remains unknown. Here, we evaluate molecular factors, known to correlate with aggressiveness, following a standardized behavioural assessment of aggression. We focus on i) the androgen pathway by quantifying testosterone serum levels and expression of its receptor in the brain; ii) the brain dopaminergic system through expression of dopamine-regulating genes, including the sex-determining Sry gene; and iii) neuroendocrine circuits, via vasopressin and oxytocin expression. These systems, although distinct, converge on hypothalamic-limbic circuits that regulate social behaviour and threat responses, providing an integrated framework for the modulation of aggression. Contrary to earlier reports, we found reduced level of aggression in X*Y females, likely to reflect a breeding facility effect. We also observe no correlations between aggressiveness and androgen levels or gene expression of the tested factors. However, our results support a stimulation of the dopaminergic system and of the oxytocin pathway following the agonistic assay suggesting their potential involvement in aggression-related responses. This further supports the idea that aggression is multifactorial. It is shaped by the interaction of several neuroendocrine and neurotransmitter pathways rather than a single determinant.

evolutionary biology↗

bioRxiv2025

HIV IMPAIRS AND EXPLOITS PULMONARY TH17 AND TH22 CELL-MEDIATED IMMUNE RESPONSES TO MYCOBACTERIUM TUBERCULOSIS

Tuberculosis (TB) kills an estimated 1.25 million people annually and is the leading cause of death in people with HIV (PWH) (1). The CD4+ T helper (Th) populations play significant roles in protective immunity to Mycobacterium tuberculosis (Mtb) and are essential hosts for HIV pathogenesis. Emerging evidence in blood and gastrointestinal mucosa of PWH suggests that, among Th cells, Th17 and Th22 may be preferentially depleted during HIV infection. Targeting of Th17 and Th22 cells by HIV could pose important and poorly understood risks for Mtb containment in those with co-infection. Mtb-driven activation of Th17 and Th22 immunity may also contribute to HIV proliferation and persistence. We employed a humanized mouse model of co-infection to assess changes in Th17 and Th22 frequency and function due to infection with HIV, Mtb, or both. In infected mice, Th17 cells were the predominant host for HIV in spleen and shown to be a source of HIV replication in pulmonary TB granulomas. Th17 cells were increased in lung of mice with TB or TB-HIV. Conversely, Th22 cells were reduced in mice with HIV or TB-HIV. Mtb infection increased the viral load in lung of co-infected mice while HIV suppressed the pulmonary Th17 family cytokine response to Mtb including IL-6, IL-22, IL-23, and IL-1{beta}. Differential transcriptome assessment demonstrated that HIV co-infection disrupted Th17 pathways activated by Mtb in lung. Overall, these results suggest that HIV may compromise Th22 immunity and exploit Th17 cells to promote viral pathogenesis in the setting of Mtb and HIV co-infection.

immunology↗

bioRxiv2025

Population and adaptation history of 739 Thlaspi arvense natural accessions

Pennycress (Thlaspi arvense) is a promising intermediate oilseed crop, producing oil suitable for conversion to biofuels--including aviation fuels. While domestication efforts are ongoing, a deeper understanding of the genetic architecture of traits is crucial for informing future breeding efforts. Here, we conducted the largest genomic and phenotypic survey of pennycress to date, analyzing 739 accessions collected across four continents. Leveraging whole-genome sequencing and field-collected phenotypes, we characterized the standing genetic variation underlying key agronomic traits and climate resilience. Our findings revealed multiple independent migration events to North America, with substantial genetic admixture. We identified homologs of Arabidopsis thaliana flowering-time genes that contribute to adaptation and demonstrated the agronomic benefits of winter-type pennycress. Furthermore, through multi-season field trials, we identified a genomic region containing a cluster of mTERF genes strongly associated with green canopy coverage, a critical trait for biomass retention and yield stability. These insights provide a genomic roadmap for accelerating pennycress domestication and improving its resilience to climate variability.

genomics↗

bioRxiv2025

A cell-type specific surveillance complex represses cryptic promoters during differentiation in an adult stem cell lineage

Regulators of chromatin accessibility play key roles in cell fate transitions, triggering onset of novel transcription programs as cells differentiate. In the Drosophila male germ line stem cell lineage, tMAC, a master regulator of spermatocyte differentiation that binds thousands of loci, is required for local opening of chromatin, allowing activation of spermatocyte-specific promoters. Here we show that a cell-type specific surveillance system involving the multiple zinc finger protein Kmg and the pipsqueak domain protein Dany dampens transcriptional output from weak tMAC dependent promoters and blocks tMAC binding at thousands of additional cryptic promoters, thus preventing massive expression of aberrant protein-coding transcripts. ChIP-seq showed Kmg enriched at the tMAC-bound promoters it repressed, consistent with direct action. In contrast, Kmg and Dany did not repress highly expressed tMAC dependent genes, where they colocalized with their binding partner, the chromatin modeler Mi-2 (NuRD), along the transcribed regions rather than at the promoter. Mi-2 has been shown to preferentially bind RNA over chromatin (Ullah et al. 2022). We propose that at highly expressed genes binding of Mi-2 to the abundant nascent RNA pulls the Kmg/Dany complex away from promoters, providing a mechanism to effectively repress ectopic promoters while protecting robust transcription.

developmental biology↗

bioRxiv2025

Epsin1 enforces a condensation-dependent checkpoint for ubiquitylated cargo during clathrin-mediated endocytosis

Clathrin-mediated endocytosis internalizes proteins and lipids from the cell surface, supporting nutrient uptake, signaling, and membrane trafficking. Recent work has demonstrated that a flexible, liquid-like network of initiator proteins is responsible for catalyzing assembly of clathrin-coated vesicles in diverse organisms including yeast, mammals, and plants. How do cells regulate the assembly of this dynamic network to produce cargo-loaded vesicles? Here we reveal the ability of an endocytic adaptor protein, Epsin1, to conditionally stabilize the initiator protein network, creating a cargo-dependent checkpoint during clathrin-mediated endocytosis. Epsin1 is known to recruit ubiquitylated transmembrane proteins to endocytic sites. Using in vitro assays, we demonstrate that Epsin1 uses competitive binding and steric repulsion to destabilize condensation of initiator proteins in the absence of ubiquitin. However, when polyubiquitin is present, Epsin1 binds to both ubiquitin and initiator proteins, creating attractive interactions that stabilize condensation. Similarly, in mammalian cells, endocytic dynamics and ligand uptake are disrupted by removal of either ubiquitin or Epsin1. Surprisingly, when Epsin1 and ubiquitin are removed simultaneously, endocytic defects are rescued to near wildtype levels, although endocytic sites lose the ability to distinguish between ubiquitylated and non-ubiquitylated cargos. Taken together, these results suggest that Epsin1 tunes protein condensation to ensure the presence of ubiquitylated cargo during assembly of clathrin-coated vesicles. More broadly, these findings illustrate how a balance of attractive and repulsive molecular interactions controls the stability of liquid-like protein networks, providing dynamic control over key cellular events.

cell biology↗

bioRxiv2024

Influence of gonadal and chromosomal sex on the brain transcriptome in a mouse species with natural sex reversal

Sex chromosomes are expected to play a role in shaping the transcriptional architecture of sexual dimorphism, through the direct expression of sex-linked genes, by regulating autosomal genes, or in interactions with hormones. Yet, their degree of involvement remains elusive partly because chromosomal sex (XX/XY or ZZ/ZW) and gonadal sex (ovaries or testes) are usually inextricably intertwined. They are however dissociated in the African pygmy mouse, Mus minutoides, in which a feminizing X (X*) has evolved resulting in three female genotypes (XX, XX* and X*Y) and one male genotype (XY). Despite hormonal levels similar to the other females, X*Y females show distinctive phenotypes with greater fertility, divergent maternal care strategies and the masculinization of some traits (e.g. enhanced aggressiveness). By comparing the brain transcriptome of the four sexual genotypes, we show, here, that differential gene expression is mainly linked to gonadal sex (male vs. female) but also and significantly, to chromosomal sex, with expression patterns matching the singularity of X*Y female traits. Genes with such patterns are over-represented on sex and sex-linked chromosomes, and some are strong candidates to explain X*Y-specific behavioral and reproductive traits. We also report the preferential inactivation of the X* chromosome in XX* females, which could explain their trait similarities with XX females. Overall, we show that sex chromosomes have profoundly impacted the brain transcriptome in ways that reflect their new transmission modes and new resulting conflicts. This opens exciting prospects on the evolution of sex differences in relation to the dynamic of sex chromosome evolution.

evolutionary biology↗

bioRxiv2024

The nucleating agent crystallophore induces instant protein crystallization

The rapid preparation of homogeneous suspensions of micro- or nano-crystals is a crucial step in serial crystallography. We show how additives, such as the crystallophore (TbXo4) that acts as a molecular glue by promoting protein-protein interactions, can facilitate sample preparation for both serial synchrotron crystallography (SSX) and micro electron diffraction (3D ED). This lanthanide complex was used here for its nucleating properties to crystallize hen egg white lysozyme. SAXS monitoring indicates that crystals formed in a few minutes in low salt conditions that would not lead to spontaneous nucleation. Resulting micro- and nano-crystals were successfully used to determine the structure of the lysozyme-TbXo4 complex by SSX and 3D ED, illustrating the diffraction quality of the produced crystals and the usefulness of such compounds in the sample preparation pipeline for serial crystallography.

biophysics↗

bioRxiv2023

Glial-derived mitochondrial signals impact neuronal proteostasis and aging.

The nervous system plays a critical role in maintaining whole-organism homeostasis; neurons experiencing mitochondrial stress can coordinate the induction of protective cellular pathways, such as the mitochondrial unfolded protein response (UPRMT), between tissues. However, these studies largely ignored non-neuronal cells of the nervous system. Here, we found that UPRMT activation in four, astrocyte-like glial cells in the nematode, C. elegans, can promote protein homeostasis by alleviating protein aggregation in neurons. Surprisingly, we find that glial cells utilize small clear vesicles (SCVs) to signal to neurons, which then relay the signal to the periphery using dense-core vesicles (DCVs). This work underlines the importance of glia in establishing and regulating protein homeostasis within the nervous system, which can then impact neuron-mediated effects in organismal homeostasis and longevity. One-Sentence SummaryGlial cells sense mitochondrial stress and signal a beneficial stress signal to promote neuronal health and longevity.

genetics↗

bioRxiv2023

Coupling remote sensing and eDNA to monitor environmental impact: A pilot to quantify the environmental benefits of sustainable agriculture in the Brazilian Amazon

Monitoring is essential to ensure that environmental goals are being achieved, including those of sustainable agriculture. Growing interest in environmental monitoring provides an opportunity to improve monitoring practices. Approaches that directly monitor land cover change and biodiversity annually by coupling the wall-to-wall coverage from remote sensing and the site-specific community composition from environmental DNA (eDNA) can provide timely, relevant results for parties interested in the success of sustainable agricultural practices. To ensure that the measured impacts are due to the environmental projects and not exogenous factors, sites where projects have been implemented should be benchmarked against counterfactuals (no project) and control (natural habitat) sites. Results can then be used to calculate diverse sets of indicators customized to monitor different projects. Here, we report on our experience developing and applying one such approach to assess the impact of shaded cocoa projects implemented by the Instituto de Manejo e Certificacao Florestal e Agricola (IMAFLORA) near Sao Felix do Xingu, in Para, Brazil. We used the Continuous Degradation Detection (CODED) and LandTrendr algorithms to create a remote sensing-based assessment of forest disturbance and regeneration, estimate carbon sequestration, and changes in essential habitats. We coupled these remote sensing methods with eDNA analyses using arthropod-targeted primers by collecting soil samples from intervention and counterfactual pasture field sites and a control secondary forest. We used a custom set of indicators from the pilot application of a coupled monitoring framework called TerraBio. Our results suggest that, due to IMAFLORAs shaded cocoa projects, over 400 acres were restored in the intervention area and the community composition of arthropods in shaded cocoa is closer to second-growth forests than that of pastures. In reviewing the coupled approach, we found multiple aspects worked well, and we conclude by presenting multiple lessons learned.

ecology↗

bioRxiv2023

Morphological limitations imposed on lizards facing urbanization

Habitat conversion in general, and urbanization in particular, are thought to create ecological filters that eliminate some species while simultaneously replacing them with others that thrive under novel conditions. The specific nature of these filters is unclear, but morphology may play an important role. Here, we seek to assess which lizard morphologies are favored in urban habitats. We quantified 17 linear measurements of morphology from museum specimens from 37 lizard species from across the continental United States. We then correlate these morphological measurements with the relative incidence of observations in urban versus non-urban environments from the citizen science database iNaturalist to determine whether particular morphologies predispose species to tolerate urban environments. We then use functional diversity and morphospace volume metrics to quantify both the total amount of unique morphological diversity represented by urban associated species, versus those restricted to natural areas. Based on our results morphology appears to be filtering lizard species from urban environments. Specifically, species with intermediate body sizes and relative tails lengths, as well as larger heads and shorter hind-limbs were more likely to occupy urban zones. As a result of this filtering, there was substantially diminished morphological diversity among urban tolerant species. While natural restricted species had a high amount of morphological diversity that was unrepresented in urban tolerant species, most urban species morphologies were shared by natural restricted ones. Only a small subset of morphologies found in natural environments persist in urban ones, but urban lizards do possess a small number of unique morphological features that may facilitate their success. Strong selection pressures in evolutionarily novel environments are not only diminishing species diversity but pruning phenotypic diversity to favor a much smaller subset of functional possibilities. Due to the connection between phenotype and function, such diminished morphological diversity is likely to impact ecosystem functioning in impoverished human-modified systems.

ecology↗

bioRxiv2023

Sex-dependent contributions of ventrolateral orbitofrontal cortex and basolateral amygdala to learning under uncertainty

Reversal learning measures the ability to form flexible associations between choice outcomes with stimuli and actions that precede them. This type of learning is thought to rely on several cortical and subcortical areas, including highly interconnected orbitofrontal cortex (OFC) and basolateral amygdala (BLA), and is often impaired in various neuropsychiatric and substance use disorders. However, unique contributions of these regions to stimulus- and action-based reversal learning have not been systematically compared using a chemogenetic approach and particularly before and after the first reversal that introduces new uncertainty. Here, we examined the roles of ventrolateral OFC (vlOFC) and BLA during reversal learning. Male and female rats were prepared with inhibitory DREADDs targeting projection neurons in these regions and tested on a series of deterministic and probabilistic reversals during which they learned about stimulus identity or side (left or right) associated with different reward probabilities. Using a counterbalanced within-subject design, we inhibited these regions prior to reversal sessions. We assessed initial and pre-post reversal changes in performance to measure learning and adjustments to reversals, respectively. We found that inhibition of vlOFC, but not BLA, eliminated adjustments to stimulus-based reversals. Inhibition of BLA, but not vlOFC, selectively impaired action-based probabilistic reversal learning, leaving deterministic reversal learning intact. vlOFC exhibited a sex-dependent role in early adjustment to action-based reversals, but not in overall learning. These results reveal dissociable roles for BLA and vlOFC in flexible learning and highlight a more crucial role for BLA in learning meaningful changes in the reward environment. Significance StatementInflexible learning is a feature of several neuropsychiatric disorders. We investigated how the ventrolateral orbitofrontal cortex (vlOFC) and basolateral amygdala (BLA) are involved in learning of stimuli or actions under reinforcement uncertainty. Following chemogenetic inhibition of these regions in both male and females, we measured learning and adjustments to deterministic and probabilistic reversals. For action learning, BLA, but not vlOFC, is needed for probabilistic reversal learning. However, BLA is not necessary for initial probabilistic learning or retention, indicating a critical role for learning of unexpected changes. For stimulus learning, vlOFC, but not BLA, is required for adjustments to reversals, particularly in females. These findings provide insight into the complementary cortico-amygdalar substrates of learning under different forms of uncertainty.

neuroscience↗