Teresa Femenía

Functional specialization in continuous systems requires balancing adaptation to environmental stress with the preservation of encoded information. Yet, the physical constraints governing how living systems reconcile selective information retention with energetic structural reorganization remain unclear–a trade-off that may offer transferable design rules for adaptive computing. Here we present a unified framework that connects cellular specialization to adaptive machine learning through principles of nonequilibrium optimization. We find that asymmetric fluctuations in key parameters act as tunable drives that, when phase-aligned, are rectified into durable functional specialization. Biologically, we show that in adipose mesenchymal cells, transient nutrient deficits trigger cytosolic pH fluctuations. These oscillations, regulated by the ATP12A proton pump, modulate nuclear compartment dynamics to coordinate mitochondrial specialization and lock in epigenetic memory for phenotype persistence. Notably, modulating ATP12A amplifies these drives, enhancing functional specialization and metabolic homeostasis in disease models. Computationally, we formalize analogous principles using a compositional framework based on operadic algebra, where structural updates act as a topological ratchet converting drive fluctuations into persistent architectures. This reveals a learning regime where gains in predictive information are accompanied by auditable residual costs for non-predictive states and reorganization. As a proof of concept, we deploy a self-organizing machine learning system that discovers latent hierarchy and reconstructs data through adaptive compartment dynamics. We show that internal organization fluctuations increase with residuals, an information-processing ledger guiding adaptive computation. Across both domains, local organization gains are directionally linked to dissipation proxies (pH variance in vivo and residuals in silico), consistent with operation under shared constraints. Overall, this work identifies asymmetric-drive rectification as a fundamental mechanism of adaptive specialization, providing thermodynamically informed design rules for both bioengineering and adaptive AI. One-Sentence Summary: Asymmetric-drive rectification is a fundamental mechanism by which cells and adaptive computational systems convert internal stress into structural memory, encoding functional specialization

Caloric restriction reduces metabolic disease and associated comorbidities. Yet, the molecular mechanisms encoding cellular memory of these benefits remain unclear. Here, we use a functional genomics approach to integrate evolutionary cues, single-cell sequencing, and metabolomics, identifying convergent signals that encode epigenetic memory of adaptive states in visceral adipose tissue natural killer (NK) cells. Cross-species analysis shows that genomic hubs linked to human accelerated regions (HARs) are conserved and active during dietary restriction, forming transcriptional compartments that regulate oxidative stress response and DNA repair genes. Targeted screens and multimodal profiling across human data and mouse models reveal convergent signals needed for persistent adaptation: cooperative transcriptional regulators (NRF2, CIRBP, NR4A2) at key HAR-linked genomic hubs, innate immune mediators (IL15-IL2RB), and metabolic cofactors from linoleic acid oxidation. Activity of these convergent signals reduces DNA damage and methylation and enhances epigenetic plasticity and cytotoxic functions, thereby decreasing tissue fibrosis and senescence while maintaining both local and systemic metabolic plasticity. Mechanistically, linoleic acid metabolism supplies acetyl-CoA to sustain H3K27ac epigenetic marks that maintain coordinated repair and cytotoxic programs after programming. IL15-IL2RB signaling links tissue metabolic state to NK cell function for coherent adaptive responses. We show that engineering of NK cells with this multimodal programming leads to long-term preservation of therapeutic phenotypes in metabolic aging models, rescuing systemic dysfunction through damaged cells clearance and leptin sensitivity. Overall, these findings establish that convergent signals encode persistent cellular phenotypes linked to metabolic plasticity, suggesting design principles for engineering therapeutic memory of cell function.

Energy conservation is at the basis of evolutionary optimization in living systems. Yet, how cells maintain function during metabolic stress while preserving adaptive capacity remains unclear. Here, we use a functional genomics approach to identify metabolic human accelerated regions (mHARs) genomic hubs (evolutionarily tuned regions) in adipose tissue that coordinate adaptive responses to nutrient deficit. During fasting, cooperative regulators PGC1A, YY1, and CTCF activate these hubs, promoting chromatin contacts that regulate lipid cycling genes such as Dgat1 and Atg4c. This activation maintains lipid and pH homeostasis while limiting oxidative stress, thereby preserving cellular plasticity. When disrupted, nutrient-stress adaptations are impaired leading to metabolic dysfunction and glucose intolerance. This is driven by NCOA7, an oxidative stress mediator that impairs lysosome function and transcriptional plasticity, triggering an inflammatory response. In cellular models, this mechanism blocks pH-mediated PGC1A droplet plasticity, further inhibiting mHAR-genomic hub activity and metabolic homeostasis. Human adipocytes show enhanced transcriptional activity of these genomic hubs compared to murine cells, with multi-enhancer mHAR regulation suppressing disease-associated variants linked to ANGPTL3 and PCSK9. Loss of this cooperative plasticity shifts cells to maladaptive responses, activating STAT1-driven disease gene expression. Our findings reveal that investigating the contextual activity of evolutionary adaptations can uncover functional hubs critical for stress resilience. This also shows that cells exploit nutrient fluctuations to drive tunable transcriptional organizations that lead to durable adaptations, identifying actionable targets for metabolic disease.

Toll-like receptors (TLRs) comprise an evolutionarily conserved family of pattern recognition receptors that detect microbial-associated molecular patterns and endogenous danger signals to orchestrate innate immune responses. While traditionally positioned at the frontline of host defense, accumulating evidence suggests that TLRs are at the nexus of immuno-metabolic regulation and central nervous system (CNS) homeostasis. They regulate a wide range of immune and non-immune functions, such as cytokine and chemokine signaling, and play key roles in modulating synaptic plasticity, neurogenesis, and neuronal survival. However, alterations in TLR signaling can drive a sustained pro-inflammatory state, mitochondrial dysfunction, and oxidative stress, which are highly associated with the disruption of emotional and cognitive functions and the pathogenesis of psychiatric disorders. In this review, we integrate findings from molecular to organismal levels to illustrate the diverse roles of TLRs in regulating emotion, cognition, metabolic balance, and gut–brain interactions. We also explore emerging molecular targets with the potential to guide the development of more effective therapeutic interventions.

Center-surround interactions are fundamental to visual saliency computation, but debate continues over whether and how subcortical visual circuits actively contribute. To address this, we developed an optogenetic approach to delineate the visual center and surround zones of individual neurons in the superficial layer of the superior colliculus (SCs) using only retinal ganglion cell input. Using whole-cell recordings, we demonstrate that surround network activation suppresses center excitability, indicating that SCs circuitry is self-sufficient in driving center-surround dynamics. Through cell-type-specific trans-synaptic tracing and large-scale modeling, we identified an SCs-based circuit with two key motifs driving surround modulation: recurrent excitation and feedback inhibition. We propose that subcortical visual circuits in the SCs have evolved to perform surround suppression alongside retinal and cortical suppression, facilitating the distribution of parallel saliency computations across different levels. Significance statement: This study questions the notion that the superior colliculus (SC) merely acts as a passive recipient of saliency information from upstream circuits. We demonstrate that the SC can independently generate center-surround interactions that could contribute to visual saliency through local circuits without top-down input. This ability represents a computation that has been conserved since the dawn of vertebrate evolution. By mapping these interactions, we reveal that the mouse SC actively induces visual surround suppression. These findings suggest that phylogenetically older circuits in the SC may play a more independent role in active vision than previously acknowledged, prompting a reevaluation of visual saliency processing across subcortical brain regions.

The crosstalk between the opioidergic system and mitogen-activated protein kinases (MAPKs) has a critical role in mediating stress-induced behaviors related to the pathophysiology of anxiety. The present study evaluated the basal status and stress-induced alterations of cortico-thalamic MAPKs and other cell fate-related signaling pathways potentially underlying the anxiogenic endophenotype of PDYN gene-deficient mice. Compared to littermates, PDYN knockout (KO) mice had lower cortical and or thalamic amounts of the phospho-activated MAPKs c-Jun N-terminal kinase (JNK1/2) and extracellular signal-regulated kinase (ERK1/2). Similarly, PDYN-KO animals displayed reduced cortico-thalamic densities of total and phosphorylated (at Ser191) species of the cell fate regulator Fas-associated protein with death domain (FADD) without alterations in the Fas receptor. Exposure to acute restraint and chronic mild stress stimuli induced the robust stimulation of JNK1/2 and ERK1/2 MAPKs, FADD, and Akt-mTOR pathways, without apparent increases in apoptotic rates. Interestingly, PDYN deficiency prevented stress-induced JNK1/2 and FADD but not ERK1/2 or Akt-mTOR hyperactivations. These findings suggest that cortico-thalamic MAPK- and FADD-dependent neuroplasticity might be altered in PDYN-KO mice. In addition, the results also indicate that the PDYN gene (and hence dynorphin release) may be required to stimulate JNK1/2 and FADD (but not ERK1/2 or Akt/mTOR) pathways under environmental stress conditions.

Cumulative evidence has pointed out cannabinoid CB2 receptors (CB₂r) as a potential therapeutic key target for treating alcohol use disorder (AUD). This review provides the most relevant results obtained from rodent and human studies, including an integrative section focused on the involvement of CB₂r in the neurobiology of alcohol addiction. A literature search was conducted using the electronic databases Medline and Scopus for articles. The search strategy was as follows: “Receptor, Cannabinoid, CB2” AND “Alcohol-Related Disorders” AND “human/or patients”; “Receptor, Cannabinoid, CB2” AND “Alcohol” OR “Ethanol” AND “rodents/or mice/or rats”. Pharmacological approaches demonstrated that the activation or blockade of CB₂r modulated different alcohol-addictive behaviors. Rodent models of alcoholism revealed significant alterations of CB₂r in brain areas of the reward system. In addition, mice lacking CB₂r (CB₂KO) show increased alcohol consumption, motivation, and relapse alterations. It has been stressed that the potential neurobiological mechanisms underlying their behavioral effects involve critical elements of the alcohol reward system. Interestingly, recent postmortem studies showed CNR2 alterations in brain areas of alcoholic patients. Moreover, although the number of studies is limited, the results revealed an association between some genetic alterations of the CNR2 and an increased risk for developing AUD. This review provides evidence that CB₂r may play a role in alcohol addiction. Clinical studies are necessary to figure out whether CB₂r ligands may prove useful for the treatment of AUD in humans.

Emotional behavior, memory, and learning have been associated with alterations in the immune system in neuropsychiatric and neurodegenerative diseases. In recent years, several studies pointed out the involvement of the cannabinoid receptor 2 (CB2r) in the immune system and the regulation of inflammation. This receptor is widely distributed in different tissues and organs with higher expression in spleen and immune system cells. However, CB2r has also been detected in several brain areas and different brain cell types, such as neurons and glia. These findings suggest that CB2r may closely relate the immune system and the brain circuits regulating inflammation, mood, and cognitive functions. Therefore, we review the studies that may help elucidate the molecular bases of CB2r in regulating inflammation in different brain cells and its role in the pathophysiology of psychiatric and neurodegenerative disorders.