Plasticity-led and mutation-led evolutions are different modes of the same developmental gene regulatory network.

The standard theory of evolution proposes that mutations cause heritable variations, which are naturally selected, leading to evolution. However, this mutation-led evolution (MLE) is being questioned by an alternative theory called plasticity-led evolution (PLE). PLE suggests that an environmental change induces adaptive phenotypes, which are later genetically accommodated. According to PLE, developmental systems should be able to respond to environmental changes adaptively. However, developmental systems are known to be robust against environmental and mutational perturbations. Thus, we expect a transition from a robust state to a plastic one. To test this hypothesis, we constructed a gene regulatory network (GRN) model that integrates developmental processes, hierarchical regulation, and environmental cues. We then simulated its evolution over different magnitudes of environmental changes. Our findings indicate that this GRN model exhibits PLE under large environmental changes and MLE under small environmental changes. Furthermore, we observed that the GRN model is susceptible to environmental or genetic fluctuations under large environmental changes but is robust under small environmental changes. This indicates a breakdown of robustness due to large environmental changes. Before the breakdown of robustness, the distribution of phenotypes is biased and aligned to the environmental changes, which would facilitate rapid adaptation should a large environmental change occur. These observations suggest that the evolutionary transition from mutation-led to plasticity-led evolution is due to a developmental transition from robust to susceptible regimes over increasing magnitudes of environmental change. Thus, the GRN model can reconcile these conflicting theories of evolution.

Evolutionary divergence of plasticity in brain morphology between ecologically divergent habitats of Trinidadian guppies.

Phenotypic plasticity is critical for organismal performance and can evolve in response to natural selection. Brain morphology is often developmentally plastic, affecting animal performance in a variety of contexts. However, the degree to which plasticity of brain morphology evolves has rarely been explored. Here we use Trinidadian guppies (Poecilia reticulata), which are known for their repeated adaptation to high-predation (HP) and low-predation (LP) environments, to examine the evolution and plasticity of brain morphology. We exposed second-generation offspring of individuals from HP and LP sites to two different treatments: predation cues and conspecific social environment. Results show that LP guppies had greater plasticity in brain morphology compared to their ancestral HP population, suggesting that plasticity can evolve in response to environmentally divergent habitats. We also show sexual dimorphism in the plasticity of brain morphology, highlighting the importance of considering sex-specific variation in adaptive diversification. Overall, these results may suggest the evolution of brain morphology plasticity as an important mechanism that allows for ecological diversification and adaptation to divergent habitats.

Daphnia uses its circadian clock for short-day recognition in environmental sex determination.

Some organisms have developed a mechanism called environmental sex determination (ESD), which allows environmental cues, rather than sex chromosomes or genes, to determine offspring sex.1,2,3,4 ESD is advantageous to optimize sex ratios according to environmental conditions, enhancing reproductive success.5,6 However, the process by which organisms perceive and translate diverse environmental signals into offspring sex remains unclear. Here, we analyzed the environmental perception mechanism in the crustacean, Daphnia pulex, a seasonal (photoperiodic) ESD arthropod, capable of producing females under long days and males under short days.7,8,9,10 Through breeding experiments, we found that their circadian clock likely contributes to perception of day length. To explore this further, we created a genetically modified daphnid by knocking out the clock gene, period, using genome editing. Knockout disrupted the daphnid's ability to sustain diel vertical migration (DVM) under constant darkness, driven by the circadian clock, and leading them to produce females regardless of day length. Additionally, when exposed to an analog of juvenile hormone (JH), an endocrine factor synthesized in mothers during male production, or subjected to unfavorable conditions of high density and low food availability, these knockout daphnids produced males regardless of day length, like wild-type daphnids. Based on these findings, we propose that recognizing short days via the circadian clock is the initial step in sex determination. This recognition subsequently triggers male production by signaling the endocrine system, specifically via the JH signal. Establishment of a connection between these two processes may be the crucial element in evolution of ESD in Daphnia.

Exploring Intraspecific Trait Variation in a Xerophytic Moss Species Indusiella thianschanica (Ptychomitriaceae) across Environmental Gradients on the Tibetan Plateau.

Investigating intraspecific trait variability is crucial for understanding plant adaptation to various environments, yet research on lithophytic mosses in extreme environments remains scarce. This study focuses on Indusiella thianschanica Broth. Hal., a unique lithophytic moss species in the extreme environments of the Tibetan Plateau, aiming to uncover its adaptation and response mechanisms to environmental changes. Specimens were collected from 26 sites across elevations ranging from 3642 m to 5528 m, and the relationships between 23 morphological traits and 15 environmental factors were analyzed. Results indicated that coefficients of variation (CV) ranged from 5.91% to 36.11%, with gametophyte height (GH) and basal cell transverse wall thickness (STW) showing the highest and lowest variations, respectively. Temperature, elevation, and potential evapo-transpiration (PET) emerged as primary environmental drivers. Leaf traits, especially those of the leaf sheath, exhibited a more pronounced response to the environment. The traits exhibited apparent covariation in response to environmental challenges and indicated flexible adaptive strategies. This study revealed the adaptation and response patterns of different morphological traits of I. thianschanica to environmental changes on the Tibetan Plateau, emphasizing the significant effect of temperature on trait variation. Our findings deepen the understanding of the ecology and adaptive strategies of lithophytic mosses.

A prenatal acoustic signal of heat reduces a biomarker of chronic stress at adulthood across seasons.

During development, phenotype can be adaptively modulated by environmental conditions, sometimes in the long-term. However, with weather variability increasing under climate change, the potential for maladaptive long-term responses to environmental variations may increase. In the arid-adapted zebra finch, parents emit "heat-calls" when experiencing heat during incubation, which adaptively affects offspring growth in the heat, and adult heat tolerance. This suggests that heat-call exposure may adjust individual phenotype to hot conditions, potentially compromising individual sensitivity to cool weather conditions. To test this hypothesis, we manipulated individual prenatal acoustic and postnatal thermal experiences during development, and sought to assess subsequent chronic responses to thermal fluctuations at adulthood. We thus measured heterophil to lymphocyte (H/L) ratios in adults, when held in outdoor aviaries during two summers and two winters. We found that birds exposed to heat-calls as embryos, had consistently lower H/L ratios than controls at adulthood, indicative of lower chronic stress, irrespective of the season. Nonetheless, in all birds, the H/L ratio did vary with short-term weather fluctuations (2, 5 or 7 days), increasing at more extreme (low and high) air temperatures. In addition, the H/L ratio was higher in males than females. Overall, while H/L ratio may reflect how individuals were being impacted by temperature, heat-call exposed individuals did not show a stronger chronic response in winter, and instead appeared more resilient to thermal variability than control individuals. Our findings therefore suggest that heat-call exposure did not compromise individual sensitivity to low temperatures at adulthood. Our study also reveals that prenatal sound can lead to long-term differences in individual physiology or quality/condition, as reflected by H/L ratios, which are consistent with previously-demonstrated reproductive fitness differences.

Morphological, Anatomical, and Physiological Characteristics of Heteroblastic Acacia melanoxylon Grown under Weak Light.

Acacia melanoxylon is a fast-growing macrophanerophyte with strong adaptability whose leaf enables heteromorphic development. Light is one of the essential environmental factors that induces the development of the heteroblastic leaf of A. melanoxylon, but its mechanism is unclear. In this study, the seedlings of A. melanoxylon clones were treated with weak light (shading net with 40% of regular light transmittance) and normal light (control) conditions for 90 d and a follow-up observation. The results show that the seedlings' growth and biomass accumulation were inhibited under weak light. After 60 days of treatment, phyllodes were raised under the control condition while the remaining compound was raised under weak light. The balance of root, stem, and leaf biomass changed to 15:11:74 under weak light, while it was 40:15:45 under control conditions. After comparing the anatomical structures of the compound leaves and phyllode, they were shown to have their own strategies for staying hydrated, while phyllodes were more able to control water loss and adapt to intense light. The compound leaves exhibited elevated levels of K, Cu, Ca, and Mg, increased antioxidant enzyme activity and proline content, and higher concentrations of chlorophyll a, carotenoids, ABA, CTK, and GA. However, they displayed a relatively limited photosynthetic capacity. Phyllodes exhibited higher levels of Fe, cellulose, lignin, IAA content, and high photosynthetic capacity with a higher maximum net photosynthetic rate, light compensation point, dark respiration rate, and water use efficiency. The comparative analysis of compound leaves and phyllodes provides a basis for understanding the diverse survival strategies that heteroblastic plants employ to adapt to environmental changes.

Social niche shapes social behavior and cortisol concentrations during adolescence in female guinea pigs.

Individualized social niches arise in social groups, resulting in divergent social behavior profiles among group members. During sensitive life phases, the individualized social niche can profoundly impact the development of social behavior and associated phenotypes such as hormone (e.g. cortisol) concentrations. Focusing on adolescence, we investigated the relationship between the individualized social niche, social behavior, and cortisol concentrations (baseline and responsiveness) in female guinea pigs. Females were pair-housed in early adolescence (initial social pair formation), and a social niche transition was induced after six weeks by replacing the partner with either a larger or smaller female. Regarding social behavior, dominance status was associated with aggression in both the initial social pairs and after the social niche transition, and the results suggest that aggression was rapidly and completely reshaped after the social niche transition. Meanwhile, submissive behavior was rapidly reshaped after the social niche transition, but this was incomplete. The dominance status attained in the initial social pair affected the extent of submissive behavior after the social niche transition, and this effect was still detected three weeks after the social niche transition. Regarding cortisol concentrations, higher baseline cortisol concentrations were measured in dominant females in the initial social pairs. After the social niche transition, cortisol responsiveness significantly increased for the females paired with a larger, older female relative to those paired with a smaller, younger female. These findings demonstrate that the social niche during adolescence plays a significant role in shaping behavior and hormone concentrations in females.

Spontaneous intersibling polymorphism in the development of dopaminergic neuroendocrine cells in sea urchin larvae: impacts on the expansion of marine benthic species.

Introduction: The plasticity of the nervous system plays a crucial role in shaping adaptive neural circuits and corresponding animal behaviors. Understanding the mechanisms underlying neural plasticity during development and its implications for animal adaptation constitutes an intriguing area of research. Sea urchin larvae offer a fascinating subject for investigation due to their remarkable evolutionary and ecological diversity, as well as their diverse developmental forms and behavioral patterns. Materials and methods: We conducted immunochemical and histochemical analyses of serotonin-containing (5-HT-neurons) and dopamine-containing (DA-positive) neurons to study their developmental dynamics in two sea urchin species: Mesocentrotus nudus and Paracentrotus lividus. Our approach involved detailed visualization of 5-HT- and DA-positive neurons at gastrula-pluteus stages, coupled with behavioral assays to assess larval upward and downward swimming in the water column, with a focus on correlating cell numbers with larval swimming ability. Results: The study reveals a heterochronic polymorphism in the appearance of post-oral DA-positive neuroendocrine cells and confirms the stable differentiation pattern of apical 5-HT neurons in larvae of both species. Notably, larvae of the same age exhibit a two- to four-fold difference in DA neurons. An increased number of DA neurons and application of dopamine positively correlate with larval downward swimming, whereas 5-HT-neurons and serotonin application induce upward swimming. The ratio of 5-HT/DA neurons determines the stage-dependent vertical distribution of larvae within the water column. Consequently, larvae from the same generation with a higher number of DA-positive neurons tend to remain at the bottom compared to those with fewer DA-positive neurons. Discussion: The proportion of 5-HT and DA neurons within larvae of the same age underlies the different potentials of individuals for upward and downward swimming. A proposed model illustrates how coordination in humoral regulation, based on heterochrony in DA-positive neuroendocrine cell differentiation, influences larval behavior, mitigates competition between siblings, and ensures optimal population expansion. The study explores the evolutionary and ecological implications of these neuroendocrine adaptations in marine species.

The role of phenotypic plasticity and corticosterone in coping with pond drying conditions in yellow-bellied toad (Bombina variegata, Linnaeus 1758) tadpoles.

Amphibian larvae inhabiting temporary ponds often exhibit the capacity to accelerate development and undergo metamorphosis in challenging conditions like desiccation. However, not all species exhibit this ability, the yellow-bellied toad (Bombina variegata) is one such example. The underlying mechanisms behind the inability to accelerate development under desiccation remain largely unexplored. The hypothalamic-pituitary-interrenal (HPI) axis and corticosterone (CORT), which act synergistically with thyroid hormone, are thought to facilitate metamorphosis in response to desiccation stress. In this study, we aimed to investigate whether modification in the HPI axis, particularly CORT levels, contributes to the absence of adaptive plasticity in B. variegata under desiccation stress. The study design included four treatments: high water level, high water level with exogenous CORT, low water level, and low water level with metyrapone (a CORT synthesis inhibitor). The main objective was to evaluate the effects of these treatments on whole-body corticosterone levels, life history, morphological traits, and oxidative stress parameters during the prometamorphic and metamorphic climax developmental stages. While low water level had no effect on total corticosterone levels, larval period, body condition index, and metamorphic body shape, it negatively affected metamorph size, mass, and growth rate. Our findings suggest that constant exposure to desiccation stress over generations may have led to modifications in the HPI axis activity in B. variegata, resulting in adaptation to changes in water level, evident through the absence of stress response. Consequently, CORT may not be a relevant stress indicator in desiccation conditions for this species.

Extending cognition: a vegetal rejoinder to extensionless thought and to extended cognition.

In this paper, we propose a crucial supplement to the framework of plant cognition, namely extending cognition. We argue that plants and other organisms with an open-ended body plan actively extend their cognition when growing tissues or organs. Their cognition expands with their body expansion. After considering the defining features of extending cognition, we present a model where growth, along with aspects of plant physiology (e.g. biochemical exudates), as well as the "negative extension" of growing away from obstacles or stressful environments, are the building blocks for a more refined understanding of plant cognition. We conclude by outlining the general implications of the theory of extending cognition and indicating directions for future research.

Transfer of membrane(s) matter(s)-non-genetic inheritance of (metabolic) phenotypes?

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are anchored at the outer phospholipid layer of eukaryotic plasma membranes exclusively by a glycolipid. GPI-APs are not only released into extracellular compartments by lipolytic cleavage. In addition, certain GPI-APs with the glycosylphosphatidylinositol anchor including their fatty acids remaining coupled to the carboxy-terminus of their protein components are also detectable in body fluids, in response to certain stimuli, such as oxidative stress, radicals or high-fat diet. As a consequence, the fatty acid moieties of GPI-APs must be shielded from access of the aqueous environment by incorporation into membranes of extracellular vesicles or into micelle-like complexes together with (lyso)phospholipids and cholesterol. The GPI-APs released from somatic cells and tissues are transferred via those complexes or EVs to somatic as well as pluripotent stem cells with metabolic consequences, such as upregulation of glycogen and lipid synthesis. From these and additional findings, the following hypotheses are developed: i) Transfer of GPI-APs via EVs or micelle-like complexes leads to the induction of new phenotypes in the daughter cells or zygotes, which are presumably not restricted to metabolism. ii) The membrane topographies transferred by the concerted action of GPI-APs and interacting components are replicated by self-organization and self-templation and remain accessible to structural changes by environmental factors. iii) Transfer from mother cells and gametes to their daughter cells and zygotes, respectively, is not restricted to DNA and genes, but also encompasses non-genetic matter, such as GPI-APs and specific membrane constituents. iv) The intergenerational transfer of membrane matter between mammalian organisms is understood as an epigenetic mechanism for phenotypic plasticity, which does not rely on modifications of DNA and histones, but is regarded as molecular mechanism for the inheritance of acquired traits, such as complex metabolic diseases. v) The missing interest in research of non-genetic matter of inheritance, which may be interpreted in the sense of Darwin's "Gemmules" or Galton's "Stirps", should be addressed in future investigations of the philosophy of science and sociology of media.

Range expansion can promote the evolution of plastic generalism in coarse-grained landscapes.

Phenotypic plasticity is one way for organisms to deal with variable environments through generalism. However, plasticity is not found universally and its evolution may be constrained by costs and other limitations such as complexity: the need for multiple mutational steps before the adaptation is realized. Theory predicts that greater experienced heterogeneity, such as organisms may encounter when spatial heterogeneity is fine-grained relative to dispersal, should favor the evolution of a broader niche. Here we tested this prediction via simulation. We found that, contrary to classical predictions, coarse-grained landscapes can be the most favorable for the evolution of plasticity, but only when populations encounter those landscapes through range expansion. During these range expansions, coarse-grained landscapes select for each step in the complex mutational pathway to plastic generalism by blocking the dispersal of specialists. These circumstances provide ecological opportunities for innovative mutations that change the niche. Our results indicate a new mechanism by which range expansion and spatially structured landscapes interact to shape evolution and reveal that the environments in which a complex adaptation has the highest fitness may not be the most favorable for its evolution.

Synergistic response to climate stressors in coral is associated with genotypic variation in baseline expression.

As environments are rapidly reshaped due to climate change, phenotypic plasticity plays an important role in the ability of organisms to persist and is considered an especially important acclimatization mechanism for long-lived sessile organisms such as reef-building corals. Often, this ability of a single genotype to display multiple phenotypes depending on the environment is modulated by changes in gene expression, which can vary in response to environmental changes via two mechanisms: baseline expression and expression plasticity. We used transcriptome-wide expression profiling of eleven genotypes of common-gardened Acropora cervicornis to explore genotypic variation in the expression response to thermal and acidification stress, both individually and in combination. We show that the combination of these two stressors elicits a synergistic gene expression response, and that both baseline expression and expression plasticity in response to stress show genotypic variation. Additionally, we demonstrate that frontloading of a large module of coexpressed genes is associated with greater retention of algal symbionts under combined stress. These results illustrate that variation in the gene expression response of individuals to climate change stressors can persist even when individuals have shared environmental histories, affecting their performance under future climate change scenarios.

Lanthanum Significantly Contributes to the Growth of the Fine Roots' Morphology and Phosphorus Uptake Efficiency by Increasing the Yield and Quality of Glycyrrhiza uralensis Taproots.

The occurrence of different degrees of phosphorus deficiency in the vast majority of G. uralensis cultivation regions worldwide is common. There is a pressing need within the cultivated G. uralensis industry to identify appropriate exogenous substances that can enhance the uptake of phosphorus and improve both the yield and quality of the taproots of G. uralensis. This study was conducted to investigate the fine root and taproot morphology, physiological characteristics, and secondary metabolite accumulation in response to the supply of varying concentrations of LaCl3 to G. uralensis, to determine the optimal concentration of LaCl3 that can effectively enhance the yield and quality of G. uralensis's taproots, while also alleviating its reliance on soil phosphate fertilizer. The findings indicate that the foliar application of lanthanum enhanced root activity and increased APase activity, eliciting alterations in the fine root morphology, leading to promoting the accumulation of biomass in grown G. uralensis when subjected to P-deficient conditions. Furthermore, it was observed that the nutrient uptake of G. uralensis was significantly improved when subjected to P-deficient conditions but treated with LaCl3. Additionally, the yield and quality of the medicinal organs of G. uralensis were significantly enhanced.

Emerging Roles of Epigenetics in Grapevine and Winegrowing.

Epigenetics refers to dynamic chemical modifications to the genome that can perpetuate gene activity without changes in the DNA sequence. Epigenetic mechanisms play important roles in growth and development. They may also drive plant adaptation to adverse environmental conditions by buffering environmental variation. Grapevine is an important perennial fruit crop cultivated worldwide, but mostly in temperate zones with hot and dry summers. The decrease in rainfall and the rise in temperature due to climate change, along with the expansion of pests and diseases, constitute serious threats to the sustainability of winegrowing. Ongoing research shows that epigenetic modifications are key regulators of important grapevine developmental processes, including berry growth and ripening. Variations in epigenetic modifications driven by genotype-environment interplay may also lead to novel phenotypes in response to environmental cues, a phenomenon called phenotypic plasticity. Here, we summarize the recent advances in the emerging field of grapevine epigenetics. We primarily highlight the impact of epigenetics to grapevine stress responses and acquisition of stress tolerance. We further discuss how epigenetics may affect winegrowing and also shape the quality of wine.

Unraveling root and rhizosphere traits in temperate maize landraces and modern cultivars: Implications for soil resource acquisition and drought adaptation.

A holistic understanding of plant strategies to acquire soil resources is pivotal in achieving sustainable food security. However, we lack knowledge about variety-specific root and rhizosphere traits for resource acquisition, their plasticity and adaptation to drought. We conducted a greenhouse experiment to phenotype root and rhizosphere traits (mean root diameter [Root D], specific root length [SRL], root tissue density, root nitrogen content, specific rhizosheath mass [SRM], arbuscular mycorrhizal fungi [AMF] colonization) of 16 landraces and 22 modern cultivars of temperate maize (Zea mays L.). Our results demonstrate that landraces and modern cultivars diverge in their root and rhizosphere traits. Although landraces follow a 'do-it-yourself' strategy with high SRLs, modern cultivars exhibit an 'outsourcing' strategy with increased mean Root Ds and a tendency towards increased root colonization by AMF. We further identified that SRM indicates an 'outsourcing' strategy. Additionally, landraces were more drought-responsive compared to modern cultivars based on multitrait response indices. We suggest that breeding leads to distinct resource acquisition strategies between temperate maize varieties. Future breeding efforts should increasingly target root and rhizosphere economics, with SRM serving as a valuable proxy for identifying varieties employing an outsourcing resource acquisition strategy.

Effects of color variation and physiological state on ascidian microbiomes.

Ascidians, known for their color variation, host species-specific microbial symbiont communities. Some ascidians can also transition into a nonfiltering (resting) physiological state. Recent studies suggest that the microbial symbiont communities may vary across different physiological states and color morphs of the host. The colonial ascidian, Polyclinum constellatum, which exhibits several color morphs in the Caribbean Sea, periodically ceases its filtering activity. To investigate if color variation in P. constellatum is indicative of sibling speciation, we sequenced fragments of the ribosomal 18S rRNA and the mitochondrial cytochrome oxidase subunit I genes. Additionally, we sequenced a fragment of the 16S rRNA gene to characterize the microbial communities of two common color morphs (red and green) in colonies that were either actively filtering (active) or nonfiltering (resting). Phylogenetic analyses of both ascidian genes resulted in well-supported monophyletic clades encompassing all color variants of P. constellatum. Interestingly, no significant differences were observed among the microbial communities of the green and red morphs, suggesting that color variation in this species is a result of intraspecific variation. However, the host's physiological state significantly influenced the microbial community structure. Nonfiltering (resting) colonies hosted higher relative abundances of Kiloniella (Alphaproteobacteria) and Fangia (Gammaproteobacteria), while filtering colonies hosted more Reugeria (Alphaproteobacteria) and Endozoicomonas (Gammaproteobacteria). This study demonstrates that microbial symbiont communities serve as reliable indicators of the taxonomic state of their host and are strongly influenced by the host's feeding condition.

Starvation resistance in the nematode Pristionchus pacificus requires a conserved supplementary nuclear receptor.

Nuclear hormone receptors (NHRs) are a deeply-conserved superfamily of metazoan transcription factors, which fine-tune the expression of their regulatory target genes in response to a plethora of sensory inputs. In nematodes, NHRs underwent an explosive expansion and many species have hundreds of nhr genes, most of which remain functionally uncharacterized. However, recent studies have reported that two sister receptors, Ppa-NHR-1 and Ppa-NHR-40, are crucial regulators of feeding-structure morphogenesis in the diplogastrid model nematode Pristionchus pacificus. In the present study, we functionally characterize Ppa-NHR-10, the sister paralog of Ppa-NHR-1 and Ppa-NHR-40, aiming to reveal whether it too regulates aspects of feeding-structure development. We used CRISPR/CAS9-mediated mutagenesis to create small frameshift mutations of this nuclear receptor gene and applied a combination of geometric morphometrics and unsupervised clustering to characterize potential mutant phenotypes. However, we found that Ppa-nhr-10 mutants do not show aberrant feeding-structure morphologies. Instead, multiple RNA-seq experiments revealed that many of the target genes of this receptor are involved in lipid catabolic processes. We hypothesized that their mis-regulation could affect the survival of mutant worms during starvation, where lipid catabolism is often essential. Indeed, using novel survival assays, we found that mutant worms show drastically decreased starvation resistance, both as young adults and as dauer larvae. We also characterized genome-wide changes to the transcriptional landscape in P. pacificus when exposed to 24 h of acute starvation, and found that Ppa-NHR-10 partially regulates some of these responses. Taken together, these results demonstrate that Ppa-NHR-10 is broadly required for starvation resistance and regulates different biological processes than its closest paralogs Ppa-NHR-1 and Ppa-NHR-40.

Neuroinflammation and acquired traumatic CNS injury: a mini review.

Acquired traumatic central nervous system (CNS) injuries, including traumatic brain injury (TBI) and spinal cord injury (SCI), are devastating conditions with limited treatment options. Neuroinflammation plays a pivotal role in secondary damage, making it a prime target for therapeutic intervention. Emerging therapeutic strategies are designed to modulate the inflammatory response, ultimately promoting neuroprotection and neuroregeneration. The use of anti-inflammatory agents has yielded limited support in improving outcomes in patients, creating a critical need to re-envision novel approaches to both quell deleterious inflammatory processes and upend the progressive cycle of neurotoxic inflammation. This demands a comprehensive exploration of individual, age, and sex differences, including the use of advanced imaging techniques, multi-omic profiling, and the expansion of translational studies from rodents to humans. Moreover, a holistic approach that combines pharmacological intervention with multidisciplinary neurorehabilitation is crucial and must include both acute and long-term care for the physical, cognitive, and emotional aspects of recovery. Ongoing research into neuroinflammatory biomarkers could revolutionize our ability to predict, diagnose, and monitor the inflammatory response in real time, allowing for timely adjustments in treatment regimens and facilitating a more precise evaluation of therapeutic efficacy. The management of neuroinflammation in acquired traumatic CNS injuries necessitates a paradigm shift in our approach that includes combining multiple therapeutic modalities and fostering a more comprehensive understanding of the intricate neuroinflammatory processes at play.

Highland deer mice support increased thermogenesis in response to chronic cold hypoxia by shifting uptake of circulating fatty acids from muscles to brown adipose tissue.

During maximal cold challenge (cold-induced V̇O2,max) in hypoxia, highland deer mice (Peromyscus maniculatus) show higher rates of circulatory fatty acid delivery compared with lowland deer mice. Fatty acid delivery also increases with acclimation to cold hypoxia (CH) and probably plays a major role in supporting the high rates of thermogenesis observed in highland deer mice. However, it is unknown which tissues take up these fatty acids and their relative contribution to thermogenesis. The goal of this study was to determine the uptake of circulating fatty acids into 24 different tissues during hypoxic cold-induced V̇O2,max, by using [1-14C]2-bromopalmitic acid. To uncover evolved and environment-induced changes in fatty acid uptake, we compared lab-born and -raised highland and lowland deer mice, acclimated to either thermoneutral (30°C, 21 kPa O2) or CH (5°C, 12 kPa O2) conditions. During hypoxic cold-induced V̇O2,max, CH-acclimated highlanders decreased muscle fatty acid uptake and increased uptake into brown adipose tissue (BAT) relative to thermoneutral highlanders, a response that was absent in lowlanders. CH acclimation was also associated with increased activities of enzymes citrate synthase and ß-hydroxyacyl-CoA dehydrogenase in the BAT of highlanders, and higher levels of fatty acid translocase CD36 (FAT/CD36) in both populations. This is the first study to show that cold-induced fatty acid uptake is distributed across a wide range of tissues. Highland deer mice show plasticity in this fatty acid distribution in response to chronic cold hypoxia, and combined with higher rates of tissue delivery, this contributes to their survival in the cold high alpine environment.