Delirium is an acute and multifactorial syndrome that remains highly prevalent in critical illness and is associated with avoidable morbidity, persistent cognitive decline, and increased mortality. Its mechanisms appear to involve a close interaction between neuroendocrine and immune pathways, including gonadal hormones, neuroactive steroids produced within the brain, and hypothalamic-pituitary-adrenal axis activity. Because these systems differ between sexes, biological sex may influence delirium risk, clinical presentation, and recovery, although this has rarely been examined in a systematic way. Here, we discuss how estradiol, progesterone, allopregnanolone, and androgens may affect microglial responses, blood-brain barrier integrity, stress reactivity, neurotransmission, inflammation, mitochondrial function, oxidative balance, and epigenetic regulation. Clinical evidence suggests possible sex-related differences in hypoactive and hyperactive presentations, antipsychotic exposure, and ICU length of stay. Future studies should integrate sex, hormonal status, neurosteroids, and cortisol dynamics to refine delirium prevention and treatment.
Longitudinal measurement and modeling are vital for understanding pubertal processes and their effects on neural and behavioral development. This practical guide for developmental scientists incorporates findings from recent large, longitudinal studies. It reviews best practices for longitudinal studies of puberty in humans, beginning with a brief overview of puberty and two overlapping processes: adrenarche and gonadarche. It emphasizes the importance of longitudinal research in assessing factors such as pubertal tempo (rate of progression). Methods for measuring puberty in humans are discussed, along with considerations for each. The article outlines statistical modeling strategies for developmental research and highlights the roles of sex, gender, adverse experiences, and racial/ethnic identity in shaping pubertal trajectories. A resource list of key papers and data analysis code is provided to support research. This paper guides research efforts to enhance understanding of pubertal development.
RORA is a molecular hub in autism spectrum disorder (ASD) that integrate sex steroid signaling, neurodevelopmental gene regulation, circadian rhythm, immune function and metabolic homeostasis. Convergent evidence from postmortem brain, peripheral blood, methylation profiling, animal models and cellular studies indicates that RORA is frequently downregulated in ASD, disrupting downstream pathways involved in synaptogenesis, cortical development, aromatase activity and neuroimmune balance. RORA is bidirectionally regulated by sex hormone, where androgens suppresses and estrogens activates its expression, supporting frameworks for male-biased ASD risk and the female protective effect. RORA-aromatase feedback loop further biases toward androgen dominance and reduced estrogen-mediated protection. Across the lifespan, RORA deficiency may contribute to prenatal neurodevelopmental disruption, childhood circadian and metabolic abnormalities, inflammatory dysregulation and hormone-sensitive symptom fluctuations including overlap with PMDD. Although RORA is a promising biomarker and therapeutic candidate, prospective sex-stratified longitudinal studies are required to clarify its prognostic and treatment-stratification utility in ASD.
Maternal behavior emerges from neural circuits that integrate hormonal, metabolic, motivational, and sensory information. While the medial preoptic area (MPOA) is recognized as a key regulator of maternal responses, increasing evidence identifies the lateral hypothalamic area (LHA) may support successful caregiving. Through extensive connections with hypothalamic, mesolimbic, limbic, and brainstem networks, the LHA links internal physiological states to maternal behavioral output. Recent single-cell transcriptomic studies have revealed remarkable cellular and molecular diversity within the LHA, extending far beyond its traditional roles in feeding and arousal. These findings suggest that distinct LHA neuronal populations may integrate endocrine, metabolic, and social signals across pregnancy and lactation to influence maternal motivation, aggression, approach-withdrawal dynamics, and behavioral flexibility. Here, we review anatomical, functional, and transcriptomic evidence supporting a role for the LHA in maternal adaptation and propose that cell-type-specific remodeling contributes to postpartum behavioral plasticity. However, current evidence is disproportionately centered on MCH neurons, whereas the maternal functions of orexin neurons and other molecularly defined LHA populations remain largely unresolved. Moreover, whether MCH and orexin neurons exert distinct functions during early, established, and late lactation is unknown. Addressing these gaps will require temporally resolved recordings and causal manipulation of cell- and projection-defined LHA populations across postpartum stages.
Focusing on the brain-essential gene revealed in our laboratory, activity-dependent neuroprotective protein (ADNP) and its neuroprotective site, the investigational drug davunetide (NAP), we discuss ADNP regulating steroid hormone biosynthesis and sex chromosome genes coupled with sex-dependent shuttling between the nuclei and cytoplasm. Further coupled with sex-dependent transcriptional control, ADNP/davunetide cytoplasmic microtubule/Tau targeting is translated into differential sex regulation of key cellular processes including neurogenesis, synaptic function, and axonal transport, then decoded into sexual dichotomy in multicellular processes directing sex-dependent behavioral outcomes. ADNP regulation of these sex-specific processes serves as a target for davunetide intervention, toward sex-directed precision medicine, revealing sexually dichotomized neuroprotection against tauopathy risk and progression spanning from coronary artery bypass grafting (CABG) to prodromal Alzheimer's disease, progressive supranuclear palsy (PSP), and schizophrenia, as well as the pediatric ADNP syndrome. Sex-specific intranasal bioavailability of davunetide, regulated by the estrous cycle, provides a mechanistic foundation for these differential outcomes.
Rodent fear conditioning paradigms are widely used to model core features of posttraumatic stress disorder (PTSD), with freezing behaviour serving as the dominant readout. However, the extent to which freezing captures biologically and clinically relevant variability, particularly with respect to sex differences, remains unclear. We conducted a systematic review and meta-analysis of studies employing fear conditioning and extinction in wild-type rodents to assess sex differences in freezing behaviour. These were not found across studies. However, freezing levels were significantly correlated with shock intensity only in male rodents. We conclude that freezing may represent a constrained and potentially low-resolution behavioural output, which may fail to detect meaningful variation in fear processing. Given that PTSD exhibits pronounced sex differences in humans, the translational validity of commonly used behavioural endpoints may be questionable. Including both sexes and refining behavioural readouts in animal models are critical for improving the translational pipeline of stress research.
Steroid 5α-reductases (5αRs) catalyze the irreversible, NADPH-dependent reduction of Δ4-3-ketosteroids. This process regulates major steroid signaling pathways, including neurosteroid biosynthesis, androgen activation, and glucocorticoid metabolism. By governing these processes, 5αRs influence GABAergic and dopaminergic neurotransmission, and behavioral responses to stress and reward. Although the two principal isoenzymes, 5αR1 and 5αR2, have overlapping functions, they are increasingly recognized as functionally distinct. 5αR1 supports constitutive neurosteroid synthesis in several brain regions. Conversely, 5αR2, long known for converting testosterone to dihydrotestosterone during male sexual differentiation, has emerged as the enzyme that mediates rapid allopregnanolone production in the prefrontal cortex of males during acute stress. These advances may provide a framework for understanding the complex neurobehavioral profile of 5αR inhibitors such as finasteride and dutasteride. These drugs have been associated with depression, anxiety, suicidality, sexual dysfunction, and, in some individuals, persistent sexual, somatic, and neuropsychiatric symptoms after discontinuation. At the same time, 5αR inhibition may have therapeutic value in conditions characterized by excessive or maladaptive neurosteroid signaling, including tic disorders, impulse-control disorders, and substance use disorders. In this comprehensive review, we synthesize pharmacological, genetic, and behavioral evidence on the distinct contributions of 5αR1 and 5αR2 to steroid signaling across stress, sex, and development. Finally, we outline several open questions in the biology of 5αRs, the resolution of which will be essential to advancing toward mechanistically precise and clinically actionable interventions.
Sunlight exposure has shaped the evolutionary biology of most life forms through circadian entrainment. Full-spectrum sunlight regulates circadian rhythms, modulates gut and skin microbiomes, influences the gut-brain-skin axis, and drives dermal melanin and vitamin D synthesis. The skin acts as the body's largest photoreceptive organ and neuroendocrine hub. Melanocytes, keratinocytes, and immune cells in the skin translate photons into hormonal, metabolic, and neuronal signals. Melanin, present across vertebrate tissues, bacteria, and fungi, is a unifying photoreceptive molecule whose redox properties and signaling within the melanocortin pathway bridge host and microbial photic cues. Light signals the suprachiasmatic nucleus, triggering hypothalamic-pituitary-adrenal glucocorticoid release and peripheral clock expression throughout the gut-brain-skin axis, influencing rhythmic gastrointestinal functions, short-chain fatty acid production, and vagal feedback to the brain. Microbial photoreceptors, including melanin, flavins, and cryptochromes, extend the photoneuroendocrinology into the holobiont, revealing a shared molecular pathway through which light calibrates the host-microbe interactions. Shift work, nocturnal blue light, sun avoidance, abnormal feeding times, and circadian desynchrony disrupt the gut-brain-skin axis, resulting in dysbiosis, intestinal and skin epithelial barrier dysfunction, shifts in immune signaling, and metabolic disorders. Vitamin D intersects with these pathways, yet its possible circadian regulation remains unknown. This review synthesizes evidence positioning host and microbial melanin as the key signaling molecule of the melanocortin pathway, which is inherently circadian-regulated, governing metabolic and immune homeostasis across the gut-brain-skin axis. We outline mechanistic models and research gaps, and propose that reframing melanin as a holobiont photoreceptor opens therapeutic opportunities across dermatology, gastroenterology, and neuroendocrinology.
Chronic stress disrupts female reproductive function, but the central mechanisms linking stress exposure to altered gonadotropin-releasing hormone (GnRH) pulsatility remain incompletely defined. The arcuate kisspeptin/neurokinin B/dynorphin (KNDy) network is a core component of the GnRH pulse generator, yet it functions within an expanded regulatory system involving fast amino-acid neurotransmission, steroid feedback, nitric oxide signaling, glial communication, metabolic cues, and stress-responsive neuropeptides. This review synthesizes evidence showing how hypothalamic-pituitary-adrenal (HPA)-axis activation may suppress KNDy-GnRH output. Corticotropin-releasing hormone, glucocorticoids, gonadotropin-inhibitory hormone/RFamide-related peptide-3, glial inflammatory mediators, serotonergic input, and energy-sensitive neuropeptides may converge to impair GnRH pulse-generator function. We further discuss the relevance of these mechanisms to functional hypothalamic amenorrhea, stress-sensitive polycystic ovary syndrome (PCOS) phenotypes, and developmental versus adult stress exposure. Overall, stress-induced reproductive dysfunction is best understood as disrupted network-level neuroendocrine rhythm regulation.
The autonomic nervous system (ANS) plays a central role in immune homeostasis by integrating sympathetic and parasympathetic signals that regulate inflammation, immune cell trafficking, and tolerance. Aging is associated with a progressive autonomic imbalance characterized by sympathetic overactivation, reduced parasympathetic tone, and impaired β-adrenergic signaling in immune cells, which together contribute to inflammaging and immune dysregulation. In this review, we discuss how aging-related alterations in adrenergic pathways affect immune cell differentiation and cytokine networks, with particular emphasis on β₂-adrenergic control of the Th17/regulatory T cell balance through cAMP-dependent mechanisms interacting with cytokine-driven STAT signaling. Chronic sympathetic stimulation and β-adrenergic desensitization weaken these regulatory constraints, favoring pro-inflammatory immune trajectories and loss of immune tolerance. Finally, we propose Long COVID as a paradigmatic condition in which pre-existing inflammaging and autonomic vulnerability are amplified by viral infection, leading to persistent inflammation, impaired immune regulation, and increased susceptibility to autoimmune manifestations.
Hormonal dysregulation is increasingly reported in ME/CFS and Long COVID, yet the broader role of neuroendocrine disruption in these conditions remains underexplored. While changes in steroid, peptide, and neuropeptide hormones have been identified, these findings are often considered in isolation and without attention to their timing or integration within broader physiological systems. The hypothalamic-pituitary axes regulate endocrine, immune, autonomic, nervous, and metabolic functions, systems commonly affected in both conditions, yet their circadian and menstrual dynamics are rarely investigated.In this review, we examine the evidence for neuroendocrine dysfunction in ME/CFS and Long COVID, focusing on hormone output, functional assays, receptor expression, and the coordination of endocrine biorhythms. Sex hormone signalling emerges as a key area of vulnerability, particularly given the female predominance in both conditions and the complexity of reproductive hormone regulation.We argue that accurate hormone measurement and time-structured sampling, including circadian and menstrual rhythms, are essential for detecting meaningful biological differences. By embedding chronobiology-aware, dense-sampling strategies and integrating multi-omic analyses into multi-system study designs, we outline a framework for investigating dynamic endocrine mechanisms underlying symptom variability and multisystem dysfunction, which may ultimately support the development of more targeted, personalised interventions.
Among environmental pollutants, microplastics (MPs) and nanoplastics (NPs) represent a major threat to marine and terrestrial ecosystems because of their widespread distribution, environmental persistence, accumulation in animal and human organs, and toxicity. MPs and NPs target the major endocrine components, including the hypothalamic-pituitary-adrenal (HPA) and gonadal (HPG) axes, thus affecting steroid milieu with repercussions for peripheral endocrine glands and brain functions. Steroid hormones, either locally synthesized by neurons and glial cells, or reaching the brain from peripheral glands, exert neuroactive actions regulating neuronal excitability, neurogenesis, mood, and behavior. Despite numerous studies investigating the endocrine-disrupting effects of MPs/NPs and their potential reproductive toxicity, the implications of such effects on brain neuroactive steroids are poorly investigated. Here, we first illustrate how neuroactive steroids affect brain functions, then we review clinical and preclinical studies assessing the effects of MPs/NPs on neuroactive steroid levels, with the aim to understand putative implications for mental health.
NMDARs and their interacting proteins drive central sensitization in neuropathic pain, yet their pathological effects are critically shaped by upstream neuroendocrine regulators. This review synthesizes evidence across three dimensions: (i) glucocorticoids amplify pain via spinal glucocorticoid receptor signaling, and prior stress history reprograms HPA axis reactivity, thereby determining individual pain susceptibility; (ii) sex hormones produce divergent effects: estrogen exacerbates while progesterone protects and pain mechanisms are sexually dimorphic, with males and females engaging distinct immune and neuronal pathways; (iii) current therapies (ketamine, gabapentinoids) have significant limitations. Emerging preclinical strategies include neuroendocrine-directed interventions (glucocorticoid receptor antagonists, progesterone, sex-stratified trial designs) alongside protein-protein interaction disruptors targeting α2δ-1, Panx1, or PSD-95. Collectively, targeting upstream hormonal drivers offers a paradigm shift from broad NMDAR blockade toward more selective and tolerable treatments, though rigorous validation across sexes and pain phases remains essential.
Variation is a fundamental principle of natural and artificial selection. Annual cycles in daylength or photoperiod are an environmental cue that most species in the plant and animal kingdoms use to determine the time of year and the direction of annual changes. Despite phylogenetic variation in mechanisms of light detection, the neural and molecular substrates that transduce photoperiod information are common across vertebrates. However, there is considerable conditional plasticity in the neuroendocrine mechanism that govern seasonal physiology leading to a spectrum of phenotypes within a single species. Here, we cover the phylogenetic history and conditional plasticity that contribute to photoperiodic polyphenisms. This Review presents the current understanding of how light is detected and represented in the vertebrate central nervous system and highlights phenotypic variation in photoperiod responses in amniotes. The Review provides future directions for addressing gaps in understanding how photoperiodic polyphenisms are involved in adaptations to changing environments.
OBJECTIVE:As fundamental primary processes in maintaining the body's health, sleep and eating habits influence reciprocally, and this relationship is also modulated by circadian rhythms. Consistently, the literature reports various levels of alterations in sleep parameters and circadian preferences among individuals exhibiting dysfunctional eating behaviors. The present review aims to provide an up-to-date overview of case-control studies conducted to date on this topic. METHOD:A systematic literature search was conducted to detect case-control studies investigating both subjective and objective sleep parameters and circadian preferences in individuals with eating disorders. Thirty-three articles published between 1980 and 2025 were included. RESULTS:Patients with eating disorders show reduced sleep efficiency, prolonged sleep onset latency, and increased arousal levels. Specifically, individuals with anorexia nervosa experience more frequent and longer nighttime awakenings, as well as reductions in both slow-wave sleep and REM sleep. In contrast, findings related to bulimia nervosa and binge eating disorder are quite inconsistent, partly due to the limited number of studies available. Overall, individuals with eating disorders tend to exhibit a preference for evening chronotypes. DISCUSSION:This review supports the existence of an association between eating disorders and alterations in sleep and circadian rhythms. Nonetheless, current research does not provide a consistent picture of the nature, characteristics, or causality of these dysfunctions. Several factors - such as body mass index, the severity of eating disorder symptoms, and orexin levels - appear to be involved. Further investigation into these relatively understudied areas could inform the development of more effective rehabilitation strategies.
The neuropeptides orexin-A (OXA) and orexin-B (OXB), central orchestrators of arousal and energy homeostasis, are increasingly recognized as key neuromodulators within the vertebrate retina. This review synthesizes current evidence demonstrating a broad extra-hypothalamic expression of the orexin system across retinal neurons, including photoreceptors, bipolar (BCs), amacrine (ACs), and ganglion cells (GCs). We detail a sophisticated, cell-type-specific signaling framework where orexins exert complex, often antagonistic, presynaptic and postsynaptic actions via orexin 1 (OX1R) and orexin 2 (OX2R) receptors. These actions fine-tune signal transmission by potentiating glutamate release from BCs while suppressing GABAergic inhibition from ACs, ultimately modulating retinal output. A central theme emerging is the system's pivotal role in non-image-forming visual functions: OXA enhances the pupillary light reflex (PLR) by increasing the excitability of specific intrinsically photosensitive retinal ganglion cells (M2 ipRGCs), while OXB potentiates scotopic (dim-light) sensitivity by disinhibiting rod bipolar circuits. Furthermore, pharmacological inhibition of orexin receptors affects circadian rhythms in both the retina and hypothalamus. However, the field is marked by intriguing paradoxes, such as the stimulatory effects of receptor antagonists and significant species differences in OX2R expression. We critically evaluate evidence for a tonically active retinal orexin system that interfaces with dopaminergic signaling and circadian photic input. By integrating molecular, cellular, and behavioral findings, this review clarifies how retinal orexinergic modulation serves as a potential crucial interface between light detection, circadian physiology, and systemic arousal, while highlighting critical translational gaps and future research directions.
Ischemic stroke involves two interrelated pathological processes: primary ischemic brain injury and secondary cerebral ischemia-reperfusion (CI/R) injury. This condition has become a global health issue; however, effective pharmacotherapies for ameliorating cerebral ischemia (CI) and CI/R injury remain critically lacking. Members of the vascular endothelial growth factor (VEGF) family, recognized as key signaling molecules, play pivotal roles in various physiological and pathological processes, including angiogenesis, neuroprotection, neuroinflammation, and vascular permeability. Recent studies have revealed that several members of the VEGF family may mitigate CI or CI/R injury through mechanisms such as promoting angiogenesis, inhibiting neuronal apoptosis, and counteracting neuroinflammation. Paradoxically, these molecules can also exacerbate ischemic and I/R-induced brain damage by promoting blood-brain barrier disruption and intensifying inflammatory responses post-stroke. This narrative review evaluates the dual roles of distinct VEGF family members in CI and I/R injury, focusing on elucidating their underlying mechanisms. The review aims to provide a theoretical framework for optimizing VEGF-targeted therapeutic strategies, thereby maximizing neuroprotective efficacy while minimizing adverse effects in stroke treatment.
The thyroid-gut axis is a bidirectional system linking maternal endocrine function and gut microbiota, with important implications for fetal brain development. During pregnancy, maternal thyroid hormones (thyroxine and triiodothyronine) regulate neuronal growth, migration, myelination, and synapse formation. Maternal hypothyroidism, even in mild forms, can disrupt these processes, impairing neurogenesis, cortical development, and long-term cognitive outcomes in offspring. At the same time, maternal gut microbiota undergoes dynamic changes that influence thyroid hormone balance, nutrient absorption, and immune signaling through metabolites such as short-chain fatty acids, bile acids, and tryptophan derivatives. Dysbiosis may alter deiodinase activity, weaken intestinal barrier integrity, and promote inflammation, worsening thyroid dysfunction and increasing fetal vulnerability. Evidence suggests a feedback loop where microbiota affects thyroid homeostasis and thyroid hormones shape gut ecology. Emerging research indicates that microbiota-targeted therapies, diet, and environmental interventions may help restore balance, though key mechanistic gaps remain.
Disfiguring skin diseases refer to skin diseases that significantly affect one’s appearance. The development of disfiguring skin diseases is multifactorial, such as genetic, immune, and endocrine factors. However, recent research suggests that emotional distress (such as anxiety, depression, and sleep disorders) has been implicated as a key contributing factor to the onset and progression of disfiguring skin diseases, including acne, rosacea, and vitiligo; in turn, the psychosocial burden imposed by these conditions exacerbates emotional disturbances, thereby creating a self-perpetuating vicious cycle. Therefore, understanding the relationship between emotional distress and disfiguring skin diseases is essential. In recent years, the proposed concept of the “brain-skin axis” has framed the nervous, endocrine, and immune systems as an intricate regulatory network, highlighting the multilayered connections between the brain and the skin. Within the mechanistic framework of the brain-skin axis, emotional distress may alter neural and endocrine signaling, potentially disrupt normal skin homeostasis, exacerbate inflammatory responses and immune dysregulation, and impair skin barrier function; based on experimental and observational evidence, these changes may elevate susceptibility to disfiguring skin diseases. In this review, we examined the complex relationship between emotional distress and three disfiguring skin diseases (acne, rosacea, and vitiligo) from the perspective of the brain-skin axis. We also discussed the potential value of various psychosomatic interventions, including psychotherapy, pharmacotherapy and integrated therapy in improving both dermatological symptoms and psychiatric comorbidities. Understanding the interactions and mechanisms linking emotional distress and disfiguring skin diseases through the lens of the brain-skin axis can provide new insights into the diagnosis and treatment of these skin conditions.
Midlife (ages 40-59) may be a critical window to preserve cognitive health; however, the long-term impact of midlife physical activity (PA) on late-life cognition remains unclear. This systematic review synthesized cohort evidence of the relationship between midlife physical activity levels and later-life cognition, while exploring the potential moderating role of biological sex. The Medline, Embase, Web of Science, APA PsycINFO, CINAHL, and SPORTDiscus databases were searched. Cohort studies that assessed midlife physical activity and used standardized neuropsychological tests in cognitively unimpaired adults were included. Risk of bias was completed using the Risk of Bias in Non-randomized Studies-of Exposure tool. Random-effects meta-analyses (Cohen's d) compared none/low vs. moderate/high PA for global cognition, verbal episodic memory, executive functions, verbal fluency, and processing speed domains. Fifteen studies (n = 33,295; 66.1% female) were included in the qualitative synthesis, with eight used in the meta-analyses. All studies relied on self-reported PA measures, and only one study completed sex-stratified analyses. Higher midlife PA was associated with better later-life global cognition (d = 0.22, 95% CI: 0.06-0.38), verbal episodic memory (d = 0.19, 95% CI: 0.06-0.32), and processing speed (d = 0.20, 95% CI: 0.03-0.36). Heterogeneity was substantial (I2 72.2-84.7%). Pooled effects were not significant for executive functions (d = 0.09, -0.16-0.34) or verbal fluency (d = - 0.03, 95% CI: -0.21-0.16). Midlife PA showed modest, albeit population-meaningful associations with higher later-life global cognition, episodic memory, and processing speed. Future cohorts should standardize and incorporate objective PA metrics and ensure inclusion of sex-stratified estimates to clarify dose-response and sex-specific effects.
