Depression has been associated with negative skeletal outcomes, but the specific characteristics and underlying mechanisms remain incompletely understood. This narrative review summarizes clinical and preclinical studies in this field. Current findings suggest that depression may be associated with lower bone mineral density, altered bone remodeling and microarchitecture, and increased risks of falls and fractures. The magnitude and pattern of these associations may vary according to depression severity and chronicity, skeletal site, sex, and life stage. Experimental studies indicate that skeletal changes may involve impaired bone formation, increased bone resorption, or both. Candidate mechanisms include dysregulation of the hypothalamic-pituitary-adrenal axis, sympathetic activation, inflammation, alterations in calcium, vitamin D metabolism, and behavioral and treatment-related factors. Better longitudinal and mechanistic studies are needed to identify patients at greatest skeletal risk.
Progesterone production by the placenta leads to elevated levels of neurosteroids in both the maternal and fetal circulations during late gestation. Among these, allopregnanolone is critical for fetal brain development, providing neuroprotective and trophic support by limiting excessive neuronal excitation and promoting oligodendrocyte development and myelination. Pregnancy complications, particularly preterm birth, can substantially reduce or eliminate this neurosteroid support, increasing vulnerability to hypoxic and excitotoxic injury. Reduced neurosteroid support is also associated with alterations in oligodendrocyte maturation and myelination, which may contribute to subsequent neurodevelopmental and behavioural abnormalities. This in turn contributes to the onset of behavioural disorders including attention deficit hyperactivity disorder (ADHD). Importantly, often experience poorer outcomes following preterm birth and other perinatal insults. Increasing allopregnanolone action using the synthetic analogue, zuranolone, markedly improved myelination after premature delivery in an animal model. Treatment with the mitochondrial translocator protein (TSPO) ligand etifoxine, which promotes endogenous allopregnanolone production, provided protective effects in primary cell cultures following oxygen-glucose deprivation in vitro. Prematurely delivered male offspring showed markedly increased hyperactive behaviour which was also reversed by zuranolone therapy. Female offspring exhibited reduced myelination following preterm birth, without evidence of oligodendrocyte maturational arrest, and this hypomyelination was restored by zuranolone therapy. In contrast, males showed oligodendrocyte maturational arrest and a hyperactive behavioural phenotype. Together, these findings suggest that the effects of preterm birth on white matter development may differ between males and females. These findings support further investigation of allopregnanolone replacement therapy after preterm birth, including pharmacokinetic, safety, toxicology and efficacy studies in neonatal populations.
Thyroid hormones (THs) are essential regulators of brain development known for their roles in neuronal proliferation, migration, differentiation, and maturation. However, brain development relies on coordinated interactions among neural, glial, vascular, and extracellular matrix components, supporting a broader role for TH beyond neuronal effects.Here, we examine how spatial regulation of TH availability contributes to neurovascular development by integrating findings from developmental animal models, human fetal tissue, cerebral organoids, and TH transport disorders. We discuss the molecular mechanisms controlling TH availability and examine how TH signaling influences angiogenesis, astrocyte maturation, extracellular matrix remodeling, and blood-brain barrier formation.Together, these findings support a conceptual framework in which local regulation of TH action may coordinate signaling among vascular, glial, and neural compartments during neurovascular unit assembly. This perspective provides a hypothesis-generating framework for understanding how impaired TH signaling may affect multiple developmental processes simultaneously, including maternal thyroid dysfunction and transport disorders.
The consequences of hypothalamic-pituitary-adrenal (HPA) axis activation depend on the area under the curve of the response, including the post-stress period. However, scarce attention has been paid to factors other than negative glucocorticoid feedback (nGF) that can affect its time course. Here, I analyze the influence of stressor characteristics, aging, prior early life and adult stress experiences. Although nGF contributes to shape the initial response, the decline during prolonged emotional stress may largely stem from a safety signal triggered when stress exposure lacks real damage, alongside an inability to sustain a high response to severe stressors. This safety signal appears to be the primary factor reducing the response after repeated experience with the same stressor, particularly during post-stress recovery. The brain origin and processes determining this safety signal remain to be characterized.
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.
