Sex differences in neuropsychiatry and neuropharmacology: animal models and clinical settings

Sex profoundly shapes brain function, behavior, and treatment response. Gonadal steroids, estrous cycle phase, and developmental hormone exposure modulate reward valuation, effort, drug taking, and relapse, and males and females differ in the efficacy and adverse-effect profile of psychoactive drugs. Yet preclinical neuroscience has historically relied on, and still runs largely on, male models, treating sex as noise rather than as a fundamental biological variable. Sex-inclusive designs are now widely required, and the proportion of studies including both sexes has risen accordingly. Analysis has not kept pace. Surveys of the published literature report that studies with factorial designs often do not test for an interaction between sex and treatment, that sex-specific effects are frequently claimed from a result significant in one sex but not the other, and that data are pooled across the sexes without first testing for a difference. Three further issues remain unresolved. Experimenter sex is a documented source of variance in rodent research, yet no widely adopted standard exists for reporting, balancing, or modelling it. Cycle monitoring methods differ in the information they return and the handling they impose, and there is no agreed guidance on when staging is required for a given readout. And the relationship between sex-inclusive design and the Reduction principle of the 3Rs remains contested: factorial designs allow both sexes to be studied within a single experiment, but powering them to detect interactions rather than main effects raises questions about animal numbers that are not yet settled. This Research Topic sets out to close these gaps. We welcome rigorous, mechanistic, and methodologically explicit work that does not merely “include females” but explicitly interrogates how sex and hormonal status shape behavior, its neural substrates, and treatment response, and that reports design and analysis in enough detail to be reused.The collection is anchored in behavioral neuroscience readouts, with particular emphasis on motivation and reward - operant self-administration, progressive-ratio responding, effort- and value-based decision-making, extinction and reinstatement - and on neuropharmacological approaches, from acute challenge to chronic treatment, across antidepressants, antipsychotics, analgesics, and drugs of abuse. Work testing the same readout in animal models and in human participants is particularly welcome.We welcome Original Research, Brief Research Reports, Methods, Reviews, Mini-Reviews, Perspectives, and Opinion articles addressing, but not limited to, the following:Behavioral phenotypes and paradigms• Sex differences in animal models of neuropsychiatric disorders, for example anxiety- and depression-like phenotypes. • Sex differences in social interaction, aggression, and parental care, including studies reporting null or partial differences.• Learning, memory, and cognitive flexibility across the estrous or menstrual cycle, and after gonadectomy or hormone replacement.• Reward, motivation, and effort- or value-based decision-making, including anhedonia-like phenotypes and natural versus drug reward.• Addiction-relevant behavior: acquisition and escalation of self-administration, progressive-ratio breakpoints, extinction, and cue-, drug-, or stress-induced reinstatement.Neurochemical and circuit mechanisms• Sex-dependent modulation of the monoamine, amino-acid, and neuropeptide systems that support motivation, reward, and affect, including established drug targets.• Circuit- and cell-type-specific sex differences in reward, stress, and decision-making circuitry, using electrophysiology, imaging, chemogenetics, or optogenetics.• Synaptic, transcriptomic, or epigenetic differences that map onto a behavioral or treatment-response phenotype.• Neuroimmune and glial contributions to sex differences in psychiatric-relevant behavior.Hormonal modulation• Organizational versus activational effects of gonadal steroids on motivated behavior and drug response, including developmental and perinatal exposure.• Estrous or menstrual cycle phase, pregnancy, lactation, and reproductive senescence as modulators of behavior and treatment response.• Interactions between gonadal hormones and stress axes in psychiatric-relevant phenotypes.Pharmacology and treatment response• Sex-dependent dose-response, efficacy, and adverse-effect profiles for antidepressants, antipsychotics, anxiolytics, analgesics, and drugs of abuse.• Acute versus repeated administration, including single-challenge designs and sex-comparative time-course or pharmacokinetic studies.• Withdrawal, tolerance, sensitization, and relapse vulnerability in males and females.• Sex-dependent effects of genetic and environmental manipulations in neuropsychiatric models.• Parallel or back-translational designs testing the same readout in animal models and in human participants or patients, including sex-biased adverse effects.Experimenter effects, methods, and monitoring• Influence of experimenter sex, cycle phase, and related characteristics on behavior, stress responses, pain sensitivity, and neuroendocrine measures.• Low-stress approaches to estrous cycle assessment: retrospective staging, non-invasive, and automated methods as alternatives to daily vaginal lavage.• Handling, restraint, and husbandry as confounds in sex-comparative designs, and how to minimise, standardise, and report them.• Standardized reporting, balancing, blinding, and statistical modeling of experimenter- and procedure-related variables.Statistics, design, and research policy• Treating sex as an explicit factor: main effects, interactions, power and sample-size planning, and balanced randomization.• Tutorials, simulations, and worked examples addressing variance, cycle staging, and pitfalls such as pooling across sex without preliminary checks or inferring a sex difference without testing the sex x treatment interaction.• The Reduction principle of the 3Rs versus sex-inclusive design: factorial approaches to including both sexes, and the sample sizes needed to power interaction tests.• Equitable inclusion, transparent rationale for single-sex designs, alignment with SABV, and translation to sex-informed therapies. Topic editors: Jana Ruda-Kucerova, Eva Drazanova, Juan M. Dominguez Source: https://www.frontiersin.org/research-topics/85350/sex-differences-in-neuropsychiatry-and-neuropharmacology-animal-models-and-clinical-settings