Sex Differences in Anxiety-Related Behavior in Rodent Models

Research into anxiety-like behaviours in rodents has revealed consistent and complex sex differences that mirror clinical observations in humans, where women exhibit a higher prevalence of anxiety disorders than men. Standard paradigms such as the elevated plus maze, open field and light–dark box have demonstrated that female rodents often display heightened avoidance and risk assessment, but these behaviours are modulated by the oestrous cycle, reproductive status and developmental stage. Historically, male-only cohorts dominated the literature, yet inclusion of females has revealed cyclical fluctuations in ovarian hormones that shape neural circuits of fear and stress. Key neurobiological substrates underlying these differences include γ-aminobutyric acid signalling, serotonergic pathways, hypothalamic–pituitary–adrenal axis regulation and hippocampal neurogenesis. Moreover, recent epigenetic studies have pointed to chromatin dynamics as a mechanism by which oestrous-phase hormone shifts can remodel gene expression in anxiety circuits. Together, these findings underscore the necessity of accounting for sex as a biological variable in preclinical research and inform the development of sex- and gender-specific therapeutic strategies.

Research from Nature Portfolio

A foundational study has revealed extraordinary dynamism of the female mouse brain at the epigenetic level, showing that neuronal chromatin organisation in the ventral hippocampus fluctuates across the oestrous cycle. These structural changes correlate with transcriptional activity of immediate-early genes such as Egr1, which are vital for synaptic plasticity and behavioural adaptation. Functional assessments demonstrated that shifts in chromatin accessibility align with variations in anxiety-like behaviours, supporting a model in which cyclical oestrogen and progesterone levels enact rapid epigenomic reprogramming of stress-related circuits. This work establishes chromatin remodelling as a mechanistic bridge between hormonal state and behavioural phenotype, opening avenues for targeted interventions that consider timing within the hormonal cycle.

Sex Differences in Anxiety-Related Behavior in Rodent Models publication trend

The graph below shows the total number of articles in sex differences in anxiety-related behavior in rodent models across all publications each year (not limited to Nature Index journals).

Technical terms

Oestrous cycle: The recurring reproductive cycle in female rodents, characterised by fluctuating levels of oestrogen and progesterone that influence brain function and behaviour.

Chromatin organisation: The structural arrangement of DNA and histone proteins in the nucleus, which regulates access to gene transcription in response to hormonal and environmental signals.

GABAA receptor: A pentameric chloride ion channel activated by the inhibitory neurotransmitter γ-aminobutyric acid, critical for modulating neuronal excitability and anxiety.

Ventral hippocampus: A subregion of the hippocampal formation implicated in emotional regulation and anxiety-related behaviours.

HPA axis: The network of interactions among the hypothalamus, pituitary gland and adrenal cortex that orchestrates stress hormone release and shapes adaptive responses to threat.

Anxiety-like behaviour: Operationally defined actions in animal models—such as avoidance of open arms in a maze—used to infer states akin to human anxiety disorders.

References

1. The impact of the ovarian cycle on anxiety, allopregnanolone, and corticotropin releasing hormone changes after motherhood in female rats and women. Translational Psychiatry (2023).
2. Effect of Estrous Cycle on Behavior of Females in Rodent Tests of Anxiety. Frontiers in Psychiatry (2021).
3. Sex hormone fluctuation and increased female risk for depression and anxiety disorders: From clinical evidence to molecular mechanisms. Frontiers in Neuroendocrinology (2022).
4. Chromatin organization in the female mouse brain fluctuates across the oestrous cycle. Nature Communications (2019).
5. Gender Differences in the Neurobiology of Anxiety: Focus on Adult Hippocampal Neurogenesis. Neural Plasticity (2016).