This Research Topic is the second volume of Research Topic "Animal Models of Anxiety and Depression: Exploring the Underlying Mechanisms of Sex Differences". Please see the first volume here.

Anxiety and depression are major global psychiatric health burdens, affecting tens of millions of individuals worldwide. Clinically, both conditions exhibit pronounced sex differences; notably, women are twice as likely to receive a diagnosis of an anxiety disorder or major depressive disorder in their lifetimes. These differences have been attributed to biological, as well as cultural and social factors. Furthermore, men and women differ in symptomatology and response to treatment, underscoring the critical need for a deeper exploration into the mechanisms leading to these sex differences.

Animal models have long been a cornerstone in the study of anxiety and depression, with a historical preference for using male animals, perhaps due to the simplicity of experimental designs among other possible explanations. However, the inclusion of both sexes in pre-clinical research presents an opportunity to explore sex differences in the biological underpinnings (e.g., inflammation, neurotransmitter dysregulation), contributions of stress (e.g., maternal separation, chronic mild stress), and other influences (e.g., resiliency, genetics and epigenetics, social factors, gut microbiota) that may underlie emotional dysregulation and abnormal performance at behavioral endpoints (e.g., forced swim test, sucrose preference test, elevated plus maze). Unfortunately, animal models have yielded inconsistent results and often report greater anxiety- or depressive-like symptoms, or increased responses to stress, in male animals than in female animals. These inconsistencies call for better standardization and normalization when designing experiments exploring sex differences underpinnings.

The aim of this Research Topic is to explore the utility of animal models in the study of sex differences in neuropsychiatric disease. We welcome original research or reviews that address outstanding questions in the pre-clinical literature regarding this topic, including but not limited to:

1. How can we improve behavioral outcomes in animal models to better represent sex differences in clinical symptoms?

2. How are behavioral tests best standardized when working with males and females?

3. How does stress differentially contribute to anxiety- and depressive-like symptoms in animal models?

4. How does hypothalamic-pituitary-adrenal (HPA) axis function differ in male and female animals, contributing to neuropsychiatric dysfunction?

5. How does the genetic and molecular pathophysiology of anxiety and/or depression differ between male and female animals?

6. What are the mechanisms underlying differences between males and females in response to anxiolytic and anti-depressant treatments?

7. Can we ever fully model the human experience of depression in rodent models when some symptoms (e.g., sadness, suicidality, introspection) cannot be adequately measured, and when some contributing factors (e.g., social, cultural) are not present in the same way as in the human condition?

Additionally, we seek insights into how artificial intelligence (AI) is being integrated with animal models to advance our understanding of these diseases. We welcome contributions that showcase the use of AI for data analysis, experimental design enhancement, and unraveling complex biological mechanisms. Submissions highlighting the synergy between AI and traditional animal research, aimed at deepening our grasp of neuropsychiatric disorders from a sex-difference angle through innovative, multidisciplinary methodologies, are especially encouraged.

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Frontiers in Behavioral Neuroscience

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