Animal Models of Anxiety and Stress Responses

Animal models have been indispensable for elucidating the neurobiological substrates of anxiety and stress‐related behaviours. Traditional paradigms such as the elevated plus maze, open field and various fear‐conditioning protocols have long provided reproducible measures of anxiety‐like and defensive responses in rodents. Over the past decade, selective breeding strategies have generated lines with divergent temperaments—ranging from high‐anxiety to high‐exploratory phenotypes—thereby offering insight into heritable components of stress sensitivity. Pharmacological manipulations targeting monoaminergic and neuropeptide systems have further revealed receptor‐specific contributions to anxiety and stress resilience. More recently, advances in genomics, transcriptomics and network biology have enabled high‐resolution mapping of gene–environment interactions and circuit dynamics underlying stress coping. By integrating behavioural assays with molecular profiling, investigators are now beginning to bridge the gap between discrete neural circuits and complex emotional phenotypes, with the ultimate aim of identifying novel therapeutic targets to prevent maladaptive stress responses.

Research from Nature Portfolio

Recent studies have applied network‐based analyses to protein–protein interactomes that are associated with distinct anxiety disorders. One investigation constructed interactomes for generalised and social anxiety, then mapped these onto striatal compartment networks (striosome versus matrix). This approach revealed that generalised anxiety genes preferentially overlap with striosomal pathways, whereas social anxiety genes align with matrix circuits. Constraining these interactomes to shared striatal genes highlighted a bifurcation in upstream regulators, implicating the anterior cingulate cortex, nucleus accumbens, amygdala and hippocampus, as well as dopaminergic signalling, in the aetiological differentiation of anxiety subtypes. Such network frameworks underscore the value of systems‐level mapping for dissecting disorder‐specific circuitry and offer a blueprint for future cross‐disorder comparisons.

Animal Models of Anxiety and Stress Responses publication trend

The graph below shows the total number of articles in animal models of anxiety and stress responses across all publications each year (not limited to Nature Index journals).

Technical terms

Elevated plus maze: A cross‐shaped apparatus with two open and two enclosed arms used to assess anxiety‐like behaviour based on rodents’ preference for protected spaces.

Fear conditioning: A learning paradigm in which an initially neutral stimulus is paired with an aversive event, leading to the expression of defensive responses upon re‐exposure to the conditioned cue.

bHR/bLR rats: Selectively bred lines denoted “bred High Responder” and “bred Low Responder” that exhibit divergent exploratory and anxiety‐like traits in novel environments.

Interactome: The full set of molecular interactions, typically protein–protein connections, that can be mapped onto biological pathways or disorder‐related networks.

Hyper‐ramified microglia: A morphological state of microglial cells characterised by elongated, highly branched processes, often indicative of a primed or early‐activated immune phenotype.

References

1. Bioenergetic-related gene expression in the hippocampus predicts internalizing vs. externalizing behavior in an animal model of temperament. Frontiers in Molecular Neuroscience (2025).
2. Differences in microglia morphological profiles reflect divergent emotional temperaments: insights from a selective breeding model. Translational Psychiatry (2022).
3. Cued Fear Conditioning in Carioca High- and Low-Conditioned Freezing Rats. Frontiers in Behavioral Neuroscience (2020).
4. Generalized and social anxiety disorder interactomes show distinctive overlaps with striosome and matrix interactomes. Scientific Reports (2021).