Decoding anxiety: Study reveals brain's role in behavioral inhibition risks

By Dr. Chinta SidharthanNov 28 2023Reviewed by Susha Cheriyedath, M.Sc.

In a recent study published in the Proceedings of the National Academy of Sciences, a team of researchers in the United States used non-human primate anxious temperament models to investigate the molecular mechanisms and neural systems underlying behavioral inhibition in humans, which is one of the dispositional risks of anxiety disorders.

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Background

The resilience or risk for the development of anxiety disorders and psychopathology related to stress is often dependent on individual variations in anxious temperaments, which can be observed early in life. Behavioral inhibition, where the individual reacts hyperactively to threats, especially in novel or uncertain situations, is one of the temperaments that is well-established to be a risk factor for anxiety disorders. Behavioral inhibition in the early years significantly increases the risk of anxiety disorders, substance abuse, major depressive disorders, and other mental health disorders that are on the internalizing spectrum.

Since behavioral inhibition can often be observed in early childhood, interventions can be implemented early to steer the developmental trajectories of children exhibiting behavioral inhibition away from psychopathologies related to stress. Understanding the molecular mechanisms and neural pathways underlying behavioral inhibition is essential for developing these interventions. Non-human primates exhibit anxious temperament, which is remarkably similar to behavioral inhibition in humans, making non-human primate anxious temperament models an excellent system to understand the underlying mechanisms of these disorders.

About the study

In the present study, the researchers used a transcriptomic approach to identify molecular markers in the posterior orbitofrontal cortex that are linked to individual variations in anxious temperament in non-human primate models. Along with the subcortical regions such as the brainstem periaqueductal grey, anterior hippocampus, and amygdala, the posterior orbitofrontal cortex, dorsolateral prefrontal cortex, and subgenual anterior cingulate cortex are also believed to be implicated in the neural circuit changes associated with variations in anxious temperament in non-human primate models.

The neural circuit in the posterior orbitofrontal cortex is thought to regulate the subcortical sections of the anxious temperament circuit, which are also linked to differences across individuals in the threat-related metabolism. Lesions in the posterior orbitofrontal cortex, specifically in the extended amygdala bed nucleus, are thought to modify both threat-related metabolism and anxious temperament. This region is also strongly interconnected to the amygdala, which is believed to be the center of the anxious temperament circuit.

Given the existing evidence about the role played by the posterior orbitofrontal cortex in the individual variations in the anxious temperament phenotype, laser capture microdissection was used to collect ribonucleic acid (RNA) samples from the deep and superficial layers of the posterior orbitofrontal cortex. RNA sequencing was conducted to characterize gene expression. Furthermore, given the differences in the functional and connectional properties of the neurons in the various cortical laminae of the region, the laminar transcriptional differences were assessed across the superficial and deep layers.

Additionally, a single nuclear RNA sequencing approach was used for cell types that were transcriptionally characterized within the posterior orbitofrontal cortex to identify specific neuronal subsets that mediate the effects of the molecular alterations associated with anxious temperament in the non-human primate models.

Results

The study identified multiple molecular systems in the posterior orbitofrontal cortex that are implicated in the individual variations in anxious temperament in non-human primates. The transcriptome of the neurons in the superficial and deep layers of the posterior orbitofrontal cortex were found to be significantly different. Furthermore, the results also reported a relationship between anxious temperament and laminar transcription, with individual variations in the cortisol expression in relation to uncertain stress in the superficial and deep layers of the posterior orbitofrontal cortex.

Apart from the insights about the underlying molecular mechanisms within the posterior orbitofrontal cortex that regulate the anxious temperament phenotype, the results also highlighted potential molecular targets to prevent and treat depressive and anxiety disorders.

One of these targets was caldesmon, which can alter the glucocorticoid receptor-related plasticity of the neurons in the deep layers that connect to the subcortical structures that mediate anxious temperament. The scientists believe that further research using overexpression of anxious temperament-related posterior orbitofrontal cortex constructs, mediated through viral vectors, can improve understanding the relationship between posterior orbitofrontal cortex plasticity and anxious temperament.

Conclusions

Overall, the findings reported that individual differences in the anxious temperament phenotype are linked to individual variations in the transcriptomes of the neurons within the posterior orbitofrontal cortex. The study also identified potential molecular targets, including those involved in glucocorticoid signaling, for preventing and treating anxiety disorders.