Gene expression in the primate orbitofrontal cortex related to anxious temperament

Abstract

Anxiety disorders are among the most prevalent psychiatric disorders, causing significant suffering and disability. Relative to other psychiatric disorders, anxiety disorders tend to emerge early in life, supporting the importance of developmental mechanisms in their emergence and maintenance. Behavioral inhibition (BI) is a temperament that emerges early in life and, when stable and extreme, is linked to an increased risk for the later development of anxiety disorders and other stress-related psychopathology. Understanding the neural systems and molecular mechanisms underlying this dispositional risk could provide insight into treatment targets for anxiety disorders. Nonhuman primates (NHPs) have an anxiety-related temperament, called anxious temperament (AT), that is remarkably similar to BI in humans, facilitating the design of highly translational models for studying the early risk for stress-related psychopathology. Because of the recent evolutionary divergence between humans and NHPs, many of the anxiety-related brain regions that contribute to psychopathology are highly similar in terms of their structure and function, particularly with respect to the prefrontal cortex. The orbitofrontal cortex plays a critical role in the flexible encoding and regulation of threat responses, in part through connections with subcortical structures like the amygdala. Here, we explore individual differences in the transcriptional profile of cells within the region, using laser capture microdissection and single nuclear sequencing, providing insight into the molecules underlying individual differences in AT-related function of the pOFC, with a particular focus on previously implicated cellular systems, including neurotrophins and glucocorticoid signaling.

Understanding the heterogeneity of anxiety using a translational neuroscience approach

“…Researchers have established similarities between early-life anxious and inhibited temperament across humans and rhesus macaques (Fox & Kalin, 2014 ; Kenwood & Kalin, 2021 ), which allow for the study of the neurobiology that gives rise to the emergence of anxiety disorders in humans. This work has revealed similarities between humans and rhesus macaques in the distributed brain network associated with individual differences in temperament (Fox & Shackman, 2019 ; Oler et al, 2010 ), identification of brain regions that likely mediate the inherited aspects of temperament (Fox, Oler, Shackman et al, 2015a ; Fox et al, 2018 ), and initial suggestions about the molecular (Fox et al, 2019 ; Kalin et al, 2016 ; Kenwood, Souaiaia et al, 2023b ; Kovner et al, 2020 ) and genetic (Fox et al, 2021 ) mechanisms that underlie the early-life risk to develop anxiety disorders. This work has been instrumental to drawing attention to the central extended amygdala, encompassing the Ce and the BST in anxiety and anxiety disorders (Fox et al, 2018 ; Fox, Oler, Tromp, et al, 2015b ; Fox & Shackman, 2019 ).…”

Astrocytic glutamate regulation is implicated in the development of stress-related psychiatric disorders

“…However, understanding how these findings translate to human populations has been challenging given the complexity associated with defining what constitutes impactful 'stress' and associating this with clinical consequences, such as diagnosis. Recent approaches to pinpoint underlying molecular signatures have highlighted that both cell-type 10,11 and spatial domains 12 of the prefrontal cortex (PFC) are essential to shaping the brain in response to stress, with astrocytes emerging as a focus across stress-related psychiatric disorders 10, 13,14 . Cerebral astrocytes are highly abundant and play essential roles across many brain functions, especially in coordinating the synaptic, metabolic, and neuroinflammatory environments 15 .…”