Brain Mechanisms Mediating Genetic Risk for Anxiety and Depression

PROJECT SUMMARY – Pathological anxiety commonly emerges during childhood and is a prominent risk factor for the later development of anxiety and depression. To gain insights into mechanisms underlying the risk to develop stress-related psychopathology, we developed a non-human primate (NHP) model, termed anxious temperament (AT). This model allows for mechanism-based studies focused on the well-developed prefrontal cortex (PFC) shared by NHPs and humans. In this regard, we demonstrated involvement of PFC regions such as the dorsolateral PFC (dlPFC) in pathological anxiety, along with the amygdala and other subcortical AT-related regions. Neuroimaging research points to hypoactivation of the dlPFC in anxiety and depression. The dlPFC is involved in emotion regulation, working memory, and cognitive control, and modulates activity of limbic regions, such as the basolateral amygdala (BLA). Importantly, the dlPFC serves as a treatment target for neuromodulation strategies such as repetitive transcranial magnetic stimulation (rTMS) and is thought to be involved in mediating the effects of various cognitive therapies. Because of the evolutionary relatedness between NHPs and humans, especially manifested in PFC development, NHPs are ideally suited for investigations of the role of the PFC in psychopathology. As a translational bridge, our laboratory employs methods that provide an in-depth mechanistic understanding of brain alterations associated with extreme anxiety, including behavioral phenotyping, functional and structural neuroimaging, RNA sequencing and viral vector-mediated gene delivery. The focus of this proposal is to characterize the molecular substrates of the dlPFC in relation to AT, to understand how its top-down regulatory influences impact the BLA, a mediator of AT, and to explore the dlPFC as a treatment target. Our laboratory is uniquely suited for this endeavor as we use an integrative strategy in NHPs with behavioral phenotyping, multimodal imaging, chemogenetics, electron microscopy and single nuclear RNA sequencing (snRNA-Seq).