Nonhuman Primate Studies to Understand the Causal Mechanisms of Pathological Anxiety
While of obvious importance, studies in humans do not allow for an understanding of the mechanisms causally involved in the development of pathological anxiety. Because of their evolutionary-relatedness to humans, and similarities in brain structure and function, rhesus monkeys are an ideal species to identify underlying causal mechanisms. Importantly, rhesus monkeys and humans share a well-developed prefrontal cortex, which is a critical region of the brain for the optimal regulation of anxiety. Over the past several decades, our lab has developed and validated a rhesus monkey model of the early childhood risk to develop anxiety disorders. We have termed this risk phenotype “anxious temperament” (AT), which is highly similar to the human temperamental risk-phenotype, behavioral inhibition. AT is a trait-like composite measure, which includes behavioral and hormonal (cortisol) responses elicited by exposure to a potential threat. Our work demonstrates a high level of convergence between AT in young monkeys, behavioral inhibition in children, and childhood anxiety disorders in relation to the behavioral phenotypes and neural circuitry involved.
As in children, monkey AT is identifiable early in life, stable across development, and heritable. AT reflects a broad, context-independent anxious disposition that is stable over time and predicts brain metabolism across contexts. Using functional neuroimaging methods such as FDG-PET to assess regional glucose metabolism and “resting-state” fMRI to assess functional connectivity, we have demonstrated that pathological anxiety is associated with alterations in the function of specific prefrontal and limbic brain regions. Our focus is on the brain regions that are components of the neural circuit that controls the expression of AT. The amygdala and the bed nucleus of the stria terminalis are at the core of the AT circuit, and other components of the AT network include the anterior hippocampus, the periaqueductal grey, as well as various regions of the prefrontal cortex. Data from our lab show that monkey AT and childhood anxiety share similar alterations in structural and functional brain connectivity. Specifically, using diffusion tensor imaging to quantify white matter integrity, our lab has demonstrated altered structural connectivity of the uncinate fasciculus, a major pathway connecting prefrontal and limbic regions, in both young monkeys and children with anxiety disorders. Collectively, these data underscore the validity of the monkey AT model and substantiate its relevance to the human childhood risk to develop anxiety and depressive disorders.
Housed across the HealthEmotions Research Institute in the Dept. of Psychiatry, the Harlow Center for Biological Psychology at UW-Madison, and the Wisconsin National Primate Research Center, our lab is dedicated to understanding the molecular and neural circuit alterations that underlie extreme AT. Using methods including intraoperative MRI for precise targeting of AT-related brain structures and multimodal brain imaging similar to that used in human studies, we are exploring the basic mechanisms that underlie primate anxiety. These mechanistic studies are essential as the monkey model enables an opportunity to perform proof-of-concept studies directly relevant to understanding and treating human illnesses. Our primary mission is to bring these and other methods to bear in the hopes of understanding the neural and molecular mechanisms that lead to maladaptive anxiety in children, and to use these methods as novel approaches for treatment development.
Watch a video of Dr. Kalin describing the lab’s research on non-human primates and how it relates to their studies on anxiety in children: