Anxiety disorders can be severely debilitating, are prevalent in females, and represent a significant public health burden. These disorders often begin with early-life dispositional anxiety that can lead to the development of anxiety and depressive disorders and co-morbid substance abuse. New treatment strategies aimed at early-life anxiety are needed and have the potential to prevent this life-long suffering. The nonhuman primate (NHP) model of early-life anxious temperament (AT) is ideal because of similarities between rhesus monkeys and humans in the development of socio-emotional behavior and its underlying neural circuits. Our work, and that of others, strongly implicates altered function of the extended amygdala as a core feature of AT and anxiety disorders. The extended amygdala includes the central nucleus of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST). The extended amygdala integrates threat-relevant information from cortical and subcortical inputs, and initiates behavioral and physiological responses to threat. Of particular interest are the orbitofrontal ?regulatory? influences on extended amygdala function and anxiety. In considering the development of new treatments, there are a number of critical questions. Advances in molecular technologies for reversibly and bi-directionally controlling brain function are beginning to make some of these questions tractable. Designer receptors exclusively activated by designer drugs (DREADDs) are ideal for examining early-life AT in NHPs because they can modulate critical brain regions for long periods of time (i.e. hours) -- particularly relevant for uncovering mechanisms related to mood and anxiety dysregulation. The DREADDs technique involves infecting a brain region with a viral vector that expresses a receptor that does not naturally occur in the brain, which is then combined with a pharmacological intervention, an otherwise ?inert? drug that selectively activates DREADDs. Importantly, DREADDs can be used to chronically alter circuit function to model long-term brain alterations associated with psychopathology. We established a Cre-Lox recombination strategy to express DREADDs in NHP amygdala neurons that project to select effector sites. This allows unprecedented control of specific projections in the brains of freely behaving NHPs during exposure to ethologically relevant contexts. This proposal will use DREADDs in young female NHPs to understand how, early in life, projections in the extended amygdala drive sustained anxiety-related behavior and how this circuit is modulated by direct projections from caudal orbitofrontal cortex. It will also explore whether chronic early-life activation of the Ce is sufficient to induce extreme anxiety accompanied by the functional and structural brain changes associated with stress-related psychopathology. Lastly, the proposed studies will identify molecular markers of projection-specific anxiety-modulating neurons that will enable development of selective circuit-based treatment approaches. Together these studies will set the stage for the feasibility of amygdala projection-specific treatments for early-life anxiety, and demonstrate the utility of an animal model to test these novel approaches.

Public Health Relevance

An extreme and stable anxious temperament (AT) during childhood is a significant risk factor for the later development of anxiety disorders, especially in adolescent girls. Using our non-human primate (NHP) model of AT, the proposed studies will use multimodal neuroimaging and advanced molecular genetic techniques to identify and selectively manipulate the activity of neurons in specific projections within the AT-related neural circuit in freely behaving young female NHPs. The work in this proposal will also identify novel molecular targets for drug discovery with the potential to prevent the consequences of chronic early life anxiety.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH046729-27
Application #
10091982
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Rossi, Andrew
Project Start
1990-07-01
Project End
2022-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
27
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Psychiatry
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Fox, Andrew S; Oler, Jonathan A; Birn, Rasmus M et al. (2018) Functional Connectivity within the Primate Extended Amygdala Is Heritable and Associated with Early-Life Anxious Temperament. J Neurosci 38:7611-7621
Alisch, Reid S; Van Hulle, Carol; Chopra, Pankaj et al. (2017) A multi-dimensional characterization of anxiety in monozygotic twin pairs reveals susceptibility loci in humans. Transl Psychiatry 7:1282
Shackman, A J; Fox, A S; Oler, J A et al. (2017) Heightened extended amygdala metabolism following threat characterizes the early phenotypic risk to develop anxiety-related psychopathology. Mol Psychiatry 22:724-732
Oler, Jonathan A; Tromp, Do P M; Fox, Andrew S et al. (2017) Connectivity between the central nucleus of the amygdala and the bed nucleus of the stria terminalis in the non-human primate: neuronal tract tracing and developmental neuroimaging studies. Brain Struct Funct 222:21-39
Kalin, Ned H (2017) Mechanisms underlying the early risk to develop anxiety and depression: A translational approach. Eur Neuropsychopharmacol 27:543-553
Kalin, Ned H; Fox, Andrew S; Kovner, Rothem et al. (2016) Overexpressing Corticotropin-Releasing Factor in the Primate Amygdala Increases Anxious Temperament and Alters Its Neural Circuit. Biol Psychiatry 80:345-55
Fox, Andrew S; Oler, Jonathan A; Shackman, Alexander J et al. (2015) Intergenerational neural mediators of early-life anxious temperament. Proc Natl Acad Sci U S A 112:9118-22
Cavanagh, James F; Shackman, Alexander J (2015) Frontal midline theta reflects anxiety and cognitive control: meta-analytic evidence. J Physiol Paris 109:3-15

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