Anxious temperament (AT) is a critical childhood risk factor for the development of anxiety and depression. Human and monkey AT is identifiable early in life, stable across development, and heritable. Children with extreme AT often meet diagnostic criteria for social anxiety disorder, demonstrating the blurred boundary between extreme temperamental anxiety and what is traditionally considered psychopathology. Elucidating the molecular mechanisms underlying extreme AT is essential for efforts aimed at altering the development of anxiety and depressive disorders. We validated a primate model of AT that is remarkably similar to childhood AT. Evidence supports this developmental rhesus monkey model as being the optimal model for establishing mechanisms underlying pathological childhood anxiety. The primate model enables mechanistic hypothesis testing that cannot be performed in humans. Furthermore, the primate model is readily translatable as it uses the same imaging, behavioral, and endocrine measures routinely used in human research. Our prior lesion and imaging studies in a large sample of juvenile macaques identified 3 key nodes in the neural circuit mediating AT: the central nucleus of the amygdala (Ce), anterior hippocampus (aHip), and orbitofrontal cortex (OFC). Our data demonstrates that the OFC has a regulatory role in relation to AT's altered Ce and aHip metabolism. Using tissue from the Ce region predictive of AT, our preliminary microarray work identified transcripts whose expression levels predicted AT and its underlying Ce activity. Some of the more exciting findings implicate alterations in the expression of neuroplasticity genes to be associated with AT, supporting a hypothesis that AT is associated with altered early neurodevelopmental processes. The proposed work will significantly extend this line of research. We will combine functionally- guided laser capture microdissection (LCM) of Ce, aHip, and OFC neurons with both RNA sequencing (RNAseq) and behavioral/neuroimaging techniques (metabolic activity and functional connectivity). This will allow us to characterize molecular neuronal mechanisms in the regions that underlie AT and its neural substrate. By using OFC lesions to permanently reduce AT and activity in its neural substrate, we will characterize the """"""""top-down"""""""" influences of OFC on the regulation of Ce/aHip genes in neuronal populations relevant to AT and its long-term maintenance. Finally, we will use RNAseq to assess the utility of using transcripts measured in blood as peripheral biomarkers of AT and its associated altered neural substrate. HEALTH/NIMH MISSION

Public Health Relevance

Childhood AT confers marked risk for the development of anxiety and depression. These disorders are associated with substantial morbidity, mortality, and socioeconomic burdens. Data from the proposed studies should substantially increase our understanding of the molecular mechanisms underlying the expression and """"""""top-down"""""""" regulation of AT and its neural substrate. Deep RNA sequencing in neurons from within the altered brain regions underlying AT will provide a detailed and comprehensive view of the genetic regulation of the neural circuitry that mediates and regulates childhood AT. These studies cannot be performed in humans but can be accomplished in young primates and will facilitate the identification of novel targets for interventions aimed at ameliorating anxiety and depression early in life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH081884-05A1
Application #
8506170
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Garvey, Marjorie A
Project Start
2007-12-01
Project End
2018-02-28
Budget Start
2013-04-16
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$647,287
Indirect Cost
$162,903
Name
University of Wisconsin Madison
Department
Psychiatry
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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
Zhao, Gengyan; Liu, Fang; Oler, Jonathan A et al. (2018) Bayesian convolutional neural network based MRI brain extraction on nonhuman primates. Neuroimage 175:32-44
Kalin, Ned H (2018) Corticotropin-Releasing Hormone Binding Protein: Stress, Psychopathology, and Antidepressant Treatment Response. Am J Psychiatry 175:204-206
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
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
Fox, Andrew S; Oler, Jonathan A; Tromp, Do P M et al. (2015) Extending the amygdala in theories of threat processing. Trends Neurosci 38:319-29
Birn, R M; Shackman, A J; Oler, J A et al. (2014) Extreme early-life anxiety is associated with an evolutionarily conserved reduction in the strength of intrinsic functional connectivity between the dorsolateral prefrontal cortex and the central nucleus of the amygdala. Mol Psychiatry 19:853

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