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Transl Psychiatry. 2018 Feb 21;8(1):49. doi: 10.1038/s41398-018-0092-z.

Amygdala hyper-connectivity in a mouse model of unpredictable early life stress.

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Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT, 06511, USA.
Department of Newborn Medicine, Boston Children's Hospital, Harvard medical school, Boston, MA, 02115, USA.
Department of Radiology & Biomedical Imaging and Magnetic Resonance Research Center, Yale University, New Haven, CT, 06520, USA.
iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Ren Building, Room B204, Zhangjiang, Pudong, Shanghai, 201210, China.
Department of Biomedical Engineering, Yale University, New Haven, CT, 06519, USA.
Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT, 06511, USA.


Childhood maltreatment is associated with a wide range of psychopathologies including anxiety that emerge in childhood and in many cases persist in adulthood. Increased amygdala activation in response to threat and abnormal amygdala connectivity with frontolimbic brain regions, such as the hippocampus and the prefrontal cortex, are some of the most consistent findings seen in individuals exposed to childhood maltreatment. The underlying mechanisms responsible for these changes are difficult to study in humans but can be elucidated using animal models of early-life stress. Such studies are especially powerful in the mouse where precise control of the genetic background and the stress paradigm can be coupled with resting-state fMRI (rsfMRI) to map abnormal connectivity in circuits that regulate anxiety. To address this issue we first compared the effects of two models of early-life stress, limited bedding (LB) and unpredictable postnatal stress (UPS), on anxiety-like behavior in juvenile and adult mice. We found that UPS, but not LB, causes a robust increase in anxiety in juvenile and adult male mice. Next, we used rsfMRI to compare frontolimbic connectivity in control and UPS adult male mice. We found increased amygdala-prefrontal cortex and amygdala-hippocampus connectivity in UPS. The strength of the amygdala-hippocampal and amygdala-prefrontal cortex connectivity was highly correlated with anxiety-like behavior in the open-field test and elevated plus maze. These findings are the first to link hyperconnectivity in frontolimbic circuits and increased anxiety in a mouse model of early-life stress, allowing for more mechanistic understanding of parallel findings in humans.

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