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

Abstract

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.

Microglial synaptic pruning on axon initial segment of dentate granule cells: sexually dimorphic effects on fear response of adult rats subjected to early life stress

“…Previous studies have shown that humans exposed to ELS have increased connectivity at amygdala in association with individual hyperreactivity (Johnson, Delpech et al 2018). This is in concordance with our results showing that normal pruning of granule cells AISS by microglia is impaired by maternal separation.…”

Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening

“…Multiple lines of research have implicated both the BLA and the dmPFC (plPFC in rodents) as critical nodal structures involved in the pathophysiology of stress-related affective disorders (Carlisi and Robinson, 2018;Kalisch and Gerlicher, 2014;Milad et al, 2009;Ongur and Price, 2000;Preuss, 1995;Robinson et al, 2014). The rodent plPFC has extensive reciprocal glutamatergic connections with the BLA that are modulated by stress exposure and capable of generating anxiety-like responses (Felix-Ortiz et al, 2015;Johnson et al, 2018;Lowery-Gionta et al, 2018;Vertes, 2004). In order to investigate the molecular mechanisms regulating BLA-plPFC connectivity and plasticity, we first sought to verify that this circuit is engaged by exposure to stressful stimuli (Figure 1a).…”

Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening

“…Multiple lines of research have implicated both the BLA and the dmPFC (plPFC in rodents) as critical nodal structures involved in the pathophysiology of stress-related affective disorders (Carlisi and Robinson, 2018;Kalisch and Gerlicher, 2014;Milad et al, 2009;Ongur and Price, 2000;Preuss, 1995;Robinson et al, 2014). The rodent plPFC has extensive reciprocal glutamatergic connections with the BLA that are modulated by stress exposure and capable of generating anxiety-like responses (Felix-Ortiz et al, 2015;Johnson et al, 2018;Lowery-Gionta et al, 2018;Vertes, 2004). In order to investigate the molecular mechanisms regulating BLA-plPFC connectivity and plasticity, we first sought to verify that this circuit is engaged by exposure to stressful stimuli (Figure 1a).…”