Fillinger, C. | bioRxiv Science

bioRxiv2022

The basolateral amygdala-anterior cingulate pathway contributes to depression and its comorbidity with chronic pain

While depression and chronic pain are frequently comorbid, underlying neuronal circuits, and their relevance for the understanding of psychopathology, remain poorly defined. Here we show in mice that hyperactivity of the neuronal pathway linking the basolateral amygdala to the anterior cingulate cortex is essential for chronic pain-induced depression. In naive animals, we demonstrate that activation of this pathway is sufficient to trigger depressive-like behaviors, as well as transcriptomic alterations that recapitulate core molecular features of depression in the human brain. These alterations notably impact gene modules related to myelination and the oligodendrocyte lineage. Among these, we show that Sema4a, a hub gene significantly upregulated in both mice and humans in the context of altered mood, is necessary for the emergence of depressive-like behaviors. Overall, these results place the BLA-ACC pathway at the core of pain and depression comorbidity, and unravel the role of impaired myelination and Sema4a in mood control.

neuroscience↗

bioRxiv2020

Prelimbic-amygdala overexcitability mediates trait vulnerability in a novel mouse model of acute social defeat stress

BACKGROUNDDepression is a debilitating neuropsychiatric disorder with 20% lifetime prevalence in the developed world but only approximately half of afflicted individuals respond to currently available therapies. While there is growing understanding of the neurobiological underpinnings of the depressed brain, much less is known about the preexisting circuitry leading to selective vulnerability versus resilience. Elucidating these networks could lead to novel preventative approaches. METHODSWe developed a model of acute social defeat stress (ASDS) that allows classification of male mice into "susceptible" (socially avoidant) versus "resilient" (expressing control-level social approach) one hour after exposure to six minutes of social stress. Using circuit tracing and high-resolution confocal imaging, we explored differences in activation and dendritic spine density and morphology in the prelimbic to basolateral amygdala (PL[->]BLA) circuit in resilient versus susceptible mice. To test the functional relevance of identified structure/function differences to divergent behavioral responses, we used an intersectional chemogenetic approach to inhibit the PL[->]BLA circuit during or prior to ASDS. RESULTSSusceptible mice had greater PL[->]BLA recruitment during ASDS and activated PL[->]BLA neurons from susceptible mice had more and larger mushroom spines compared to resilient mice. Inhibition of the PL[->]BLA circuit led to a population shift towards resilience. CONCLUSIONPreexisting PL[->]BLA structure/function differences mediate divergent behavioral responses to ASDS in male mice. These results support the PL[->]BLA circuit as a biomarker of trait vulnerability and potential target for prevention of stress-induced psychopathology.

neuroscience↗