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While depression and chronic pain are frequently comorbid, underlying neuronal circuits and their psychopathological relevance 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. Moreover, activation of this pathway in naive male mice, in the absence of on-going pain, 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, which was significantly upregulated in both male mice and humans in the context of altered mood, is necessary for the emergence of emotional dysfunction. Overall, these results place the amygdalo-cingulate pathway at the core of pain and depression comorbidity, and unravel the role of Sema4a and impaired myelination in mood control.

Areas 24a and 24b of the anterior cingulate cortex (ACC) play a major role in cognition, emotion and pain. While their connectivity has been studied in primate and in rat, a complete mapping was still missing in the mouse. Here, we analyzed the afferents to the mouse ACC by injecting retrograde tracers in the ventral and dorsal areas of the ACC (areas 24a/b) and of the midcingulate cortex (MCC; areas 24a'/b'). Our results reveal inputs from five principal groups of structures: (1) cortical areas, mainly the orbital, medial prefrontal, retrosplenial, parietal associative, primary and secondary sensory areas and the hippocampus, (2) basal forebrain, mainly the basolateral amygdaloid nucleus, the claustrum and the horizontal limb of the diagonal band of Broca, (3) the thalamus, mainly the anteromedial, lateral mediodorsal, ventromedial, centrolateral, central medial and reuniens/rhomboid nuclei, (4) the hypothalamus, mainly the lateral and retromammillary areas, and (5) the brainstem, mainly the monoaminergic centers. The neurochemical nature of inputs from the diagonal band of Broca and brainstem centers was also investigated by double-labeling, showing that only a part of these afferents were cholinergic or monoaminergic. Comparisons between the areas indicate that areas 24a and 24b receive qualitatively similar inputs, but with different densities. These differences are more pronounced when comparing the inputs to ACC's areas 24a/24b to the inputs to MCC's areas 24a'/24b'. These results provide a complete analysis of the afferents to the mouse areas 24a/24b and 24a'/24b', which shows important similarity with the connectivity of homologous areas in rats, and brings the anatomical basis necessary to address the roles of cingulate areas in mice.

The anterior cingulate cortex (ACC), constituted by areas 25, 32, 24a and 24b in rodents, plays a major role in cognition, emotion and pain. In a previous study, we described the afferents of areas 24a and 24b and those of areas 24a' and 24b' of midcingulate cortex (MCC) in mice and highlighted some density differences among cingulate inputs (Fillinger et al., Brain Struct Funct 222:1509-1532, 2017). To complete this connectome, we analyzed here the efferents of ACC and MCC by injecting anterograde tracers in areas 24a/24b of ACC and 24a'/24b' of MCC. Our results reveal a common projections pattern from both ACC and MCC, targeting the cortical mantle (intracingulate, retrosplenial and parietal associative cortex), the non-cortical basal forebrain, (dorsal striatum, septum, claustrum, basolateral amygdala), the hypothalamus (anterior, lateral, posterior), the thalamus (anterior, laterodorsal, ventral, mediodorsal, midline and intralaminar nuclei), the brainstem (periaqueductal gray, superior colliculus, pontomesencephalic reticular formation, pontine nuclei, tegmental nuclei) and the spinal cord. In addition to an overall denser ACC projection pattern compared to MCC, our analysis revealed clear differences in the density and topography of efferents between ACC and MCC, as well as between dorsal (24b/24b') and ventral (24a/24a') areas, suggesting a common functionality of these two cingulate regions supplemented by specific roles of each area. These results provide a detailed analysis of the efferents of the mouse areas 24a/24b and 24a'/24b' and achieve the description of the cingulate connectome, which bring the anatomical basis necessary to address the roles of ACC and MCC in mice.