Characterizing Sex Differences in Depressive-Like Behavior and Glial Brain Cell Changes Following Peripheral Nerve Injury in Mice

Abstract

Chronic pain and depression are intimately linked; the combination of the two leads to higher health care costs, lower quality of life, and worse treatment outcomes with both conditions exhibiting higher prevalence among women. In the current study, we examined the development of depressive-like behavior in male and female mice using the spared nerve injury (SNI) model of neuropathic pain. Males displayed increased immobility on the forced-swim test – a measure of depressive-like behavior – 2 weeks following injury, while females developed depressive-like behavior at 3-week. Since the pathogenesis of chronic pain and depression may involve overlapping mechanisms including the activation of microglial cells, we explored glial cell changes in brain regions associated with pain processing and affect. Immunohistochemical analyses revealed that microglial cells were more numerous in female SNI mice in the contralateral ventral anterior cingulate cortex (ACC), a brain region important for pain processing and affect behavior, 2-week following surgery. Microglial cell activation was not different between any of the groups for the dorsal ACC or nucleus accumbens. Analysis of astrocyte density did not reveal any significant changes in glial fibrillary acidic protein (GFAP) staining in the ACC or nucleus accumbens. Overall, the current study characterized peripheral nerve injury induced depression-like behavior in male and female mice, which may be associated with different patterns of glial cell activation in regions important for pain processing and affect.

The basolateral amygdala-anterior cingulate pathway contributes to depression-like behaviors and comorbidity with chronic pain behaviors in male mice

“…Accordingly, a limitation of the present study is that we focused on males only. Since sexual differences have been described in relation to chronic pain and associated emotional dysregulation [79][80][81] , future studies will be necessary to investigate sex as a biological variable in behavioral and transcriptomic consequences of various models (including NPID), as well as in interactions among structures such as the BLA and the ACC (with no concrete evidence available to date).…”

Neuropathic injury drives a generalized negative affective state in mice

“…There are many different sucrose preference protocols in the literature [28,41,45,86]. Typically points of divergence in sucrose preference protocols include sucrose concentration, habituation paradigms, and counterbalancing access to water and sucrose [61]. It is worth noting that different protocols have shown significant results following injury models [86].…”

Genetic evidence of the function of Phox2a-expressing anterolateral system neurons in the transmission of chronic pain

“…All experiments were performed with male animals since females do not consistently model the full range of SNI-associated behavioral phenotypes found in males. 38,39 We first verified whether Phox2a cKO mice exhibit molecular changes normally associated with SNI; in this model of neuropathic pain, the dorsal horn of the spinal cord exhibits increased expression of Fos, a protein associated with increased neuronal activity. 40,41 Another consequence of SNI is increased microglial activity in the dorsal horn, evidenced by the increased number of microglia expressing the activation marker Iba1 with star shape morphology.…”