Neurogenesis of medium spiny neurons in the nucleus accumbens continues into adulthood and is enhanced by pathological pain

Abstract

In mammals, most adult neural stem cells (NSCs) are located in the ventricular–subventricular zone (V-SVZ) along the wall of the lateral ventricles and they are the source of olfactory bulb interneurons. Adult NSCs exhibit an apico-basal polarity; they harbor a short apical process and a long basal process, reminiscent of radial glia morphology. In the adult mouse brain, we detected extremely long radial glia-like fibers that originate from the anterior–ventral V-SVZ and that are directed to the ventral striatum. Interestingly, a fraction of adult V-SVZ-derived neuroblasts dispersed in close association with the radial glia-like fibers in the nucleus accumbens (NAc). Using several in vivo mouse models, we show that newborn neurons integrate into preexisting circuits in the NAc where they mature as medium spiny neurons (MSNs), i.e., a type of projection neurons formerly believed to be generated only during embryonic development. Moreover, we found that the number of newborn neurons in the NAc is dynamically regulated by persistent pain, suggesting that adult neurogenesis of MSNs is an experience-modulated process.

Neurogenesis in the adult brain functionally contributes to the maintenance of chronic neuropathic pain

“…In this study, we show that neurogenesis-mediated mechanisms do not appear to be involved in the developmental early stages of pain onset, but rather becomes a major contributor at later stages of pain chronicity. Indeed, the absence of adult neurogenesis likely prevented the maladaptive processes in mesolimbic circuits, where we have recently shown that a proportion of adult neural stem cells in the SVZ have the capacity to integrate into pre-existing circuits and mature into medium spiny projection neurons in the nucleus accumbens 12 . Intriguingly, newly generated neurons in the nucleus accumbens are significantly increased 6 weeks after sciatic nerve injury 12 and our current result demonstrates that the absence of adult neurogenesis significantly attenuated painful behaviors after 5 weeks post-nerve injury.…”

“…Indeed, the absence of adult neurogenesis likely prevented the maladaptive processes in mesolimbic circuits, where we have recently shown that a proportion of adult neural stem cells in the SVZ have the capacity to integrate into pre-existing circuits and mature into medium spiny projection neurons in the nucleus accumbens 12 . Intriguingly, newly generated neurons in the nucleus accumbens are significantly increased 6 weeks after sciatic nerve injury 12 and our current result demonstrates that the absence of adult neurogenesis significantly attenuated painful behaviors after 5 weeks post-nerve injury. Taken together, given the similar time course, we speculate that the functional integration of newly generated medium spiny neurons into pre-existing circuits within the nucleus accumbens subserve a pro-nociceptive role.…”

“…Although the genetic mouse model we used precludes us from determining which specific neurogenic areas of the brain are involved in the chronic pain phenotypes observed in this study, available evidence suggests that newborn cells maturing and integrating in regions such as the hippocampus, amygdala, nucleus accumbens and prefrontal cortical regions likely orchestrate a cascade of plastic changes at the cellular and circuit level over the course of months after injury 1 , 5 , 12 , 23 . Such reorganisation of network activity in these brain regions has been shown to underlie the altered sensorimotor and emotional-motivational processing that are frequently observed in chronic pain patients and preclinical models 24 – 26 .…”

“…Furthermore, the process of neurogenesis during pathological pain also appears to be highly susceptible to environmental factors such as stress from chronic immobilization, which exacerbated the loss of neuroblasts and reduced survival of new mature neurons in hippocampal granular layers 11 . Additionally, our recent work has also demonstrated that pathological pain enhances neurogenesis of SVZ-derived adult-born medium spiny neurons that populate the ventral striatum 12 . However, to date, it remains unclear if and how active adult neurogenesis becomes critical over the course of pathological pain.…”

Network preservation reveals shared and unique biological processes associated with chronic alcohol abuse in NAc and PFC

“…It is well understood that most adult neuronal stem cells originate in the ventricularsubventricular zones (V-SVZ) and migrate to adjacent cortical and subcortical brain regions as neuroblasts to promote neurogenesis [50]. A recent study showed increased adult neurogenesis of medium spiny neurons within the NAc and that the migration and incorporation of new neurons was experience-based [51]. We believe that the increased expression of genes that encode for the cilia assembly complex may reflective of experience mediated neurogenesis of medium spiny neurons in NAc, except being driven by chronic alcohol consumption instead of pain.…”