Frontal cortical regulation of neurogenesis and cellular proliferation in the ventral subventricular zone

Abstract

The maintenance and differentiation of the adult neural stem cells (NSCs) in the subventricular zone (SVZ) are controlled by cell-intrinsic molecular pathways that interact with extrinsic signaling cues. How neurogenesis in the SVZ is regulated by neural circuit activity remains poorly understood. Here we identified a novel neural circuit that regulates the state of lateral ventricular wall (LV) NSCs. Our results demonstrate that direct glutamatergic inputs from the frontal cortex, as well as local inhibitory interneurons, control the activity of subependymal cholinergic neurons. In vivo optogenetic and chemogenetic stimulation of defined neuronal populations within this circuit were sufficient to control LV NSC proliferation and SVZ neurogenesis. Moreover, acetylcholine (ACh), which activates M1 muscarinic ACh receptors, triggers the activation of quiescent NSCs. These findings shed light on neural activity-dependent regulation of postnatal and adult LV NSCs activation and SVZ neurogenesis.

A Cholinergic Signaling Pathway underlying Cortical Circuit Regulation of Lateral Ventricle Quiescent Neural Stem Cells

“…Our previous studies have demonstrated that stimulating the ACC-subep-ChAT + circuit for a day leads to an increased proliferation of LV NSCs in close proximity to the subep-ChAT + neurons (27). In order to investigate the molecular mechanism responsible for the circuit’s impact on cellular proliferation, we first used optogenetics to directly manipulate subep-ChAT + neurons in this circuit for 6 hours only.…”

“…The subep-ChAT + neurons, a cholinergic population in the SVZ, regulate LV NSCs proliferation in an activity-dependent manner (26). Furthermore, these local cholinergic neurons receive inputs from both local GABAergic and cingulate glutamatergic neurons, which play a role in regulating SVZ neurogenesis in the ventral SVZ (27). Consequently, this study sheds light on the role of cholinergic signaling and the specific molecular mechanisms involved in the regulation of ventral LV NSCs activation and proliferation.…”

“…The SVZ wholemounts were dissected out from the brains and incubated in a blocking solution containing 5% donkey serum and TBST for 100 minutes at room temperature. They were then incubated overnight at room temperature in PBS containing 1% donkey serum and specific antibodies, which had been validated in our previous publication (27) or by publications available on the vendor’s website for each antibody. After incubation, the SVZ wholemounts were washed with PBS and incubated with secondary antibodies, such as Alexa-594 (1:1000, LifeTech), Alexa-488 (1:1000, LifeTech), or Alexa-647 (1:1000, LifeTech), for 2 hours at room temperature, followed by washing with PBS.…”

“…An example of these neuronal regulators is subep-ChAT + neurons, which release acetylcholine (ACh) locally in the ventral SVZ and modulate LV NSC proliferation and neuroblasts generation (26). These cholinergic neurons receive inhibitory inputs from local GABAergic neurons and excitatory inputs from the anterior cingulate cortex (ACC) (27). However, the molecular mechanisms underlying the circuit regulation of LV NSC proliferation remain unknown.…”

Significance of the anterior cingulate cortex in neurogenesis plasticity: Connections, functions, and disorders across postnatal and adult stages

“…Furthermore, the recent discovery of a direct neural connection between the ACC and the subventricular zone (SVZ), responsible for olfactory neurogenesis, has sparked interest in the ACC's potential role in this process (Figure 1). [9] Therefore, it is imperative to conduct further research on the ACC's involvement in olfactory neurogenesis, as it holds the promise of providing valuable insights into brain functions and neuronal plasticity.…”