Despite recent advances in biomedical sciences, effective treatment options remain limited for patients suffering from neuropsychiatric diseases. While the underlying etiology and pathophysiology remain unclear for majority of the human cases, it has become increasingly clear that early neurodevelopmental defects can be a contributor to behavioral sequelae later in life. Recently, neural progenitor proliferation and differentiation abnormalities have been described in mouse models of human neuropsychiatric disorders. The postnatal rodent subventricular zone (SVZ) niche around the lateral brain ventricles is a specialized environment housing GFAP+ astrocytes functioning as neural stem cells (NSCs), producing mainly GABAergic interneurons. Postnatal SVZ neurogenesis is regulated by NSC-intrinsic mechanisms, interacting with extracellular/niche-driven cues. It is generally believed that these local effects are responsible for sustaining neurogenesis, though behavioral paradigms and disease states have pointed to possibilities for higher-level modulation. It is currently unclear if activity states from groups of neurons, or discrete neural circuits can directly control postnatal SVZ neurogenesis. We have identified acetylcholine (ACh) release by neuronal terminals into the SVZ niche. Our preliminary results have uncovered a previously undescribed population of cholinergic neurons, projecting their processes directly onto SVZ NSCs. Optogenetic stimulation or inhibition of these novel cholinergic neurons resulted in measurable electrical current induction in SVZ NSCs and concurrent changes in the rates of neurogenesis. We plan to further explore these observations by determining the following: 1) which higher-level brain regions provide excitatory drive to induce ACh release in the SVZ; 2) what are the molecular mechanisms required in SVZ NSCs downstream of ACh activation to promote neurogenesis; and 3) which are the SVZ niche cellular structures/organizations that can transform neuronal firing frequencies into NSC proliferation and increased neurogenesis. Our study proposes to explore a direct connection between neuronal activity from cholinergic neurons and postnatal SVZ NSC proliferation. To make this research question tractable, we have developed new mouse reagents, as well as optogenetic and live-imaging platforms to directly measure the interactions between neuronal activity patterns and SVZ neurogenesis. We believe these findings will have a positive impact by vertically advancing our functional understanding of postnatal SVZ neurogenesis control by circuit-level activity, with potentially important implications for cholinergic circuit dysfunctionin neuropsychiatric diseases.
Neuropsychiatric diseases represent a significant health burden, but modern medicine has few curative options for patients suffering from conditions such as schizophrenia and depression. It has become increasingly clear in recent years that neurodevelopmental abnormalities underlie many forms of neuropsychiatric diseases. Both neural progenitor mis-differentiation and functional defects in cholinergic circuit development have been implicated as potential mechanisms for disease, though the connections between these two processes in the brain are poorly understood. Our proposal examines a novel hypothesis that a previously unknown population of cholinergic neurons, in an activity-dependent fashion secreting acetylcholine, can directly control GABAergic interneuron production from neural stem cells in the postnatal subventricular zone (SVZ) niche. Our results from these studies should have a direct impact by unlocking an important gateway connecting neurodevelopmental processes and cholinergic circuit function in health and disease.
