Multiple populations of wake-promoting neurons have been characterized in mammals, but few sleep-promoting neurons have been identified1. Wake-promoting cell types include hypocretin and GABA (γ-aminobutyric-acid)-releasing neurons of the lateral hypothalamus, which promote the transition to wakefulness from non-rapid eye movement (NREM) and rapid eye movement (REM) sleep2,3. Here we show that a subset of GABAergic neurons in the mouse ventral zona incerta, which express the LIM homeodomain factor Lhx6 and are activated by sleep pressure, both directly inhibit wake-active hypocretin and GABAergic cells in the lateral hypothalamus and receive inputs from multiple sleep–wake-regulating neurons. Conditional deletion of Lhx6 from the developing diencephalon leads to decreases in both NREM and REM sleep. Furthermore, selective activation and inhibition of Lhx6-positive neurons in the ventral zona incerta bidirectionally regulate sleep time in adult mice, in part through hypocretin-dependent mechanisms. These studies identify a GABAergic subpopulation of neurons in the ventral zona incerta that promote sleep.

Summary Mossy cells (MCs) represent a major population of excitatory neurons in the adult dentate gyrus, a brain region where new neurons are generated from radial neural stem cells (rNSCs) throughout life. Little is known about the role of MCs in regulating rNSCs. Here we demonstrate that MC commissural projections structurally and functionally interact with rNSCs through both direct glutamatergic MC-rNSC pathway and indirect GABAergic MC-local interneuron-rNSC pathway. Specifically, moderate MC activation increases rNSC quiescence through dominant indirect pathway; while high MC activation increases rNSC activation through dominant direct pathway. In contrast, MC inhibition or ablation leads to a transient increase of rNSC activation, but rNSC depletion only occurs after chronic ablation of MCs. Together, our study identifies MCs as a critical stem cell niche component that dynamically controls adult NSC quiescence and maintenance under various MC activity states through a balance of direct glutamatergic and indirect GABAergic signaling onto rNSCs.

Summary The quiescence of adult neural stem cells (NSCs) is regulated by local parvalbumin (PV) interneurons within the dentate gyrus (DG). Little is known about how local PV interneurons communicate with distal brain regions to regulate NSCs and hippocampal neurogenesis. Here we identify GABAergic projection neurons from the medial septum (MS) as the major afferents to dentate PV interneurons. Surprisingly, dentate PV interneurons are depolarized by GABA signaling, which is in sharp contrast to most mature neurons hyperpolarized by GABA. Functionally, these long-range GABAergic inputs are necessary and sufficient to maintain adult NSC quiescence, and ablating them leads to NSC activation and subsequent depletion of the NSC pool. Taken together, these findings delineate a GABAergic network involving long-range GABAergic projection neurons and local PV interneurons that couples dynamic brain activity to the neurogenic niche in controlling NSC quiescence and hippocampal neurogenesis.

Within the dentate gyrus of the adult hippocampus is the subgranular zone, which contains a neurogenic niche for radial-glia like cells, the most primitive neural stem cells in the adult brain. The quiescence of neural stem cells is maintained by tonic gamma-aminobutyric acid (GABA) released from local interneurons. Once these cells differentiate into neural progenitor cells, GABA continues to regulate their development into mature granule cells, the principal cell type of the dentate gyrus. Here, we review the role of GABA circuits, signaling, and receptors in regulating development of adult-born cells, as well as the molecular players that modulate GABA signaling. Furthermore, we review recent findings linking dysregulation of adult hippocampal neurogenesis to the altered GABAergic circuitry and signaling under various pathological conditions.