On September 22, 2025, the Chen Zhong/Wang Yi team from Zhejiang University of Traditional Chinese MedicineNature NeuroscienceOnline publication title:“A bottom-up septal inhibitory circuit mediates anticipatory control of drinking”The research paper revealed an inhibitory loop in the conduction of the medial septal nucleus (MS) to SFO in mice, which is involved in the expected control of drinking behavior in mice. MSgamma-aminobutyric acidGABAergic neurons encode water satiety signals by integrating oral cues and tracking gastrointestinal signals. These neurons receive signals from the brachiocephalic nucleus and transmit them to CaMKII neurons in the SFO, forming a bottom-up active pathway to prevent excessive water intake. When this pathway is damaged, it can lead to excessive drinking and triggerhyponatremia.

Screenshot of the online publication of the paper

Firstly, researchers found through retrograde tracking and FosTrap that MS is not only an important upstream of the central nervous system (SFO) that controls drinking behavior, but also the GABAergic neurons of MS are significantly activated under water saturation conditions.

Considering MS^vGAT-The complexity of SFO circuit in drinking water behavior, researchers utilizeUltra dimensional miniaturized two-photon microscopeCalcium imaging recordings were conducted, and the results showed that these neurons exhibited biphasic activity patterns during the drinking process: rapid inhibition at the beginning of licking, followed by gradually increasing activity during the drinking process. The GABAergic neurons of MS simultaneously encode two types of prior information: first, inhibition signals related to oral immediate feedback from licking; Secondly, the activation of signals from the gastrointestinal tract is followed by a 'slow signal'.

By precisely manipulating this neural circuit, researchers found that optogenetic selective activation of the GABAergic neural circuit of MS-SFO can immediately terminate the drinking behavior of thirsty mice; Inhibiting this pathway will allow mice that are already full to continue drinking water, indicating that this circuit has a "state dependent bidirectional regulation" of drinking water: activating the MS → SFO loop in a thirsty state brings about immediate "cessation of drinking" and a positive valence effect; Inhibiting this pathway under water saturation conditions generates negative valence drive, inducing "pseudo thirst" and prolonging water intake.

In order to explore the molecular characteristics of GABAergic neurons projected onto the SFO, the research team used spatial transcriptome sequencing (spatial seq) technology and found significant differences in gene expression between these neurons and adjacent GABAergic neurons in the medial prefrontal area (MnPO). Specifically, the GABAergic neurons of MnPO are mainly marked by the glucagon like peptide 1 receptor (GLP1r) gene, while the GABAergic neurons projected by SFO selectively express SRY Box Transcription Factor 6 (Sox6). Sox6 is considered to play an important role in regulating fluid balance.

Next, the researchers defined the downstream SFO functional cell types of MS GABAergic neurons. Firstly, single synapse tracing and electrophysiological analysis of rabies virus confirmed that the excitatory CaMKII neurons of SFO are the main direct downstream of MS GABAergic neurons, forming inhibitory single synapse connections. Further functional connectivity experiments have shown that activating MS GABAergic neurons can immediately inhibit SFO in a light following manner^CaMKIICalcium activity. The key is that when SFO is activated in a dehydrated state^CaMKIINeurons can significantly reverse photoactive MS^vGAT-The inhibitory water uptake effect generated by the SFO loop indicates that SFO^CaMKIINeurons are the core 'effectors' of this inhibitory loop regulating drinking water.

So, how do these GABAergic neurons in MS know that we have drunk enough water? Research has found that these neurons are capable of simultaneously receiving oral and gastrointestinal signals from PBN inputs, integrating these sensory information and transmitting it to the lower SFO to regulate drinking behavior. PBN serves as a relay station for key signals, transmitting sensory information from the oral and gastrointestinal tract to GABAergic neurons in the MS area, providing a more complete neural network framework for water regulation. After cutting off the signal input from PBN to MS, the calcium activity of GABA neurons in MS is also "passivated" during the process of drinking water. Mice will drink excessively and develop hyponatremia - it's like a vehicle without brakes, running all the way and causing accidents.