# Nomilin Regulates Depressive‐Like Behaviors in Mice via the Ventral Part of the Lateral Septum to Bed Nucleus of the Stria Terminalis Circuit

## TL;DR

Nomilin, a natural compound, reduces depression-like behaviors in mice by activating specific brain circuits involving GABAergic neurons.

## Contribution

This study identifies nomilin's novel antidepressant mechanism via the LSv to BNST neural circuit in mice.

## Key findings

- Nomilin alleviates depressive-like behaviors and increases LSv GABAergic neuron excitability.
- LSv GABAergic neurons are critical for nomilin's antidepressant effects.
- GABAA receptors mediate the LSvGABA → BNST circuit's antidepressant function.

## Abstract

The limitations of current clinical antidepressants and the slow progress in developing novel treatments highlight the need for rapid‐acting, long‐lasting antidepressants with minimal side effects. Nomilin, a naturally occurring limonoid compound, exhibits diverse pharmacological properties, including anti‐inflammatory and anti‐tumor activities. However, its potential antidepressant effects remain largely unclear.

In this study, we used lipopolysaccharide (LPS)‐induced and chronic restraint stress (CRS)‐induced depression mouse models to verify the antidepressant effects of nomilin. The brain regions with altered activity after nomilin administration were identified using c‐fos immunofluorescence staining. Then chemogenetics, viral tracing, fiber photometry and pharmacological strategies were conducted to further investigate the neural circuit mechanisms of nomilin's antidepressant effects.

This study demonstrated that nomilin significantly alleviated depressive‐like behaviors and increased the excitability of GABAergic neurons in the ventral part of the lateral septal nucleus (LSv), a region exhibiting diminished activity in depressive states. Chemogenetic activation of LSv GABAergic neurons ameliorated LPS‐induced depressive‐like behaviors, whereas their inhibition attenuated the antidepressant effects of nomilin. Nomilin exerted its antidepressant effects via LSv to bed nucleus of the stria terminalis (BNST) GABAergic projections, with downstream GABAA receptors playing a crucial role in regulating the LSvGABA → BNST neural circuit.

Collectively, these findings identify nomilin as a potential candidate for depression and provide novel insights into the development of antidepressant drugs.

Nomilin ameliorates LPS‐induced depressive‐like behaviors in mice by activating LSv GABAergic neurons and the LSvGABA → BNST neural circuit, with downstream modulation mediated by GABAA receptors.