Time  : 14:00-15:30 on Tues.,Mar.11, 2025

Venue：E109,Biomedicine Hall

Speaker: Dr. Hailan Hu

Host: Dr. Kexin Yuan、Dr. Kun Li

Title: Decoding the Neural Mechanisms of Depression: Insights Through Ketamine’s Pharmacological Lens

Abstract ：

Depression, a highly polygenic and heterogeneous disorder, has long eluded mechanistic understanding due to the limitations of traditional forward genetic approaches. Here, we propose a complementary strategy: leveraging the rapid, targeted action of ketamine—a potent NMDA receptor (NMDAR) antagonist with robust antidepressant effects—to reverse-engineer the primary neural mechanisms underlying depression. By dissecting how ketamine acutely disrupts pathological circuitry, we aim to bypass indirect downstream effects and pinpoint core drivers of the disease.

Our recent work demonstrates that ketamine silences NMDAR-dependent burst firing in the lateral habenula (LHb), the brain’s “anti-reward” hub. In depressive-like states, LHb hyperactivity suppresses downstream aminergic reward circuits, perpetuating anhedonia and emotional dysregulation. Ketamine’s rapid antidepressant action arises from its ability to suppress this hyperactivity, disinhibiting reward pathways within minutes. Furthermore, we identified that ketamine’s sustained efficacy stems from a trapping blockade of LHb-NMDARs—a pharmacological mechanism that prolongs receptor inhibition even after drug clearance. Finally, ketamine’s brain-region specificity is mediated by use-dependent NMDAR inhibition, selectively targeting hyperactive LHb neurons while sparing baseline activity in other regions. Collectively, by mapping ketamine’s site-specific modulation of cellular and circuit dynamics, we uncover a unified framework linking NMDAR dysfunction to depression etiology and treatment.

Building on this, our recent work extends this framework beyond NMDARs, identifying two additional ion channels as critical mediators of LHb bursts and antidepressant efficacy. Through the charaterization of one these channels, a glia-specific potassium channel Kir4.1, we identified a novel form of neuron-glia interaction, wherby astrocytic processes tightly envelop neuronal soma to regulate neuronal bursts. I will present our ongoing work delineating how neurons and astrocytes dynamically interact in the LHb to regulate stress response and depressive-like behaviors.

Biography：

胡海岚，浙江大学医学院脑科学与脑医学学院院长、浙江大学教育部脑与脑机融合前沿科学中心主任。致力于研究社会行为和情绪的神经编码和调控机制，特别是抑郁症的基础及转化研究。发现了社会竞争中“胜利者效应”的脑机制，揭示了后天的经历可以通过重塑神经环路来改变先天的弱势；从分子、细胞和系统等多层面对抑郁症的成因提出了新的阐释，为研发更好、更安全的抗抑郁药物提供了新思路。曾获谈家桢生命科学奖、何梁何利科技进步奖、国际脑研究组织-凯默理神经科学奖、欧莱雅-联合国教科文组织世界杰出女科学家奖、国家自然科学二等奖等。担任Cell、Neuron、Annu Rev Neurosci等期刊编委。