外侧缰核作用于抑郁的神经生理机制

本文旨在梳理国内外有关外侧缰核作用于抑郁神经生理机制的研究成果，以期为今后抑郁研究提供借鉴和参考。首先，阐明了外侧缰核的过度兴奋会加强对下游奖赏中心单胺能脑区的抑制从而诱发抑郁的内在通路。然后，进一步论述了介导外侧缰核过度兴奋的分子机制。最后，未来要重点以人类为被试，采用纵向设计，加强外侧缰核对抑郁的影响、作用机制及其性别差异的研究,同时考察遗传基因和环境在其间的调控效应等问题。

Neurophysiological Mechanism underlying Depression: the role of Lateral Habenula

Depression is one of the most prevalent mental health problems. According to World Health Organization (WHO) statistics, the total estimated number of people living with depression increased by 18.4% between 2005 and 2015. By 2015, the number of depressive individuals in the world had reached 322 million, accounting for 4.4% of the global population, and by 2030, depression will become the leading cause of death and disease burden. Therefore, it is particularly important to explore the underlying mechanism of depression. As a core brain region connecting the limbic forebrain with the monoamine center of the midbrain, the excitatory state of lateral habenula（LHb） will affect the activity of monoaminergic brain regions (mainly refers to the brain region where monoamine neurotransmitter such as serotonin and dopamine gather): when LHb is excited, the activity of monoaminergic brain regions is inhibited, while when LHb is inhibited, the monoaminergic brain regions will be excited instead. Animal model and neuroimaging studies show that the excessive excitation of LHb is an important cause of depression. Existing literature has demonstrated that overexpression of Beta βCaMKII and glutamatergic receptor membrane of GluR1 subtype may be the molecular mechanism mediating LHb hyperexcitation. Recent studies have indicated that the bursting pattern of neurons also play an important role in mediating LHb over-excitation to induce depression.The specific neurophysiological pathways underlying the bursting are as follows: astroglial potassium channel (Kir4.1) is upregulated in the LHb, and then the potassium channels of astrocytes are opened. The potassium ions outside LHb neurons will be rapidly cleared, resulting in a decrease in the concentration of potassium ions outside neurons, which will promote the hyperpolarization of membrane potential. Then, the low-voltage-sensitive T-type calcium channel (T-VSCC）and the N-methyl-d-aspartate receptor (NMDAR) channel will be opened one after the other, which will result in the conversion of neurons from a single discharge mode to a bursting mode, thus triggering excessive excitation of LHb neurons. As an anti-reward center, LHb will be activated by negative stimuli such as disappointment, fear, etc. Based on previous studies, we believe that there may be such a pathway for depression: under the condition of repeated negative stimulation such as stress and anxiety, excessive excitation of LHb strengthens the inhibition of monoaminergic brain regions activity in the downstream reward center, thus inducing depression. It should be noted that the vast majority of existing findings on the neurophysiological mechanism of LHb on depression were obtained from animal models. Given that there are essential distinctions between human depression and animal depression-like behavior, the available conclusions should be further verified among human beings. Previous literature has demonstrated that there are significant gender differences in the incidence rate of depression, and in the brain structure and function of depressed patients. However, no study has paid attention to whether the role of LHb on depression is moderated by gender so far. In addition, depression has important genetic and environmental underpinnings, whether and how the LHb-related genes, together with other candidate genes and environment, impact the function and structure of LHb and then trigger depression still remain unclear. Finally, existing studies on the effect of LHb on depression mainly employ cross-sectional design. Therefore, future study could focus on the dynamic development of LHb’s effect on depression by using longitudinal design.