1. Background and significance of the current study Major depressive disorder (MDD), or depression is one of the leading causes of psychiatric disability in the United States and worldwide. Even though the risk for depression is highly genetic, the search for "depression genes" has been difficult, likely due to the multifaceted nature of depressive disorders. In addition to possible genetic components, there appears to be an environmental component in the neurobiology of MDD. This reinforces the idea that depression is a combination of genetic and environmental factors. Among various hypotheses regarding the etiology of depressive disorder, the theory suggests that modifications in monoaminergic neurotransmission are instrumental in the pathophysiology and treatment of depression. Anatomically, the lateral habenula (LHb), a part of the epithalamus, is quite unique since it projects to the all the major monoamine centers in the brain such as the ventral tegmental area (VTA, dopamine center), dorsal raphe nucleus (DRN, serotonin center), as well as locus coeruleus (LC, norepinephrine center). These distinctive projections make the LHb a very strong candidate area of interest to study pathophysiology of depression. In this study, we focused on the LHb projection to the dopamine center, VTA, which controls reward-seeking behavior. In two well-established animal models of depression, the synaptic activity of LHb neurons that project to the VTA is remarkably potentiated in the helpless animals compared to the control na?ve animals, as if the LHb may act as a "disappointment center." The LHb is known to suppress the activity of the VTA, the main source of a reward signal, dopamine. So, the activation of the LHb, in turn, reduces dopamine release from the VTA, therefore animal feels dissatisfaction or disappointment. So one can picture that the hyperactivity in the LHb observed in the helpless animals, therefore, perhaps serves as higher expectation for positive events, therefore sending stronger disappointment signals upon same events, or more easily getting upset at neutral events. Our study revealed an aberrant cellular process that has not previously been examined in the context of mood disorders. Future studies aimed to manipulate the synaptic activity onto the LHb neurons may contribute to offer a valuable intervention target for the treatment of depression. Furthermore, delineating synaptic connections between the LHb and other monoamine systems are also of great future interest as well as their possible interactions. 2. About UCSD and Malinow Lab I am working with Dr. Roberto Malinow at UCSD. UCSD is now highly recognized as one of top research schools thus requires no further explanation. San Diego area is also well known as a great biology community including the Salk Institute, the Scripps Research Institute, and the Burnham Institute. Robert has been greatly contributed to the field by providing solid observations and provocative insights in understanding cellular model of memory under various circumstances. Malinow's lab moved from CSHL at 2008 spring to UCSD, the Center for Neural Circuits and Behavior (CNCB). UCSD Neuroscience department recently recruited more investigators whose interest is dissecting the brain activity at the system/circuit level. It sure is a great place to be as all the members in our lab and in the building are exceedingly driven to the science and you can initiate constructive discussions with anyone any time. 3. While preparing this paper While preparing this paper, one of many obstacles we encountered was the individuality among animals. As not all stressful life events result in depression to the general population and not everyone responds to stress in a similar fashion, I found substantial amount of variability in synaptic activity between recorded animals. The question of susceptibility towards depressive disorder itself is of great interest yet at the same time, it makes the interpretation of my results more complicated. I proposed to perform a series of experiments in where I would measure the behavioral deficit and record synaptic activity of VTA-projecting LHb neurons. I remained blinded to animal's performances. As my colleagues were pretty skeptical about the possibility, it was quite exciting when I saw a very strong correlation between animal's helplessness and synaptic activity measured in LHb. This observation lends strong support to our model proposed in this study. 4. Advice for young students I don't think I am qualified enough to give any advice to young students who want to disclose the mystery of the brain or biological phenomena in general so here I will share my favorite quote from Richard Feynman. "In the search for new laws, you always have the psychological excitement of feeling that possibly nobody has yet thought of the crazy possibility you are looking at right now". There are many qualities required for being a good scientist/biologists such as creativity, perseverance, patience, critical thinking, precision, and passion. For me, the most important thing is enjoying what I am doing now. Recording is so much fun, even with the days when things are not working and you get frustrated, which actually is most of the time. I am still mesmerized by beautiful, highly coordinated synaptic activities and having fun. Hope you have fun in the lab too. 5. Future plans I am currently delving further into the characterized circuit in this study (lateral habenula and ventral tegmental area) using more diverse approaches. My present goal is to understand depressive disorders with synaptic terms, as synaptic transmission is the language of our brain. I would like to carry on studies in search of synaptic basis of mood disorders, which is expected to shed light on the understanding of our feelings and emotions-what they are and how they work. 6. Acknowledement I am glad to have a chance to share my work with fellow Korean scientists. It has been a unique journey for me so far. I am indebt to all the mentors who opened my eyes to the wonder of the brain and to the charm of electrophysiology. I've been extremely lucky to have met extraordinary scientific peers and collegues along this journey and some of them I even managed to make my friends! And most of all, I would like thank my family in Korea for their endless encouragement and unwavering trust. Without their untiring support, none of these would have been possible.