Abstract
Major depressive disorder (MDD) is a prevalent and debilitating mental health condition affecting approximately 280 million people worldwide. According to the World Health Organization (WHO), the prevalence of anxiety and depression increased by 25% during the COVID-19 pandemic. Current treatments for depression, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are limited by their delayed therapeutic onset, suboptimal efficacy, and potential adverse effects during the initial phase of treatment. These limitations underscore the urgent need to deepen our understanding of the pathophysiological mechanisms underlying depression to develop more effective and targeted therapies.Among the complex etiological factors contributing to depression, chronic stress and exposure to aversive experiences are recognized as major risk factors. Stress has been shown to induce synaptic dysfunction and neural plasticity changes, particularly within brain circuits involved in reward and aversion processing, alterations that are strongly implicated in the pathogenesis of depression.
Within this network, the amygdala is a key brain structure responsible for encoding and storing emotionally salient memories. Numerous neuroimaging and postmortem studies have reported structural, metabolic, and functional alterations in the amygdala of individuals with depression. Another critical structure, the dorsal raphe nucleus (DRN), serves as a major source of serotonin (5-HT) and plays a central role in regulating emotion and stress responses. Augmented serotonergic availability is associated with improved mood and reduced anxiety, forming the basis for many antidepressant therapies. Conversely, decreased 5-HT levels are closely linked to stress-related psychopathologies, including depression. However, it remains unclear whether altered amygdala activity directly contributes to reductions in serotonin release and subsequent depressive states. This dissertation investigates how restrained inescapable stress (RIS) alters amygdala activity and how this change influences serotonin neural dynamics in the brain.
First, we show that RIS induces depressive-like behaviors, increases c-Fos expression (a marker of neural activity) in the amygdala, and results in decreased serotonin and elevated glucocorticoid levels. Second, chemogenetic inhibition of the amygdala attenuates depressive-like behaviors, reduces c-Fos expression, and restores both serotonin and glucocorticoid levels to baseline. Third, using anterograde and retrograde tracing, we demonstrate that the amygdala, particularly the central amygdala (CeA), which is composed predominantly of GABAergic neurons, projects directly to the DRN. These projections preferentially target serotonergic neurons, although inputs to DRN GABAergic neurons are also observed.
Finally, through fiber photometry and optogenetic approaches, we reveal that aversive footshock stimuli, along with CeA activation, increase DRN neuronal activity both before and after RIS. However, cell-type-specific recordings indicate that CeA activation during footshock following RIS selectively suppresses the activity of serotonergic, but not GABAergic, DRN neurons.
In conclusion, this work identifies the CeA-DRN pathway as a critical circuit regulating serotonergic tone and depressive-like behaviors in response to chronic stress. These findings highlight the amygdala’s central role in depression and suggest that targeting specific CeA-DRN projections may offer novel therapeutic avenues for stress-related mood disorders.
| Date of Award | 20 Aug 2025 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Jufang HE (Supervisor) & Youngjin LEE (Co-supervisor) |