Depression is the leading cause of disability worldwide and a key contributor to the overall global burden of disease with a lifetime prevalence of ~17%. According to some reports, the lifetime prevalence reaches 36% among the hong kong population. The currently available treatment for depression includes SSRIs and SNRIs antidepressants which have limitations due to their slow onset and limited efficacy. Moreover, some patients showed adverse effects at the beginning of treatment. Therefore, it is critical need to understand the pathophysiology of depression to develop a new treatment for this lethal disease.

Among the complicated etiology of depression, chronic stress or aversive stimuli experiences is a major risk factor. Stress leads to synaptic dysfunction, which can be a potential therapeutic target for stress-related mood disorders, particularly depression. Stress-induced neural plasticity changes in the brain’s rewards and aversion systems are strongly implicated in depression.

Among several stress-related emotional memory coding regions, the basolateral amygdala (BLA) is considered a brain-centric nucleus where emotional memories are processed and stored. Numerous human studies showed alteration in the structure, metabolism, and valence response of BLA in depressed patients. However, how the external stressful events are processed and stored in the BLA and ultimately translated into depressive-like behavior remains elusive. In this dissertation, it was investigated how aversive stimuli affect the BLA neuronal activity and how the BLA GABAergic and glutamatergic neurons modulate depressive-like behaviors.

Firstly, it was shown that chronic stress increased the c-fos (neural activity marker) activity in the BLA. The results are further confirmed with fiber photometry calcium recording, proving that the aversive stimuli elevated the BLA^CAMKII calcium responses which is an indicator of increased neuronal activity. The optogenetic activation of BLA^CAMKII neurons or chemogenetic inhibition of BLA^GABA neurons mediates depressive-like behavior.

Secondly, it was demonstrated that the BLA^GABA presents major functional input onto BLA^CAMKII neurons. The high-frequency optogenetic activation of BLA^GABA neurons decreased the aversive stimulus-induced BLA^CAMKII neuronal activity. However, this effect was not seen in low-frequency as well as control group mice with high-frequency activation. The results are further confirmed by using the chemogenetic method. Chemogenetic activation of BLA^GABA also decreased the aversive stimulus-induced BLA^CAMKII neuronal activity. Contrarily, chemogenetic inhibition of BLA^GABA neurons increased the firing frequency and the number of spikes of BLA^CAMKII neurons.

Thirdly, a well-established chronic social defeat depression model was adopted and proved that enhancing the inhibition in the BLA alleviates the depressive-like phenotype in mice. The high-frequency activation of BLA^GABA neurons in susceptible mice attenuates depressive-like behavior. Furthermore, high-frequency activation of BLA^GABA neurons during chronic stress also increased the number of resilient mice. Alternatively, direct inhibition of BLA^CAMKII neurons also mediates the antidepressant-like effects.

Although the stress-induced synaptic plasticity changes materialized in the BLA, this nucleus governs the stress responses by interacting with its upstream and downstream target regions. Retrograde labeling exhibited dense labeling in the lateral entorhinal cortex (Lent), medial prefrontal cortex (mPFC), auditory cortex (AuC), insular cortex (IC), and paraventricular nucleus of the thalamus (PVT). All these structures are previously known to mediate stress responses. Recently, our group has shown that the BLA received dense cholecystokinin projections from the entorhinal cortex and enabled neuroplasticity in the lateral amygdala of anesthetized mice. Hence, lastly, it has been explored whether EC^CCK afferents to BLA modulate depressive-like behavior. Optogenetic activation of EC^CCK neurons increased the BLA^CAMKII neuronal activity in the freely behaving mice. Besides, it has been demonstrated that the activation of EC^CCK terminals in the BLA facilitates the induction of a depressive-like phenotype, and inhibition of terminals mediates the antidepressant-like response.

In conclusion, BLA plays a crucial role in the development of depression and BLA^GABA neurons present the major functional input onto BLA^CAMKII neurons and are a critical component for the regulation of depressive-like behavior. Additional experiments elucidated that EC^CCK neurons induced BLA neuronal activities and mediates depressive-like behavior. As demonstrated via an array of congruent results, it is evident that enhancing the inhibition in the BLA by high-frequency activation of BLA^GABA neurons or direct inhibition of glutamatergic neurons alleviates depressive-like behavior.