Background Depression is recognized as a significant challenge for individuals diagnosed with a variety of cancer types, with a particular emphasis on colorectal cancer (CRC). Mapping depression-related brain regions through the gut-brain axis can help understand the process, but the mechanisms are still unknown. The lateral habenular nucleus (LHb) is a key neuronal structure located within the epithalamus, and it is known to play a crucial role in the pathophysiology of depression. LHb is innervated by serotonin (5-HT) fibers, and the 5-HT system is considered a pivotal factor in the pathophysiology of depression. Thus, we speculate that the LHb 5-HT₆ receptors may function in regulating depression in CRC.

Methods We used a 1,2-dimethylhydrazine-induced rat model to evoke CRC-related depression-like behaviors. Behavioral (forced swimming and sucrose preference) tests, electrophysiological recordings and neurochemical methods were adopted to identify the role of LHb 5-HT₆ receptors in CRC-related depression.

Results Intra-LHb injection of 5-HT₆ receptor agonist WAY208466 and antagonist SB258585 produced antidepressant-like responses in sham-operated and CRC model rats. Neurochemical results showed that intra-LHb injection of WAY208466 and SB258585 decreased or increased dopamine (DA) and noradrenaline (NA) levels in the medial prefrontal cortex, amygdala, habenula and ventral hippocampus in both rats, respectively. Compared to sham-operated rats, the duration of WAY208466 and SB258585 action on the firing rate of glutamate neurons was markedly prolonged in the model rats. These findings indicate that LHb 5-HT₆ receptors are involved in the regulation of depressive-like behaviors, which attribute to changes in DA and NA levels in the limbic and limbic-related brain regions. Additionally, the results suggest that the CRC leads to a hypersensitization of 5-HT₆ receptors on glutamate neurons in the LHb.

Conclusions The current research offers a significant discovery to further understand the role of LHb 5-HT₆ receptors in the modulation of depression, especially in CRC-related depression.