Diabetes mellitus (DM) is a chronic, metabolic disease characterized by elevated blood glucose levels; it is a widespread disease worldwide and continues to be on the rise, thus making it a serious health concern warranting effective strategies (Saeedi et al., 2019). Hyperglycemia-associated tissue damage and dysfunction involve multiple systems, including the central nervous system (The Lancet Diabetes, E, 2015). Depressive symptom is one of the manifestations of central nervous system being damaged. Presently, the prevalence of depression in DM patients is 10%–15%, which is 2–3 times higher than that in the general population (Sartorius, 2018). Depression severely affects the quality of life in patients with DM and is an important cause of death in this population. Limited knowledge about the pathogenesis of DM-induced depression has significantly hindered the development of targeted and effective treatment for these patients. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are the new types of oral hypoglycemic drug which predominantly play a hypoglycemic role by inhibiting the reabsorption of glucose in proximal tubules of the kidney. A study of 117 patients with type 2 DM showed that SGLT2 inhibitors reduced the risk of developing depression more effectively than the classic oral hypoglycemic drugs, such as metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) analogs (Wium-Andersen et al., 2022). This suggests that SGLT2 inhibitors may be more efficacious than the current therapies in alleviating DM-induced depression, However, its mechanism remains unclear.

The level of 5-hydroxytryptamine (5-HT) has been shown to significantly decrease in the brain tissue of DM model animals (Martin et al., 2021). Accordingly, the importance of 5-HT in the pathogenesis of depression has been emphasized and has attracted the investigators' interest (Kohler et al., 2016). The lateral habenula (LHb), an important nucleus in the brain, which is located in the thalamus, affects the synthesis and release of 5-HT (Lecourtier and Kelly, 2007; Yang et al., 2008a). And more importantly, increased blood glucose (e.g., via intragastric glucose administration) reportedly causes increased LHb neuronal activity in rats (Otsubo et al., 2011). Some studies have shown that the LHb is closely associated with the onset of depression. Increased activity of LHb neurons has been found in different depression models (Yang et al., 2014). Simulation of the LHb by photogenetic techniques could trigger depressive-like behavior (Yang et al., 2018). The LHb lesions could alleviate depressive-like behavior (Yang et al., 2008b) and certain antidepressants exert their antidepressant effect by inhibiting the activity of LHb neurons (Yang et al., 2014). These results suggest that increased LHb neuronal activity may also contribute to the occurrence and development of DM-induced depression.

SGLT2 is widely expressed in the central nervous system (Koekkoek et al., 2017), and SGLT2 inhibitors have neuroprotective effects that help alleviate the symptoms of epilepsy, Alzheimer's disease, Parkinson's disease, cognitive impairment (Wicinski et al., 2020; Lin et al., 2021), and scopolamine-induced memory impairment by increasing 5-HT levels in the brain (Arafa et al., 2017). We speculate that SGLT2 inhibitors alleviate DM-induced depression by inhibiting the activity of LHb neurons and increasing 5-HT levels in the brain. It would be interesting to learn how SGLT2 exerts its inhibitory effect on the neuronal activity of the LHb.

Studies have reported that deep electrical stimulation of the LHb alleviates adrenaline-induced depressive-like behavior, which is accompanied by the activation of AMP-activated protein kinase (AMPK) in the LHb, and notably, the degree of AMPK activation was positively correlated with the efficacy of the antidepressant treatment (Kim et al., 2016). These results suggest that the activity of AMPK is closely related to the activity of LHb neurons. AMPK is the main regulator of brain cell energy homeostasis (Lopez-Gambero et al., 2019), and it is instrumental in regulating various physiological functions, including feeding, sleep homeostasis, and neuronal excitability. Studies have linked the abnormal function of AMPK with many neuropsychiatric diseases, such as Alzheimer's disease, Parkinson's disease, stroke, and depression (Liu and Chern, 2015). AMPK agonists and their analogs, such as metformin, resveratrol, and alginate, alleviate the depressive-like behavior induced by different factors, such as high-fat diet (HFD), corticosterone, and lipopolysaccharide (Liu et al., 2014; Gu et al., 2019); in particular, alginate serve as an antidepressant by activating AMPK in the prefrontal cortex, hippocampus, and hypothalamus (Jiang et al., 2019). Sertraline (Hwang et al., 2021), ketamine (Xu et al., 2013), and other classical antidepressants also play their role by activating AMPK. Conversely, inhibiting AMPK activity weakens or even abolishes their antidepressant effect. DM model animals have down-regulated AMPK activity in several regions of the brain, such as the hippocampus, cortex, prefrontal cortex and hypothalamus (Palleria et al., 2017; Peng et al., 2016; Son et al., 2015), which are associated with the onset of depression. AMPK reportedly activates G-protein-activated inwardly rectifying K+ (GIRK) channels by acting on the GABAB receptor (GABABR) on hippocampal neurons, which increases potassium outflow and causes hyperpolarization of neurons (Luscher and Slesinger, 2010).

SGLT2 inhibitors play a hypoglycemic role by increasing urinary glucose excretion, which is similar to caloric restriction and activates AMPK signaling pathway (Jaikumkao et al., 2021). Dapagliflozin was first approved in Europe in November 2012 and is the first SGLT2 inhibitor in the world to be approved as a hypoglycemic drug. Dapagliflozin reportedly activates the AMPK signaling pathway and exerts a neuroprotective effect (Jaikumkao et al., 2021; Ibrahim et al., 2022; Kamel et al., 2022).

Taken together, we hypothesized that the increased activity of LHb neurons and decreased AMPK signaling pathway in the LHb of DM rats may be associated with DM-induced depressive behavior. Inhibition of the LHb could alleviate depressive-like behavior in DM rats. Dapagliflozin may achieve antidepressant effects by inhibiting the activity of the LHb through activation of the AMPK signaling pathway. To test our hypothesis, we conducted the current study with an aim to investigate the role of the LHb in the pathogenesis of DM-induced depression and identify whether dapagliflozin, an SGLT2 inhibitor, alleviates DM-induced depression by affecting the activity of LHb neurons. We believe the outcomes of this study will advance our understanding of the pathogenesis of DM-induced depression and help identify new therapeutic targets and develop effective intervention strategies.