Numerous investigations have demonstrated that hemorrhagic shock and resuscitation (HSR) causes long-term neurological diseases, such as cognitive deficits and mental change (Halaweish et al., 2015; Plaschke, 2009). Notably, a systemic ischemia-reperfusion process under severe HSR contributes to memory deficits (Hu et al., 2018). As the principal excitatory neurons, glutamatergic neurons, play vital roles in a series of pathophysiological processes, such as information integration, cognitive function-associated neural oscillations, and neural circuitry (Gécz, 2010). Thus, it is crucial to do more research to explore the relationship between glutamatergic neurons and memory deficits and therapeutic approaches.

A variety of cognitive and memory associated brain regions project to the ventral tegmental area (VTA), which contributes to the mammalian reward system (Lammel et al., 2014). It was reported that the hippocampus and its inputs including VTA are implicated in reward-related memory (Liu et al., 2022; Ben-Shaanan et al., 2016). In the VTA, there is a diverse population of dopamine (DA), GABA, and glutamate (Glu)-releasing neurons, which send long-range projections to a variety of brain regions (Yu et al., 2019; Ntamati and Lüscher, 2016). There is growing evidence that neurological disorders following traumatic stress attribute to the alteration of glutamatergic neurons in the VTA (Chambers et al., 1999). Intriguingly, glutamatergic neurons are reportedly vulnerable to ischemia and reperfusion injury, subsequently contributing to memory dysfunction (Howells and Russell, 2008; Cao et al., 2016). Until now, the roles of glutamatergic neurons in the VTA under HSR condition remains unknown.

Hydrogen sulfide (H2S), a gasotransmitter with pleiotropic roles, is naturally produced in almost all tissues and signalled through sulfhydration and persulfidation. Evidence from research shows that H2S has neuroprotective functions at physiological concentrations apart from its role as an endothelial-derived relaxation factor. Interestingly, disrupted metabolism of cysteine and H2S may be pathogenic in neurodegenerative conditions such as Parkinson's disease (PD) and Huntington's disease (HD). However, there was no evidence that H2S mitigated memory deficits through the activation of glutamatergic neurons in the VTA post-HSR.

Here, we explored whether remarkable memory impairments and injured VTA glutamatergic neurons could be found in a rodent model of HSR. In addition, this study also explored whether exogenous H2S administration could mitigate memory impairment following HSR via the activation of glutamatergic neurons.