Postoperative Cognitive Dysfunction (POCD), a condition also encompassed by the broader term ‘Postoperative Neurocognitive Disorders (PND)’ [1], is a prevalent neurological complication following surgery, with a markedly higher incidence in older individuals [[2], [3], [4]]. As our animal model, with cognitive assessments commencing 7 days post-surgery, is designed to investigate this specific delayed phenotype, we use the term ‘POCD’ herein to reflect this focus. Manifesting as deficits in memory, attention, executive function, and processing speed, POCD can hinder recovery, diminish quality of life, increase healthcare burdens, and contribute to long-term cognitive decline and higher mortality [2,3]. Despite considerable research, the precise pathophysiology, particularly the molecular underpinnings of age-related susceptibility to POCD, remains incompletely elucidated.

Current investigations into the molecular basis of POCD suggest that multiple pathological processes interact synergistically, including neuroinflammatory cascades [5], heightened oxidative stress [4], compromised synaptic plasticity [6], and disruption of cellular homeostasis [7]. Among these, neuroinflammation, principally characterized by the excessive and sustained activation of microglia and astrocytes and the subsequent release of pro-inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6), is considered a central driver of POCD pathogenesis, ultimately leading to neuronal damage and cognitive deficits [5,8,9]. Notably, aging itself is associated with chronic alterations in the brain's inflammatory milieu, a phenomenon termed “inflammaging”, which may substantially contribute to the increased vulnerability of older individuals to surgery-induced cognitive impairment [10,11].

In parallel, endoplasmic reticulum (ER) stress, a cellular response to diverse pathological stimuli, has garnered considerable attention for its role in neurological diseases and cognitive disturbances [12,13]. ER stress arises from the accumulation of improperly folded proteins within the ER lumen, activating the unfolded protein response (UPR) and initiating adaptive or detrimental signaling cascades [14]. Persistent or excessive ER stress can culminate in cellular dysfunction and apoptosis, frequently mediated via the PERK-eIF2α-ATF4-CHOP pathway [15,16]. Within the context of POCD, surgical trauma and anesthetic agents may directly or indirectly perturb ER homeostasis in hippocampal neurons, thereby inducing ER stress and impairing neuronal function and synaptic plasticity [15,17]. Nevertheless, the interplay between these diverse pathological processes and the identification of upstream regulatory molecules, particularly those mediating age-related susceptibility to POCD, require further investigation.

The Sigma-1 receptor (Sigma-1R), a molecular chaperone residing on the endoplasmic reticulum membrane, particularly at ER-mitochondria contact sites (MAMs), functions as a crucial cellular stress modulator [18,19]. Extensively expressed throughout the central nervous system and concentrated in cognition-relevant regions such as the hippocampus, Sigma-1R is integral to regulating ER calcium homeostasis, mitochondrial bioenergetics, ion channel activity, ER integrity, and autophagy [[18], [19], [20]]. Sigma-1R demonstrates substantial neuroprotective effects, including enhancement of synaptic plasticity, mitigation of cellular stress, and modulation of neuroinflammation, as observed in animal models of ischemic stroke [19], amyotrophic lateral sclerosis [21], and Alzheimer's disease [22]. Considering that aging is potentially associated with diminished Sigma-1R expression or function [23], we hypothesize that this receptor plays a critical role in the pathogenesis of POCD, particularly concerning the increased vulnerability of older individuals. Consequently, targeting Sigma-1R could offer novel interventional strategies.

Accordingly, the present study aims to: (1) investigate age-dependent alterations in hippocampal Sigma-1R expression within a murine model of POCD and analyze their correlation with cognitive dysfunction; (2) determine the precise cellular localization of Sigma-1R in the murine hippocampus to provide a microanatomical basis for its functional mechanisms; (3) evaluate the therapeutic efficacy of the specific Sigma-1R agonist PRE-084 on cognitive function in aged mice experiencing POCD; and (4) explore the molecular mechanisms underlying the neuroprotective effects of PRE-084, with a specific focus on its modulation of hippocampal ER stress, neuroinflammation, and the activity of NF-κB and CREB signaling pathways.