Social isolation refers to a state in which an individual's interaction with their environment is minimized. Chronic social isolation is recognized as a significant stressor, adversely impacting both mental and physical health. It has been identified as a critical risk factor for increased morbidity and mortality rates (House et al., 1988). Although social isolation can affect individuals across all age groups, it disproportionately impacts the elderly, who are more frequently exposed to this condition. Despite growing interest in the effects of social isolation on aging, there remains a significant gap in the literature regarding how these effects vary by sex, particularly in elderly animals. Notably, studies involving female subjects are markedly underrepresented.

Oxytocin, a neuropeptide synthesized in the supraoptic and paraventricular nuclei (PVN) of the hypothalamus, exerts both peripheral and central effects. Beyond its well-established roles in parturition and lactation, oxytocin is critically involved in processes such as social bonding and interaction. Its anxiolytic properties and positive effects on social behavior position oxytocin as an essential neuromodulator influencing emotional and behavioral regulation. (Shi et al., 2024). Chronic stress induces significant changes in gene expression in both the prefrontal cortex and hippocampus. In the prefrontal cortex, signaling pathways related to neuroplasticity are activated, leading to disruptions in dendritic connectivity, which can impair cognitive functions. In the hippocampus, stress negatively affects neurogenesis, reducing the production of new neurons, thereby impairing memory and learning processes. The interaction between the prefrontal cortex and hippocampus mediates the effects of stress on both regions (Musaelyan et al., 2020). Intranasal administration is a widely favored route for delivering oxytocin due to its non-invasive nature and its ability to bypass the blood-brain barrier. This method facilitates drug delivery via multiple pathways, including olfactory and vascular routes, the trigeminal nerve, perivascular channels, cerebrospinal fluid, and lymphatic systems (Dhuria et al., 2010).

Neurotrophins, a class of proteins that regulate neuronal growth, development, and synaptic plasticity, play a critical role in healthy synaptic function. Among these, brain-derived neurotrophic factor (BDNF) is pivotal for neural development and neuroplasticity mechanisms (Kakizawa, 2021). Similarly, vascular endothelial growth factor (VEGF) contributes to hippocampus-dependent functions such as learning and memory while offering neuroprotective effects on dopaminergic neurons (Cao et al., 2004). Reductions in these neurotrophic factors have been linked to neuronal atrophy and cell loss in brain regions like the hippocampus and prefrontal cortex, which are involved in stress modulation. These growth factors are also associated with anxiety regulation (Duman and Monteggia, 2006). Oxytocin has been demonstrated to exert protective effects on neurotrophic factors, though the underlying mechanisms remain incompletely understood and warrant further investigation (Dayi et al., 2019).

Given these considerations, the present study aims to investigate the effects of intranasally administered oxytocin on cognitive performance, behavioral outcomes, and hippocampal and prefrontal levels of BDNF and VEGF in socially isolated aged female rats.