Early-life experiences are known to permanently alter gene expression and may affect multiple domains of behaviors, health, and well-being (Heim et al., 2002; O'Donnell et al., 2014; Tabbaa et al., 2017). In humans, adverse childhood experiences, such as unstable family structure, are associated with the vulnerability to develop psychopathologies related to emotional and social disturbances later in life (Heim and Nemeroff, 2001; Park et al., 2016; Suglia et al., 2020; Tsuda and Ogawa, 2012; Yam et al., 2015). Children who grow up in fatherless households are more vulnerable to further stressors and develop a host of negative outcomes (Culpin et al., 2013; McLanahan et al., 2013; Sidor et al., 2017). In some rodents, paternal care also plays a crucial role in the behavioral and physiological development of offspring (Bredy et al., 2004; Frazier et al., 2006; Jia et al., 2009; Stone and Bales, 2010). For example, paternal care could affect cognitive development and subsequent aggressive behaviors of offspring in California mice (Bredy et al., 2004; Frazier et al., 2006). Paternal deprivation (PD) impaired the ability to form a pair bond of the prairie voles (Microtus ochrogaster) in adulthood (Ahern et al., 2011; Ahern and Young, 2009; Gillera et al., 2022). PD could also contribute to offspring survival and modulate the structural and functional neuroplasticity of the hippocampus in California Mice (Peromyscus californicus) (Glasper et al., 2018; Glasper et al., 2016). In mandarin voles, PD increased anxiety-like behavior and reduced social preference during adulthood (He et al., 2019). It is imperative to reveal the neural mechanisms underlying the association between early PD and abnormalities in adult behaviors and well-being for the prevention and treatment of related psychological diseases. The mandarin voles (Microtus mandarinus), socially monogamous rodents with high levels of biparental care, can be used as an animal model to study the effects of PD on emotional and social behavior, and their underlying neurochemical mechanisms.

Empathy refers to the capacity to understand and respond to the thoughts and emotions of others (Burkett et al., 2016; Meyza et al., 2017; Singer et al., 2004). A growing body of research shows that empathy exists in a variety of species, such as birds (Gallup et al., 2015), rodents (Ben-Ami Bartal et al., 2011; Ben-Ami Bartal et al., 2016; Romero et al., 2013), and non-human primates (Campbell and de Waal, 2011; Pruetz, 2011). Previous studies showed that early adverse experiences may lead to a deficit in empathy (Dadds et al., 2011; Dadds et al., 2018). The impairment of empathetic behaviors may be linked to aggressive behaviors (Winter et al., 2017), callous-unemotional traits (Blair, 2013), alexithymia (Bird et al., 2010), and autism spectrum disorders (Kallergis, 2019; Preston and de Waal, 2002). However, whether and how PD affects empathetic behaviors remains unclear.

According to its function, empathy can be categorized into affective and cognitive empathy (Cuff et al., 2014; Komeda et al., 2019; Milone et al., 2019). Emotional empathy refers to experiencing the feelings of others. Cognitive empathy, a higher layer of the empathetic sphere, refers to understanding their emotions and perspectives (Johander et al., 2022; Walter, 2012). Extensive research has shown that the medial prefrontal cortex (mPFC) is a key mediator of empathy since the dominance of its involvement in the processing of empathy information (Farrow et al., 2001; Seitz et al., 2006). The anterior cingulate cortex (ACC), a part of the mPFC, has been shown to play an important role in complex behaviors such as empathy, impulse control, emotion, and decision-making (Bush et al., 2000; Bzdok et al., 2012), while the impairment of ACC is linked to psychopathology and emotional dysregulation (Stevens et al., 2011). Results from fMRI studies showed that the ACC of the observer was activated in response to the perception of the pain of others (Singer et al., 2004). Similarly, the ACC was activated in prairie voles upon consolation, an empathy-like behavior (Burkett et al., 2016). When the rats that had previously experienced foot shocks watched others receiving foot shocks, the neuronal firing of ACC was enhanced (Atsak et al., 2011). The ACC receives sensory inputs from multiple brain regions, such as the cortex and thalamus, and mediates the empathy of pain or fear in mice by influencing different downstream targets (Smith et al., 2021). However, whether the ACC participates in the influence of PD on empathetic behavior requires further investigation.

Oxytocin (OT) is mostly synthesized in neurons in the paraventricular nucleus (PVN) and the supraoptic nucleus (Quintana et al., 2019). OT plays an important role in social approach, recognition, stress buffering, reward, and learning. OT via binding with the oxytocin receptor (OTR) plays an important role in empathic behaviors (Donaldson and Young, 2008; Li et al., 2023). For instance, studies involving OTR knockout prairie voles have demonstrated that the inhibition of OT function disrupts empathic processes (Kitano et al., 2022). Many studies also sought to confirm whether OT modulates empathetic behaviors. Intranasal administration of OT to human subjects could help men with low empathic ability reach the same level as women with high empathetic ability (Hurlemann et al., 2010). The enhancement of emotion recognition and empathy may be achieved through the modulation of amygdala activity by OT (Hurlemann et al., 2010; Shahrestani et al., 2013). In rodents, exposure to the stressed cage mate increased activity in the ACC of prairie voles (Burkett et al., 2016). Acute intranasal OT administration enhanced cellular activity in the ACC of mice (Pisansky et al., 2017). One recent study has proven that PVN oxytocin neurons projecting to ACC are involved in regulating many types of behaviors (Li et al., 2021). Nevertheless, it remains unclear whether the OTR in the ACC is involved in the effects of PD on empathic behavior.

In the current study, we investigated the involvement of the ACC OTR in the effects of PD on empathetic behaviors. Using male and female mandarin voles, we first compared sociality and empathetic behaviors between control groups and PD groups. We also assessed the mRNA level of OTR in the ACC and the number of OT neurons in the PVN in control and PD groups. Next, given the role of the ACC in empathetic behavior and abnormalities of the OT system induced by PD, we investigated whether overexpression of OTR mRNA expression in the ACC of PD offspring and interference of OTR mRNA expression in non-PD males could affect social and empathetic behaviors respectively. Our study suggests that OTR in the ACC is involved in regulating empathic dissonance induced by PD.