Some decisions and behaviors involving other individuals can be driven by empathy (Bartal et al., 2011; Burkett et al., 2016), while other kinds of prosocial behaviors, such as cooperation, are not necessarily related to empathy (Decety et al., 2016). The role of oxytocin in modulating empathy-driven behaviors—such as parental care and prosocial behaviors—has been largely explored in humans (Hurlemann et al., 2010; Guastella and Hickie, 2016) and rodents (Gur et al., 2014; Nakajima et al., 2014; Burkett et al., 2016). Marlin and colleagues found that, in mice, the oxytocinergic signaling in the left auditory cortex processes the behavioral response to a mouse pup’s distress calls and is also necessary for the maternal retrieval of isolated pups, enhancing the salience of vocal stimuli (Marlin et al., 2015).

Empathy can also motivate prosocial behaviors that are different from parental care. In a modified version of the human dictator game, in which one subject can choose between sharing or keeping the rewards from another participant, the infusion of oxytocin in the basolateral amygdala (BLA) of non-human primates favored the selection of prosocial tendencies (Chang et al., 2015). Oxytocin transmission in the insular cortex also mediates social decision-making in rats, modulating both approach and avoidance behaviors in a model of social affective preference (Rogers-Carter et al., 2018). Microinjections of an OTR antagonist in the insular cortex inhibited affective social behavior, with rats specifically avoiding juvenile stressed rats rather than stressed adults (Rogers-Carter et al., 2018). The oxytocin system is also involved in partner choice within groups of prairie voles. The intracerebroventricular infusion of a selective OTR antagonist prevented partner preference acquisition in mated male prairie voles, demonstrating the key role of oxytocin in pair bonding, which involves social decision-making processes (Johnson et al., 2016).

Several behavioral paradigms have been developed in the last decade aimed at investigating prosocial behaviors in rodents. It was found that rodents tend to approach and help stressed or trapped conspecifics (Bartal et al., 2011), avoid painful stimuli for the benefit of others (Hernandez-Lallement et al., 2020), and share food rewards with them (Scheggia et al., 2022), similarly to primates (Tan et al., 2017; Dal Monte et al., 2020). Yamagishi and colleagues found that the pharmacological block of the OTR in the anterior cingulate cortex (ACC) provoked a delay in learning helping behavior in rats, while the full acquisition of this behavior increased the activation of the immediate early gene c-Fos in ACC OTR-expressing neurons (Yamagishi et al., 2020). Another work from the same group revealed that OTR-knock-out prairie voles demonstrated impaired learning of the door-opening task and less interest in the soaked conspecific, suggesting that oxytocin modulates these helping and empathy-like behaviors in rodents (Kitano et al., 2022).

Social decisions require continuous interpretation of the surrounding context that also includes other social agents and their mental states and actions (Bartz et al., 2011). These decisions are multidimensional in nature, and involve cognitive and emotional facets related to both the self and others. These include emotional discrimination, emotional contagion, previous experiences, and other social factors such as group dynamics, where oxytocin transmission is profoundly implicated.

Identifying and recognizing a conspecific is crucial in making appropriate social decisions. This ability is influenced by intra- and inter-species differences, in which the perception of the conspecific varies widely. For example, while in primates the use of vision and gaze plays a critical role in social perception and cognition, rodents largely rely on olfactive information (Gangopadhyay et al., 2021). Oxytocin is involved from the beginning of the processes of decision-making, during which sensory information is extracted from the social context. In the olfactory system, oxytocin is required for social cue processing (Oettl et al., 2016). Perception of social cues is the basis of understanding others’ mental and emotional states. It has been reported that the PVN neurons projecting to the central amygdala (CeA) in mouse brains are selectively involved in emotional discrimination, likely through the interplay between oxytocin signaling and corticotropin-releasing factor, highly expressed in the CeA and involved in fear encoding (Ferretti et al., 2019). In addition, cortical areas are involved in the discrimination of conspecifics based on emotional states. Indeed, optogenetic inhibition of somatostatin-positive cells in the prelimbic region of the PFC (PL), which are highly enriched in OTR (Nakajima et al., 2014), impairs this ability (Scheggia et al., 2020).

Oxytocinergic signaling is also associated with mouse models of emotional contagion, a cognitive process by which observation of a conspecific in distress induces a similar affective experience in the observer. For example, both intranasal oxytocin administration (Pisansky et al., 2017; Zoratto et al., 2018) and chemogenetic stimulation of OTR-containing neurons (Pisansky et al., 2017) in mice increased the socially transmitted adoption of others’ emotional states, with a subsequent downregulation of OTR in the amygdala when oxytocin was chronically given (Pisansky et al., 2017). State matching with a familiar conspecific under stress can also motivate consolation behavior (Burkett et al., 2016), providing social buffering. This behavior was abolished by infusing an oxytocin receptor antagonist into the ACC. These reports highlight the relevance of oxytocinergic transmission in recognizing, understanding, and eventually sharing others’ emotions, which is often crucial for successfully navigating the social environment.

Social groups involve dominant and subordinate members, forming a hierarchy that can affect multiple behaviors (Qu et al., 2017). Therefore, hierarchies represent an important variable in social interactions and prosocial behaviors (Cronin, 2012). In both mice and rats, social dominance consistently promotes prosocial actions (Gachomba et al., 2022; Scheggia et al., 2022) similarly to non-human primates, showing that prosocial behaviors are more often directed towards downward ranks (Cronin, 2012). In this context, oxytocin reduces the differences in social behavior between dominant and subordinate members, thereby flattening the status hierarchy (Jiang and Platt, 2018). In line with this evidence, the oxytocinergic system underlying the establishment and maintenance of social hierarchies in rats (Timmer et al., 2011) and dominant mice shows increased OTR levels when compared with subordinate individuals (Lee et al., 2019).

The oxytocinergic network is sensitive to early-life stressors that can provoke long-term social impairments. He and colleagues showed that when mandarin voles— socially monogamous rodents with biparental attachment in their pups—were raised under paternal deprivation, they manifested anxiety-like behavior and lower social preference during adulthood (He et al., 2019). Importantly, the authors found that voles deprived of paternal influence had significantly fewer oxytocin neurons in the PVN and a decreased OTR in the medial PFC (mPFC) in both females and males, and optogenetic stimulation of PVN-to-PL projecting neurons restored this impairment (He et al., 2019).

The PVN oxytocin neurons also project to the anterior olfactory bulb, where OTR is largely expressed (Knobloch et al., 2012). Stimulating this pathway increased social recognition memory in female rats, while its inhibition prevented the ability (Oettl et al., 2016). Social memory is another important aspect with an influence on social decision-making processes. The role of the hippocampus in social behaviors has recently gained attention (Okuyama et al., 2016; for review, see Okuyama, 2018). In particular, the identification of the so-called “social place cells” in the dorsal hippocampus of bats (Omer et al., 2018) and rats (Danjo et al., 2018) points to this area as fundamental for processing self- and other-related information in the spatial dimension. The OTR is largely expressed across different subfields of the hippocampus (for review, see Cilz et al., 2019) and has an influence on social behaviors. It has been reported that the OTR conditional silencing selectively in CA2/CA3 or forebrain pyramidal neurons reduced the persistence of long-term social memory without affecting sociability or social novelty. In agreement with these findings, pharmacological stimulation of OTR on hippocampal slices provoked long-term potentiation (Lin et al., 2018). Intriguingly, Raam and colleagues showed that optogenetic inhibition of intrahippocampal connections between OTR-containing cells in dorsal CA2/CA3, projecting to the ventral CA1, impaired social but not non-social discrimination in mice (Raam et al., 2017). In a Magel^2tm1.1Mus-deficient mouse, a model of autism-like disorders, an enhanced GABAergic activity of CA3 glutamatergic cells was found to be associated with an increased expression of OTR and somatostatin interneurons in both the dentate gyrus and CA2/CA3 regions. This effect might be responsible for their deficits in social memory, assessed using the social three-chamber task (Bertoni et al., 2021). Importantly, systemic administration of oxytocin in Magel^2tm1.1Mus-deficient pups restored both hippocampal dysfunction and behavioral deficits during adulthood (Bertoni et al., 2021), highlighting the clinical relevance of oxytocin in the sphere of social cognition and behavior.

This evidence strongly supports the crucial role of oxytocin in modulating neural activity across several brain areas, recruited at different levels of the decision-making process, with significant effects on social and prosocial behaviors.

Fluctuations in endogenous oxytocin levels have been connected to both positive and negative modulations of social and prosocial behaviors (Crockford et al., 2014; Marsh et al., 2021; Tabak et al., 2022). This can be attributed to the influence of the oxytocin system on neural areas or circuitries related to reward (Scheele et al., 2013) and emotional processing, such as fear processing (Meyer-Lindenberg et al., 2011), attentional resources, and salience attribution to social stimuli (Dölen et al., 2013; Wei et al., 2022). Moreover, the anxiolytic effects driven by oxytocin changes can further contribute to the expression of social behaviors mainly due to the influence on the hypothalamic–pituitary–adrenal axis and the amygdala activity (Eckstein et al., 2015; Mitre et al., 2016; Neumann and Slattery, 2016). Furthermore, endogenous oxytocin levels are highly susceptible to sex, age, personality traits and predisposition, previous history, and context (Marsh et al., 2021). Genetics, epigenetics, and neurobiological factors have an impact on endogenous oxytocin, such as OTR variances (Rodrigues et al., 2009; Saphire-Bernstein et al., 2011; Spencer et al., 2022) and fluctuations across the lifespan (Audunsdottir and Quintana, 2022; Zak et al., 2022). These factors could modify the modulatory effects of oxytocin on social behaviors (Van IJzendoorn et al., 2011; Declerck et al., 2020; Marsh et al., 2021). For instance, contextual information associated with danger or social threat can stimulate oxytocin release that can be associated with aggressive-defensive or antisocial behaviors (Hurlemann and Marsh, 2019).

Dysregulation or malfunctioning of the oxytocin system has been reported in neuropsychiatric (Green et al., 2001; Yamasue and Domes, 2017; Goh et al., 2021) and neurodegenerative disorders (Gabery et al., 2015; Unti et al., 2018), mostly in the form of reduced endogenous oxytocin levels. In this case, the downregulation of the oxytocinergic transmission might be associated with anomalies in attention, evaluation, and response to external socio-emotional stimuli (Crockford et al., 2014; Gulliver et al., 2019). This could affect the cognitive and socio-emotional components necessary for expressing effective social decisions and behaviors regarding others (Marsh et al., 2021). Therefore, the assessment of endogenous oxytocin levels becomes crucial for the evaluation of the real effects of oxytocin-based treatments in the clinical setting (Marsh et al., 2021; Tabak et al., 2022).

Targeting oxytocinergic signaling has been considered to be an effective strategy to contrast social deficits in clinical populations. Intranasal application has been perhaps the principal route of oxytocin administration when compared with others, such as oral or intravenous, in the clinical and non-clinical setting (Quintana et al., 2021), due to the direct link with the central nervous system and the neglectable side-effects reported (Born et al., 2002; MacDonald et al., 2011; Bakermans-Kranenburg and van IJzendoorn, 2013). A good body of evidence revealed that the administration of intranasal oxytocin (IN-OXT) has beneficial properties on empathy and prosocial behaviors both in human (MacDonald and MacDonald, 2010; Geng et al., 2018; Leng and Leng, 2021) and nonhuman animals (Neumann et al., 2013; Huang et al., 2014; Chang et al., 2015; Pisansky et al., 2017; Zoratto et al., 2018). Specifically, studies on healthy human participants performing behavioral tasks readapted from the economic field (Sanfey, 2007) revealed that IN-OXT promotes and likely enhances relevant prosocial manifestations such as trust (Kosfeld et al., 2005), generosity (Domes et al., 2007), cooperation (De Dreu, 2012), altruism (Marsh et al., 2015), and social bonding (Lim and Young, 2006). However, subsequent efforts for replicating these initial results have failed, forcing researchers to downsize or review the claims around IN-OXT and its social properties (Nave et al., 2015; Declerck et al., 2020; Macchia et al., 2022).

Clinical studies reported beneficial effects on social dysfunctions following IN-OXT, including social decision-making deficits. Andari and colleagues reported increased trust and social preference within a virtual social interaction game involving 13 adult subjects with autistic spectrum disorder (ASD; Andari et al., 2010). More recently, clinical trials involving ASD participants revealed that long-term oxytocin-based treatments rescued neural activity or led to functional readaptations of areas such as the amygdala and the PFC, which are considered essential for establishing social interactions and making social decisions (Alaerts et al., 2020; Bernaerts et al., 2020). Nonetheless, Sikich et al. recently reported no effects after IN-OXT in measures of social functioning in a large-scale placebo-controlled study involving children and adolescents affected by ASD (Sikich et al., 2021). This was in line with a previous meta-analysis of 12 randomized clinical trials regarding the use of IN-OXT in ASD (Ooi et al., 2017).

In a meta-analysis by Bürkner and colleagues evaluating 12 randomized controlled trials in patients with schizophrenia, small but considerable effects of IN-OXT treatment on high-level social cognition were reported, including metallization and social inference abilities regarding others’ intentions and actions (Bürkner et al., 2017). Further, Wigton and colleagues observed a higher prosocial tendency after a single-dose oxytocin inhalation in 20 adult patients with schizophrenia during a rewarded decision-making task, likely due to better emotional and metallization capacities driving their decisions (Wigton et al., 2022). This improvement was linked to significant changes in the level of neural activity in key regions within the social decision-making system such as the amygdala, the ACC, and the insula (Wigton et al., 2022). The literature reports contrasting results, showing no significant benefits for social functioning in patients with schizophrenia following IN-OXT when compared with other treatments (Williams and Bürkner, 2017).

Administration of IN-OXT has also been applied in patients with neurodegenerative disorders that are characterized by social dysfunction, including social decision-making deficits (Manuel et al., 2020; Mason et al., 2021). Patients with frontotemporal dementia (FTD) who were administered a single dose of IN-OXT improved their abilities to recognize facial expressions (Jesso et al., 2011). Particularly, the authors indicated a reduced emotional response from FTD patients to negative faces. They also found a trend for better recognition of positive faces, which might lead to augmented trust and cooperative behavior within the social context (Jesso et al., 2011). Accordingly, Finger et al. used IN-OXT in a randomized clinical trial including 23 FTD patients and reported, indirectly, increased levels of empathy and social exchange in their relationships with their caregivers (Finger et al., 2015). Further, an ongoing trial is considering the long-term beneficial effects of IN-OXT for FTD patients (Finger et al., 2018). Finally, Labuschagne and colleagues described a significant recovery in Huntington’s disease patients’ ability to discriminate between emotions after oxytocin inhalation, a skill associated with restored neural activity in the areas involving emotion processing (Labuschagne et al., 2018). Despite this evidence, negative results have been reported on the effects of IN-OXT in neurodegenerative disorders. For instance, a recent meta-analysis did not find any improvement in emotion recognition or expression for the FTD population after IN-OXT treatment (Leppanen et al., 2017).