Oxytocin and cardiometabolic interoception: knowing oneself affects ingestive and social behaviors

Abstract

Maintaining homeostasis while navigating one’s environment involves accurately assessing and interacting with external stimuli while remaining consciously in tune with internal signals such as hunger and thirst. Both atypical social interactions and unhealthy eating patterns emerge as a result of dysregulation in factors that mediate the prioritization and attention to salient stimuli. Oxytocin is an evolutionarily conserved peptide that regulates attention to exteroceptive and interoceptive stimuli in a social environment by functioning in the brain as a modulatory neuropeptide to control social behavior, but also in the periphery as a hormone acting at oxytocin receptors (Oxtr) expressed in the heart, gut, and peripheral ganglia. Specialized sensory afferent nerve endings of Oxtr-expressing nodose ganglia cells transmit cardiometabolic signals via the Vagus nerve to integrative regions in the brain that also express Oxtr(s). These brain regions are influenced by vagal sensory pathways and coordinate with external events such as those demanding attention to social stimuli, thus the sensations related to cardiometabolic function and social interactions are influenced by oxytocin signaling. This review investigates the literature supporting the idea that oxytocin mediates the interoception of cardiovascular and gastrointestinal systems, and that the modulation of this awareness likewise influences social cognition. These concepts are then considered in relation to Autism Spectrum Disorder, exploring how atypical social behavior is comorbid with cardiometabolic dysfunction.

1. Introduction

Obesity is a serious global public health challenge. Obesity rates have nearly tripled around the world in the past 40 years (World Health Organization, 2021), and obesity is expected to affect nearly 50% of the US population by 2030 (Ward et al., 2019). The underlying mechanisms responsible for the onset of obesity remain poorly understood. The underlying mechanisms responsible for the onset of obesity remain poorly understood; however, genetic predisposition (Zhang et al., 1994), and consuming more calories than are expended are considered primary driving factors for excess energy storage and weight gain. Obesity is associated with multiple comorbidities including cardiovascular disease (Yusuf et al., 2004), but also leads to social stigma (Fruh et al., 2021), psychosocial impairments (Ambwani et al., 2021), and depression (Perry et al., 2021). This suggests an interplay between metabolism and other physiological and psychological processes. In support of this concept, decisions regarding the amount and type of food to consume are the cumulative result of 1) biological determinants that modulate hunger and satiety via sensory nerve signals from the gastrointestinal tract (Browning & Carson, 2021), 2) social factors that influence income and access to a variety of foods, as well as 3) conscious and subconscious determinants in the brain that are influenced by a food environment which is characterized by an abundance of visual cues that promote consumption of cheap, easily accessible highly-processed foods (Friedman & Halaas, 1998; Kojima et al., 1999; Peyron et al., 1998; Schwartz et al., 2000); All three of these components are disrupted in obesity (de Lartigue, 2016). Thus, obesity is a complex, multifaceted disease that manifests from reduced sensitivity to internal physiological signaling and altered response to external components that influence psychology and social factors. We argue here that perception of others and oneself is an ideal novel framework for understanding the pathogenesis of obesity.

Perception of the external or internal environment involves navigating our physical and social environment to meet our physiological needs. Various physiological and/or homeostatic processes exist, such as stretch, pain, heat, hunger, or thirst that convey sensory information about our internal needs. In particular, the cardiovascular and gastrointestinal interoceptive processes involve mechanosensation and chemosensation transmitted, in part, along the vagus nerve by way of nodose ganglia neurons. The biological mechanisms underlying exteroception including the senses of touch, taste, smell, sight, and sound allow us to make sense of our external world. Simultaneous interoceptive and exteroceptive stimuli, such as the sensations of a rapid heartbeat or churning stomach in a social situation, enable us to prioritize attention and evaluate the necessity of a behavioral response. Thus, central integration of interoceptive and exteroceptive signals is critical.

Oxytocin has captivated the scientific community largely due to the range of physiological, psychological, and societal processes it inextricably links. Oxytocin is known as an important neuropeptide in the development and expression of social behavior. Preclinical and clinical data indicate that oxytocin is a modulator of exteroception, particularly regarding the ability to focus attention towards and developing accurate representations of social stimuli (Ferguson et al., 2000; Kirsch et al., 2005; Meyer-Lindenberg et al., 2011). Intriguingly, atypical social attention is a general characteristic of Autism Spectrum Disorder (ASD) (Amso et al., 2014; Baranek, 1999), which oxytocin is being evaluated to treat (S. Yao et al., 2018). Notably, at the physiological level oxytocin signaling plays a key role in specifically the gastrointestinal interoceptive states of hunger (Sabatier et al., 2013), and cardiovascular function (Gutkowska & Jankowski, 2008; Gutkowska et al., 2000,; Jankowski et al., 1998). The identification of oxytocin receptors (Oxtr(s)) on cells of the nodose ganglia (Welch et al, 2009) that transmit sensory information from the heart, stomach, and intestine indicates that oxytocin likely mediates transmission of visceral information by acting on peripheral sensory neurons. Thus, the oxytocin system integrates physiological responses and behavioral outcomes to ensure adaptation to the internal and external world.

The synthetic form of oxytocin, Pitocin, is approved for peripartum use and multiple clinical trials have been or are currently being conducted to evaluate the safety and efficacy of using oxytocin derivatives in a variety of settings. Recently, the use of Carbetocin, a potent variant of oxytocin, is being evaluated to treat Prader-Willi syndrome (ClinicalTrials.gov, 2021d). Prader-Willi syndrome is a rare disease characterized by very low oxytocin production and extreme, unrelenting hunger causing significant distress and pronounced life-threatening hyperphagia (Holm et al, 1993). This clinical trial and many others utilize intranasal administration to test the effects of increased activation of Oxtr(s) in the brain. These clinical findings provide little insight into the role of endogenous oxytocin or the site of action, but support a role for exogenous oxytocin in enhancing therapeutic engagement (ClinicalTrials.gov, 2021e), susceptibility to stress-induced drug relapse (ClinicalTrials.gov, 2021c), social impairment in ASD (ClinicalTrials.gov, 2021f), social functioning in Prader-Willi Syndrome (ClinicalTrials.gov, 2021b), and reducing obesity (ClinicalTrials.gov, 2021a). Furthermore, numerous pre-clinical experiments support a key role of oxytocin as a mediator of social behavior and suggest that oxytocin can augment the sensitivity to cardiovascular/gastrointestinal systems that culminate in awareness of the internal state.

The consideration of central and peripheral represents a relatively novel holistic approach for treating obesity. Here, we review the literature regarding oxytocin, with a focus on interoceptive cardiometabolic signaling and exteroceptive central processing that influences emotional and cognitive circuits tied to social behavior. Specifically, we present a brief background of some of the fundamental aspects of oxytocin, how it relates to regions of the brain responsible for interoception, and importantly, describe the way oxytocin influences the internal signaling routes from the heart and gut. We then relate this molecular and anatomical information to the effects of oxytocin on social behavior and ASD, which is characterized by deficits in social functioning that are comorbid with traits characteristic of over- or under-sensitive interoceptive modalities, concluding that these may be targets for a more selective oxytocin-based intervention.

2. Oxytocin

Oxytocin is a peptide produced in discrete areas of the brain and periphery that initiates or augments the function of several vital physiological processes both directly by acting at Oxtr(s) expressed on target tissues and indirectly through Oxtr-mediated behavior modification. While primarily produced in cells of the paraventricular and supraoptic nuclei of the hypothalamus along with a separate population of cells producing the structurally similar peptide vasopressin, oxytocin is also produced sparsely in cells of the heart atria (Jankowski et al., 1998) and small intestine (Paiva et al., 2021), as well as the ovaries (Dawood & Khandawood, 1986), vascular endothelium (Jankowski et al., 2000) and throughout the male reproductive tract (Thackare et al., 2006). Hypothalamic oxytocin is transmitted in the brain via passive diffusion (Ludwig, 1998) or axonal release (Knobloch et al, 2012) and reaches peripheral targets by release into the bloodstream via the posterior pituitary. Oxytocin signaling via release from other organs acts in a paracrine or autocrine fashion (Higuchi, 1995; Shojo & Kaneko, 2000;) and often competes with vasopressin for Oxtr and vasopressin receptor binding which has complicated the development of selective Oxtr agonists (Cid-Jofre et al., 2021). The effects of oxytocin are largely regulated by controlling the sensitivity and expression of the Oxtr, a G protein-coupled receptor found in the brain, kidney, heart, thymus, pancreas, adipocytes, uterus, intestines, and peripheral ganglia (Gimpl & Farenholz, 2001). The expression of Oxtr in the brain is sexually dimorphic which facilitates sex-specific social behavior (Smith et al., 2017). Some of the first studies of oxytocin-dependent physiological processes identified the mechanisms of lactation, as well as myometrial contraction of the uterus during labor (Dale, 1906; Ott & Scott, 1910). These studies were expanded upon to highlight a role for oxytocin in bond formation of mother and offspring, which then gave rise to a rich and varied literature devoted to uncovering the role of oxytocin in mediating aspects of the social mind including: recognition of emotional state (Febo & Ferris, 2014; Guastella et al., 2010; Lane et al., 2013; Uzefovsky et al., 2019; Yao et al., 2018), altruism (Marsh et al., 2021; Wong et al., 2021), trust (Botsford et al., 2021; Kurokawa et al., 2021) cooperation (Yang et al., 2021), and social recognition (Tan et al., 2019). As a mediator of social behavior, oxytocin emerged as a key component to the development of a functional social brain (Neumann, 2008) and in the etiology of social dysfunction, particularly in ASD (Muhle et al., 2004). Overall, oxytocin markedly influences perception of the external environment during development, particularly in recognizing and referring to universal social cues necessary to make accurate predictions (Liu et al., 2015; Putnam et al., 2016; Theodoridou et al., 2009).

Stimuli transduced to sensory information is transmitted to increasingly complex, oxytocin-sensitive brain regions to form a representation of the experience in a classic bottom-up processing scheme (see Figure). Subsequently, similar sensory information is compared to the established representation to adjust as necessary (i.e., top-down processing, see Figure). Multiple lines of evidence have established that oxytocin is integral to forming and augmenting representations during both processing schemes (Antonucci et al., 2020; Crucianelli et al., 2019; Xu et al., 2019; Zhuang et al., 2021), and is particularly involved in the exteroception of other individuals. What is far less understood is how bottom-up processing is mediated by oxytocin during interoceptive signaling, a complex process that involves autonomic responses to physiological stimuli, as well as emotions and behavior.

Figure 1. Convergent vagal pathways impacting neural circuits and behavior.

Repeated input from external sensory stimuli update representations created in the brain to manifest the sense of self in relation to others. This manifestation dictates the interactions with individuals during social behavior. At the same time, continuous internal signals from the heart and gut update many of the same neural networks to culminate in awareness of the internal environment. These internal signals drive ingestive behavior to maintain homeostasis but may also alter processing of social cues and associated social interactions. The presence of oxytocin receptors on the nodose ganglia represent a potential site of action for tuning the saliency of cardiometabolic interoception relative to conspecific exteroception. This potential has important implications for restoring balance in conditions of atypical social behavior, dysregulated eating, cardiovascular disease, and their comorbidities.

3. Oxytocin and Interoception

Interoception can be thought of as any self-monitoring process which is often accompanied by an emotion and is typically coupled with a homeostatic process; however, there are interoceptive processes that cannot be consciously identified. Moreover, there are distinctions that allow for the separate investigation of circuits controlling emotion apart from interoception. Several informative reviews cover emotional signal processing (Adolphs & Andler, 2018) or the subject of interoception alone (Carvalho & Damasio, 2021; Chen et al., 2021; Quigley et al., 2021).

Oxytocin receptors are expressed in brain regions that encode interoceptive signals in relation to past experiences. Current understanding of how perception of the internal environment is encoded has progressed well beyond the theory that activated sensory neurons in turn trigger otherwise quiescent neurons in the brain. Instead, interoception is dynamic and continuously updated, hence the development and usage of common phrases such as: “listen to your gut,” “gut feeling,” and “follow your heart.” Modern theories point towards prior knowledge and current state as a framework for how perception of interoceptive signals ultimately brings about a homeostatic change or behavioral shift (Barrett & Simmons, 2015; Berntson & Khalsa, 2021); thus, activated brain regions and neural circuits are dependent on these factors and may vary. For example, a recent MRI study found that increased emotional distress associated with somatic symptoms including epigastric discomfort (resulting in appetite loss), tachycardia/dyspnea, and weight loss were positively correlated with recent adverse life events and decreased local gray matter volume in the ventral medial prefrontal cortex (mPFC), anterior insula and hippocampus (Wei et al., 2020) implicating prior experience as a factor influencing the degree to which conscious perception of the gastrointestinal tract occurs. Oxytocin receptors are densely expressed in these brain regions, suggesting the potential for oxytocin-mediated modulation of perception. Oxytocin receptor activation in the mPFC leads to synaptic plasticity (Ninan, 2011) and altered glutamate transmission (Qi et al., 2012,) in mice, while intranasal oxytocin improves anterior insula responsiveness and social reward (Nawijn et al., 2017) in male and female PTSD patients. Oxytocin receptor activation in the hippocampus promotes neurogenesis (Cai et al., 2022; Che et al., 2021) and attenuates apoptosis (Li et al., 2021). Taken together, these studies suggest that Oxtr(s) alter the activity of neurons within brain regions involved with experience-dependent interoception. Moreover, as past experiences and environment play an important role in the study of addiction, improvements in interoception mediated by oxytocin have been investigated for efficacy in treating drug addiction and alcoholism (Che et al., 2021; Sundar et al., 2021), drug abuse associated with social subordination stress (Ferrer-Perez et al., 2021), and drug abuse associated with early life social adversity (Bardo et al., 2021). Fundamental to these investigations is the idea that oxytocin may normalize the imbalance between attention to internal and external stimuli by restoring appropriate salience. This correction of attention associated with oxytocin has been observed in studies of drug abuse/alcoholism (Betka et al., 2018; Yao et al., 2018) and mental stress (Tracy et al., 2018). Brain regions implicated in attention and interoception overlap and share connectivity with brain regions involved with determining the saliency of a stimulus.

Integration of vagal afferent signals in the brain involves a saliency network and the effectiveness of its connectivity is robustly altered by intranasal oxytocin. The saliency network (reviewed in Uddin, 2015) is comprised of interconnected brain nodes, first described by Greicius et al., that are active at rest and reduce activity during tasks requiring mental effort (Greicius et al., 2003). The network, which primarily includes the anterior cingulate and ventral anterior insular cortices, but also the amygdala, hypothalamus, ventral striatum, thalamus, and hindbrain nuclei, has become the neurobiological basis for prioritizing stimuli and assigning resources. In an fMRI study of 200 healthy subjects receiving a single intranasal dose of oxytocin, males exhibited an increase in dynamic connectivity from the dorsal anterior cingulate cortex to the anterior insula while both males and females showed an increase from anterior insula to posterior insula, as well as increased functional connectivity between the saliency network and other networks implicated in emotion, reward, attention and social cognition (Jiang et al., 2021). Furthermore, oxytocin administration was associated with greater functional connectivity from the insula to both the ventromedial and dorsomedial PFC, as well as from emotional processing regions to the amygdala. This is of particular relevance here because the insula is also integral to an awareness of cardiometabolic sensory afferent processing. A majority of epilepsy patients with a partial or complete resection of the insula reported a persistent reduction in hunger while patients that had resection of the temporal lobe including parts of the amygdala and hippocampus did not (Hebert-Seropian et al., 2021). Additionally, insular resection was associated with significant alterations to other interoceptive measures including perception of cold and bladder fullness. In a heartbeat detection task meant to measure accuracy of specifically heart-related interoception, subjects given oxytocin intranasally had decreased accuracy when identifying their own heartbeat relative to controls, but only when viewing neutral and emotional faces (Yao et al., 2018). These subjects also exhibited increased right anterior insula activation and increased functional connectivity with the left posterior insula. The authors concluded that oxytocin facilitated an enhancement or prioritization of the external social stimuli relative to the focus on interoceptive cardiovascular signals.

Together, these studies demonstrate that past experience and current environment are primary factors influencing perception of the internal milieu, and Oxtr(s) in brain areas mediating cognition, memory, and saliency have the capacity to influence this interoception. The Oxtr-mediated alterations in central processing leads executive brain regions to influence decision making and behavior. Intriguingly, Oxtr-mediated influences on interoception can also begin in the periphery with afferent neurons that transmit sensory information related to the activity of specific organs.

4. Vagal sensory afferents, oxytocin, and the gastrointestinal tract

Ingested food moves from the stomach to the duodenum causing volume changes that increase or decrease tension and stretch of the intestinal wall and also allows for the detection of specific types of nutrients. Forces produced by the passage of chyme are sensed and transmitted via the Vagus nerve by specialized endings in the muscular layers of the gut known as intraganglionic laminar endings (Berthoud et al., 1997) and intramuscular arrays (IMAs) (reviewed in Wang, 2020). The feedback of these signals along with hormones such as leptin and ghrelin, are imperative for behavioral alterations effecting meal size (Williams et al., 2016). Recently, Tan et al. found a relationship between stomach IMAs and motor responses in the small intestine of rats, discovering that stimulating areas of the stomach known to have dense IMAs produced the most robust responses in the duodenum (Tan et al., 2021). A separate classification of endings that project past the muscular layers into the mucosa encode forces created by chyme passing through the lumen and also function as chemoreceptors via connectivity with gut epithelial cells (Page et al., 2002; Paintal, 1973; Powley et al., 2011). Serlin and Fox classified three subtypes of vagal mucosal endings in the small intestine of mice (Serlin & Fox, 2020). The sensory information relayed by mucosal afferents provides feedback affecting glucose metabolism and food intake (Morais et al., 2019). Bai et al. demonstrated that Oxtr(s) are expressed on vagal sensory neurons that form IGLEs and not on those that form mucosal endings (Bai et al., 2019). In this study, chemogenetic stimulation of Oxtr-containing sensory afferents resulted in significant reductions in food and water intake, suggesting that Oxtr-expressing cells with IGLEs indicate the sensation of fullness related to meal termination. This sensation and the accompanying ability to regulate food consumption is imperative to maintaining normal energy balance by turning attention inwardly.

The anatomical hierarchy involved with the formation of gastrointestinal interoception has multiple sites of action for oxytocin from the instigating stimulus in the gut along the Vagus to the brain. An appreciation for the diversity represented by these areas of influence by oxytocin is important for recognizing the physical sites of pathological and therapeutic potential. Oxytocin receptors are present throughout the gastrointestinal tract of humans, mice, and rats specifically on villus-crypt enterocytes and are mostly implicated in early life development (Klein et al., 2014; Gross Margolis et al., 2017; Welch et al., 2009). Moreover, oxytocin is produced and released from enteric cells (Paiva et al., 2021). While the function of oxytocin release and receptor activation specifically in the enteric nervous system is still unclear in adults, it is apparent that enteric actions of oxytocin cause changes that influence the stretch and tension, but not chemical signals that are sensed by vagal afferents which also express Oxtr(s). A site of action for peripheral oxytocin modulation of gastrointestinal vagal sensory afferents includes the peripheral ganglia themselves: The soma of vagal sensory nerves reside predominantly in the nodose ganglia which also express Oxtr mRNA and protein (Dantzler & Kline, 2020); although, Oxtr expression on other parts of these neurons has not been ruled out. The activity of individual nodose ganglion cells influences the firing frequency of neighboring cells (Cawthon et al., 2020), thus the modulatory action of oxytocin on Oxtr-expressing nodose cells may affect the activity of the nodose proper, which greatly increases the permutations of possible functional outcomes mediated by gut vagal sensory afferents. Further increasing this complexity, the central pathways affected by signaling from the right nodose differ from those of the left (Han et al., 2018) and it is possible that oxytocin has lateralized actions on gut vagal sensory afferents. In the rat, the right nodose preferentially receives sensory afferents from the distal duodenum and jejunum while the left nodose receives the majority of afferents from the proximal duodenum (Berthoud et al., 1997). The right, but not left, nodose afferents share connectivity with dopamine cells in the substantia nigra and central reward pathways which, when stimulated at the level of the Vagus, sustain conditioned flavor and place preference as well as self-stimulatory behavior while stimulation of either side produces satiety (Han et al., 2018). Together, the data clearly show that considerations such as oxytocin receptor location, intraganglionic dynamics, and lateralization present mechanisms by which intervention can be targeted to specific types of dysfunction based on anatomy.

The development of obesity by overeating is at least partially related to dysregulation of signals from sensory afferent endings in the gut. Electrophysiological recordings of mechanoreceptive sensory nerves in the intestine of rats fasted for 7 consecutive days, and the stomach of chronically-stressed rats show enhanced sensitivity (Bao et al., 2020; Browning, 2019) while high-fat diet compromises the sensitivity of gastric vagal afferent signaling (Loper et al., 2021; Troy et al., 2016) and contributes to clinically-relevant decreases in sensory nerve amplitudes (Buschbacher, 1998). Furthermore, high-fat diet disrupts circadian variation in gastric vagal afferent signaling related to stomach content (Kentish et al., 2016). However, deafferentation increases meal frequency on a normal diet and intact vagal signaling is necessary for terminating high-fat meals (McDougle et al., 2021) demonstrating that selective connections in the vagal gut-brain pathway are necessary for remediating unhealthy eating habits. In a study using obese, diabetic, db/db mice, peripheral oxytocin both activated vagal neurons and suppressed food intake while decreasing body weight (Iwasaki et al., 2015). Vagal stimulation is an FDA approved therapy for both obesity and refractory affective disorders with social components (Marjenin et al., 2020); however, it is possible that a more precise technique with the ability to focus modulation to a subset of vagal afferents may yield superior results.

5. Vagal sensory afferents, oxytocin, and cardiovascular function

Conscious perception of cardiovascular function, particularly changes in the speed and force of one’s heartbeat, may dramatically alter emotion and behavior. Many aspects of the anatomical basis for regulating heartbeat and blood pressure are sensitive to oxytocin and travel in parallel with vagal gastrointestinal sensory afferents to the brain. Rapid continuous feedback from sensory afferents in the heart, carotid sinus (Blombery & Korner, 1979), and aortic arch (Min et al., 2019) to the brain controls organ perfusion pressure, urine output, and vascular resistance (Guo et al., 1982; Sun & Guyenet, 1987), all of which maintain cardiovascular homeostasis and can also influence affective state. This feedback or “baroreflex” is comprised of arterial high-pressure and cardiopulmonary low-pressure baroreceptors that function as stretch-sensitive afferent endings (Brown, 1980). These baroreceptors transduce stretch exerted on vasculature into action potentials that are carried by vagal sensory afferents to hindbrain nuclei that initiate autonomic, neuroendocrine and behavioral responses that maintain cardiovascular homeostasis (Berthoud & Neuhuber, 2000). While most baroreflex activity occurs subconsciously, certain external or internal stimuli elevate the subconscious activity to consciousness through sensory afferent signals terminating in the hindbrain (Schulz, 2016).

Sensory afferent fibers sensitive to oxytocin and originating in pressure-sensing areas of the heart and vasculature converge on the nucleus of the solitary tract (NTS). As a locus of sensory afferent processing in the hindbrain, the NTS: 1) receives the vast majority of cardiovascular vagal sensory afferents (Benarroch, 2008), 2) receives oxytocinergic afferents from the hypothalamus (Buijs, 1978), and 3) innervates multiple autonomic efferent output nuclei, such as the ventrally-adjacent dorsal motor nucleus of the vagus (DMV) (Wehrwein & Joyner, 2013), making the NTS complex a site of baroreflex modulation by oxytocin. Studies in oxytocin-deficient mice confirm this modulatory role of oxytocin on the baroreflex as these mice exhibited hypotension and alterations in baroreflex gain and operating pressure range (Charpak et al.,1984). Higa et al reported that oxytocin directly injected into the NTS/DMV of rats potentiated a decrease in heart rate during baroreceptor activation and an Oxtr antagonist reduced the operating range of the baroreflex (gain) (Higa et al., 2002). In another study, electrophysiological recordings of NTS neurons with profiles identifying them as receiving vagal sensory input revealed that oxytocin increases glutamate release from visceral afferents and enhances excitability of neurons within the NTS (Peters et al., 2008). The implication is that oxytocin enhances vagal afferent signaling at the level of the NTS. In addition to vagal afferent modulation, oxytocin also modulates vagal efferent signaling by increasing firing of neurons in the DMV and augmenting parasympathetic outflow (Dreifuss et al., 1988). In further support of this, a recent study revealed that peripherally released oxytocin influences restraint stress-induced baroreflex activation (Belem-Filho et al., 2021). Peripheral Oxtr activation reduced the increase in heart rate caused by restraint, and this effect was blocked by Oxtr antagonism, hypophysectomy, sinoaortic denervation, or parasympathetic blockade (Belem-Filho et al., 2021). This suggests that peripheral oxytocin has a cardioprotective effect by reducing the magnitude of autonomic compensation to an acute stressor by increasing parasympathetic output, and that this effect is dependent on intact vagal signaling, although there may also be contributions from cardiac Oxtr activation. The role for hypothalamic oxytocin in promoting attenuation of autonomic stress responsiveness is in line with several lines of research indicating oxytocin dampens the neurohumoral and behavioral response to stressors (Frazier et al., 2013; Krause, 2014; Krause et al., 2011; Smith et al., 2015; Smith et al., 2014). However, chronic peripheral administration of oxytocin results in a sustained attenuation of blood pressure under normal (Petersson et al., 1996) and hypertensive conditions (Petersson et al., 1997), and protects against obesity-induced cardiomyopathy (Plante et al., 2015). This attenuation of blood pressure most likely occurs through central mechanisms involving vagal signaling. In support of this, a recent study revealed stimulation of PVN oxytocinergic neurons results in decreased blood pressure and heart rate and this response is mediated by cardiac vagal neurons (Dyavanapalli et al., 2020). Collectively, these studies reveal oxytocin modulates cardiovascular activity by acting on the afferent and efferent limbs of the baroreflex arc.

In addition to maintaining cardiovascular function through regulation of blood pressure and heart rate, the baroreflex system also preserves cardiovascular function by way of altering ingestive behavior to maintain blood volume. Along these lines, a volume deficit (or excess) is transmitted to the central nervous system by way of the above-described vagal baroreceptor afferents, as well as stretch receptors within the heart itself (Toth et al., 1987). These signals then confer the need to rectify volume loss or excess to restore homeostasis in the cardiovascular system. Of particular relevance here, oxytocin is one of several interdependent hormones that regulate ingestive behavior to maintain blood volume (Stricker & Verbalis, 1986; Verbalis et al., 1993), and it accomplishes this largely by influencing sodium intake.

While the levels of both water and sodium are important dictators of extracellular blood volume, the primary determinant for preserving adequate volume to maintain perfusion pressure is the level of sodium (Verbalis, 2003). Thus, while intracellular dehydration can be corrected by water retention and stimulating thirst, hypovolemia caused by water and sodium deficiency is corrected by distinct mechanisms (Geerling & Loewy, 2008). The hypovolemia that follows sodium depletion is followed by increased activation of the renin-angiotensin-aldosterone system (Stricker et al., 1979) which activates both central and peripheral pathways to elicit salt appetite and renal sodium reabsorption (Krause et al., 2007). Oxytocin, on the other hand, reduces salt intake and activation of brain Oxtrs inhibits salt appetite (Ryan et al., 2017; Verbalis et al., 1993; Stricker & Verbalis, 1996). Mice lacking oxytocin will consume typically aversive concentrations of sodium-chloride with no effect on water intake (Puryear et al., 2001), highlighting the role of oxytocin specific to sodium intake. Along these same lines, during states of volume expansion, oxytocin also stimulates the release of atrial natriuretic peptide (Haanwinckel et al., 1995; Gutkowska et al., 1997) which acts through several mechanisms, including altering ingestive behavior and modulation of vagal signaling (Clemo et al., 1996), to restore hydromineral balance and reduce blood volume.

Baroreceptor input to the hypothalamus is crucial in mediating oxytocin release related to changes in volume status. Following baroreceptor denervation, animals decrease ad libitum sodium intake (Rocha et al., 1997) and do not exhibit sodium appetite when faced with a volume or sodium deficit (Thunhorst et al., 1994), likely because of the lack of feedback pertaining to blood pressure and volume status. Thus, it is plausible that oxytocin also enhances vagal afferent transmission of baroreceptor signals, which affects salt intake and hydromineral balance. The overall implication for cardiovascular homeostasis is that oxytocin acts through several mechanisms to stabilize blood volume and maintain cardiovascular function; including enhancement of interoceptive signals that arise from the cardiovascular system and potential alteration of ingestive behavior.

6. Interoception, emotional and cognitive processes of social behavior

Oxytocin signaling in the brain can have a profound influence on emotional and cognitive processes dictating social behavior. The pathways described, thus far, have focused on the molecular mechanisms and neuronal circuits producing visceral sensations. However, the interoception of cardiometabolic signals can be part of a feedback loop in the generation of emotions (Keay & Bandler, 2001; Wei et al., 2020). In this regard, brain Oxtrs mediate accurate emotion identification in others (Domes et al., 2007; Guastella et al., 2010), suggesting oxytocin-mediated improvements in relating the internal state of others to one’s own internal environment. Furthermore, alexithymia or an inability to identify one’s own emotions that often co-occurs with ASD, is improved with intranasal oxytocin administration (Lane et al., 2013; Luminet et al., 2011). Clearly, as oxytocin directly influences the vagal sensory afferents producing sensations of the internal state, effects the emotional state, and impacts the ability to identify the emotions of others, interoception mediated by oxytocin has the potential to greatly impact social interactions through central and peripheral mechanisms.

Social behavior arguably evolved from oxytocin-mediated internal signals to states that are perceivable by conspecifics to guide the interactions most important to survival (Donaldson & Young, 2008; Goodson & Bass, 2001; Lee et al., 2009; Macdonald & Macdonald, 2010). Location and ingestion of life-sustaining nutrients is a prominent social activity (Dunbar, 2017) that is cross-cultural (Rozin, 2005) and instinctive across a wide range of species. In mammals, both the first social bond and the first ingestion of food often occur between mother and offspring, and maternal nurturing behavior is dependent on oxytocin signaling in the brain during and following parturition (Marlin et al., 2015; Numan & Young, 2016). Similarly, the attachment of infant to mother is primed and strengthened through oxytocin released upon physical contact (Scatliffe et al., 2019). These early bonds facilitate survival through adolescence and establish the bond-forming neurocircuitry mediating social behavior with other individuals later in life (Numan & Young, 2016) including those with siblings (Greenberg et al., 2012; Olazabal, 2014), platonic friendships (Ziegler & Crockford, 2017), mating partners (Young & Wang, 2004), and dominant/subordinate relationships (Basil et al., 2018;Grieb et al., 2021; Rijnders et al., 2021; Teed et al., 2019). Essentially, the gearing of the individual mind towards (or away) from another by oxytocin signaling is an evolutionary trait that promotes survival through mechanisms that associate a conspecific with a perceived benefit or reward. In the brain, along the nigro-striatal reward pathway, oxytocin is integrated with dopamine to neurobiologically produce strong bonds (Feldman, 2017; Olszewski et al., 2016; Peris et al., 2017; Sotoyama et al., 2021; Ulmer-Yaniv et al., 2016). Bond formation is strengthened into a relationship by other forms of oxytocin-dependent processes in the brain (Ferguson et al., 2001, 2001; Kirsch et al., 2005; Tan et al., 2019) and social memory (Dantzer et al., 1987; Ferguson et al., 2000; Hollander et al., 2007; Hurlemann et al., 2010). Rogers-Carter et al. investigated the role of Oxtrs of the insular cortex in male rats, finding that Oxtr antagonism disrupted social behavior as the preference for interacting with a stressed juvenile and avoidance of a stressed adult was attenuated (Rogers-Carter et al., 2018). While the avoidance of a stressed male was likely due to innate threat avoidance, the motivation for interacting with a stressed juvenile was less clear, but likely related to prosocial empathetic behavior (Rogers-Carter et al., 2018). Thus, oxytocin is central to determining the perception of another as important to one’s own survival beginning at birth and extending throughout adulthood.

The strong bonds facilitated by oxytocin at birth are soon followed by oxytocin-induced lactation and suckling, illustrating a basis for social development in concert with the development of feeding and metabolism. Just as the development of social behavior becomes more nuanced and species-specific as aging progresses so do oxytocin-related ingestive behaviors and metabolic processes. The relationship between oxytocin-facilitated behaviors and metabolism are quite clear in some cases as mate selection, copulation, parturition, and raising young all increase energy expenditure, creating a need to coordinate social behavior with metabolic demand and calorie replacement. Not all social behaviors are as obviously intertwined with feeding and metabolism, but, in a general sense, the more responsive an individual is to social cues (i.e., exteroception of social stimuli), the more active one becomes and it would therefore be advantageous to link interoceptive cardiometabolic signals to the engagement of social behavior to adjust calorie intake accordingly. In this regard, peripherally-injected oxytocin both reduces food intake and activates hypothalamic oxytocin-producing neurons, but the anorectic effect is lost with vagotomy or central Oxtr antagonism suggesting a behaviorally-relevant synchronization between peripheral and central oxytocin systems (Iwasaki et al., 2019). Moreover, an fMRI study showed that intranasal oxytocin reduced the activation of dopamine reward pathways by high-calorie food while increasing activation of brain areas mediating cognitive control and conflict resolution (Plessow et al., 2018). The restoration of a healthy balance between cognitive control and feeding behavior via oxytocin administration is an area of active clinical research. Anorexia nervosa is an eating disorder characterized by impaired post-prandial oxytocinergic signaling and lowered food motivation that correlates with the severity of anxiety and depression (Lawson et al., 2013). Blood oxytocin levels in anorexic women are basally lower than normal, but higher than controls following stimulation with food-related images, and this elevation was associated with disordered eating psychopathology and fMRI activation in interoceptive and disordered eating areas of the brain such as the amygdala, hippocampus, and insula (Lawson et al., 2012). This suggests that the sensitivity of exteroceptive and interoceptive mechanisms to oxytocin promotes coordination of ingestive, cognitive and social behaviors, but also represents areas where dysregulation results in social functioning deficits accompanied by a loss of homeostasis that is particularly evident in maintaining normal energy balance.

7. Oxytocin, interoception, and Austism Spectrum Disorders (ASDs)

Although ASDs are most commonly thought of in terms of social and communicative deficits and atypical sensory processing of external stimuli, there is also evidence that interoceptive dysregulation is another key component (Neurodevelopmental Disorders). Atypical bodily awareness is often reported in ASDs, and this inability to integrate external and internal cues is thought to contribute to comorbidity with gastrointestinal and cardiometabolic disease (Bishop-Fitzpatrick & Rubenstein, 2019; Tyler et al., 2011). Given the critical role that oxytocin plays in sensory processing and cardiovascular and metabolic health, there is mounting evidence that this neuropeptide may serve as an attractive target for the development of therapeutics not only for behavioral aspects of ASD, but for gastrointestinal dysfunction and cardiometabolic pathology.

Oxytocin dysregulation has long been implicated in the social impairments associated with ASD. Oxytocin levels in serum, plasma and saliva are lower in autistic children, with lower levels correlating to more severe symptomology (Taurines et al., 2014). ASDs are highly heritable, suggesting a strong genetic component, and polymorphisms associated with oxytocin signaling have indeed been identified. Single nucleotide polymorphisms (SNPs) in the oxytocin gene are associated with stereotypic behaviors (Yrigollen et al., 2008), while SNPs in several loci of the Oxtr gene are associated with social impairments (LoParo & Waldman, 2015). Oxtr variants have been linked to atypical social processing, reflected by altered activity in the supramarginal gyrus, a known empathy center (Uzefovsky et al., 2019). Furthermore, methylation of the Oxtr gene at exon 1 is associated with impairments in relating interoception to external processing, such as Theory of Mind and self-awareness measures in individuals with ASD (Andari & Rilling, 2021). These clinical studies support the idea of complex oxytocin dysregulation in ASD and the negative impact of this dysregulation on social processing. Along these same lines, while laboratory animals that have genetic modifications that lead to dysregulated oxytocin signaling do not reliably model all social aspects of ASD, there are several lines of evidence demonstrating its importance in mediating social behavior (Crawley et al., 2007).

8. Evidence of oxytocin’s role in cardiometabolic disease associated with ASD

Autistic individuals are at higher risk for gastrointestinal disease and obesity (DaWalt et al., 2021; Penzol et al., 2019; Tyler et al., 2011), and altered sensory processing and sensitivity may contribute to some of these effects. Heightened food selectivity (Demir & Özcan, 2021) and increased sensitivity to olfactory (Luisier et al., 2015), gustatory, oral, and tactile (Avery et al., 2018; Kral et al., 2015) input is commonly observed in individuals with ASD. These alterations in perception may contribute to the development of interoceptive pathology; issues processing external cues surrounding feeding may contribute to alterations in feeding behavior, with food choice reflecting preference for high fat, high energy foods (Plaza-Diaz et al., 2021). The relationship of these externally driven behaviors to the physiology of the individual is undoubtedly crucial in the pathology of ASD. Individuals with ASD often experience symptoms such as constipation, diarrhea (Shindler et al., 2020), gastric reflux (Kamionkowski et al., 2021), and other functional disorders of the small intestine and bowel, and also frequently report chronic abdominal pain (Wasilewska & Klukowski, 2015). Given the critical role of vagal afferents in transmitting sensory information to the brain, dysregulation of this enteric oxytocin circuitry may contribute to altered gastrointestinal function and visceral sensitivity observed in ASD. Alterations in gut microbiota are also observed in ASD, although whether these alterations are a cause or consequence of ASD is not entirely clear. Interestingly, a recent study by Huang et al. (2021) revealed that in comparison with neurotypical children, autistic children exhibit gut dysbiosis and lower circulating oxytocin, and lower levels of oxytocin correlate to the severity of gastrointestinal symptoms (Huang et al., 2021).

Animal studies similarly support the link between disordered oxytocin signaling and digestive disorders and metabolic dysfunction associated with ASD, while also demonstrating a potential interaction with diet and gut microbiome. Genetic deletion of oxytocin or oxytocin receptors in mice leads to numerous metabolic abnormalities, including obesity, hyperleptinemia, impaired glucose tolerance and insulin resistance (Camerino, 2009; Kasahara et al., 2007; Sun et al., 2019; Takayanagi et al., 2019). Peripheral oxytocin administration has also been demonstrated to ameliorate obesity and improve glucose metabolism in rats and mice with diet-induced obesity (Morton et al., 2012; Maejima et al., 2011). Buffington et al. (2016) found that maternal exposure to HFD impairs social preference of mouse offspring, which was linked to concomitant reductions in both Lactobacillus reuteri (L. reuteri) and hypothalamic oxytocin expression, as well as impaired dopaminergic signaling within the ventral tegmental area (VTA) (Buffington et al., 2016). Interestingly, providing L. reuteri in the drinking water of offspring at weaning ameliorated these effects of maternal HFD (Buffington et al., 2016). Furthermore, they demonstrated that intranasal oxytocin administration similarly rescued the social deficits caused by maternal high fat diet (Buffington et al., 2016). The effects of L. reuteri are likely mediated by the vagus as subdiaphragmatic vagotomy abrogates its oxytocin-enhancing effects (Sgritta et al., 2019; Poutahadis et al., 2013).

In addition to gut and metabolic irregularities, there is a high incidence of comorbid ASD and cardiovascular disease (Bernardi et al., 2020; Bishop-Fitzpatrick & Rubenstein, 2019; Sun et al., 2021). Individuals with ASD tend to have lower heart rate variability at resting state (Thapa et al., 2019), suggesting that autonomic dysfunction in ASD may also contribute to CVD. Cardiovascular dysfunction and ASD are inextricably linked; congenital heart defects are associated with an increased risk of ASD diagnosis (Sigmon et al., 2019), and markers of irregular osmoregulation have also been noted in parents of children with ASD (Yao et al., 2021). Disordered physiology may further impact external processing relating to cardiovascular function, as patients with ASD demonstrate impaired autonomic adaptation to novel vs familiar social interaction (Neuhaus et al., 2016). The most convincing evidence, however, for cardiovascular dysfunction and impaired interoception in ASD is highlighted by a clinical study that revealed that ASD is associated with lowered baroreflex sensitivity and vagal tone, as well as increased mean arterial pressure, heart rate, and diastolic blood pressure (Ming et al., 2005). These results demonstrate the significance of impaired interoception and its impact on processing of the outside world in ASD pathology. Given its critical role as a mediator of autonomic function and interoception, the dysregulation of oxytocin signaling associated with ASD is likely implicated in these cardiovascular findings. Indeed, genetic deletion of Oxtr in mice also leads to alterations in sympathetic and vagal tone (Michelini et al., 2003). In humans, Oxtr gene variants associated with ASD risk are also implicated in impaired autonomic function (Campbell et al., 2011) that may contribute to cardiovascular disease.

The overall implication is that in addition to atypical social behavior, altered visceral perception is a key component of ASDs, which gives rise to comorbid cardiometabolic disease. Furthermore, oxytocinergic signaling, which is altered in ASDs has been demonstrated to have profound effects on cardiovascular and metabolic health. Given the role of the vagus in bidirectional communication between brain and the periphery, oxytocin receptors expressed on vagal afferents may be unique targets for therapeutics for not only atypical social behaviors associated with ASDs but with cardiovascular and metabolic disorders with which they are often associated.

9. Summary

A great interest in the many biological processes mediated by oxytocin signaling in the brain and periphery have produced a varied and rich literature. Here, we have focused on research relating oxytocin-sensitive circuits, physiology, and behavior on the central idea of perception (see Figure). Oxytocin signaling normally serves to alter the perception of others, sometimes elevating them to a preferred status while also providing for the physiological and cognitive processes necessary to initiate and maintain a relationship. Furthermore, the effects of oxytocin can alter the perception of oneself by influencing the coherence and relative importance of internal drives and desires such as those generating hunger or salt appetite. Dysregulation of oxytocin signaling can result in a complex mismatch between what is perceived as important and which stimuli actually represent beneficial opportunities for social interaction and/or consuming food. Vagal sensory afferents of the nodose ganglia transmit continuous cardiometabolic status updates to the brain that vary in intensity from subconscious to overwhelming sensations impossible to ignore. Oxytocin receptors on these cells represent a potential mechanism by which this intensity can be intentionally tuned to adjust the magnitude of interoception. While initially specific, this strategy of intervention then integrates with complex upstream networks that coordinate cardiometabolic interoception with other interoceptive signals and the external environment. Externally, these networks are fed continuous stimuli that often includes conspecifics, and the purposeful tuning of Oxtr-expressing sensory afferents necessarily impacts attention to and interactions with other individuals. Moreover, the central processing networks involved with social interactions are themselves substantially regulated by oxytocin as are the social memory and recognition facilitating the repeated interactions with certain individuals that are necessary to establish a relationship. The end-goal intervention to improve treatments for cardiometabolic disease, as well as disorders like ASD, could benefit from the more precise targeting of Oxtr suggested here, but also fully appreciate and consider the more global ramifications of altering oxytocin signaling in the brain and periphery.