Bridging the gap between rodents and humans: The role of non‐human primates in oxytocin research

“Marmosets will typically form and maintain monogamous socio-sexualrelationships(Evans,1983;French,Cavanaugh,Mustoe,Carp,& Womack, 2018), however exhibit flexibility in their willingness to interact with opposite-sex strangers in the absence of their pair-mate much like humans (Buss & Schmitt, 1993).”

“…of subjects to discriminate facial expressions in others (Domes, Heinrichs, Michel, Berger, & Herpertz, 2007; Lischke et al., 2012), promoted trust (Kosfeld, Heinrichs, Zak, Fischbacher, & Fehr, 2005), and improved socially reinforced learning (Hurlemann et al., 2010), although the robustness of…”

“Particularly interesting are the NBM and PPT, which serveasmajorsourcesofcholinergicinputtowiderangeofstructurein the brain including the amygdala (Kitt, Mitchell, DeLong, Wainer, & Price, 1987; Mesulam, Mufson, Levey, & Wainer, 1983).”

“Pair-bonding in these monogamous voles is critically dependent on the action of OT in specific brain circuits, including the nucleus accumbens and prefrontal cortex (Donaldson & Young,2008;Johnson&Young,2015,2017;Johnsonetal.,2016;Young & Wang, 2004).”

“The social functions of OT are not restricted to reproductive behaviors such as pair bonding and parental care.”

“…of others (Auyeung et al., 2015; Guastella, Mitchell, & Dadds, 2008), enhanced the ability of subjects to discriminate facial expressions in others (Domes, Heinrichs, Michel, Berger, & Herpertz, 2007; Lischke et al., 2012), promoted trust (Kosfeld, Heinrichs, Zak, Fischbacher, & Fehr, 2005), and…”

“…other words, localization of OXTR mRNA with in situ hybridization identifies the location of the cell bodies synthesizing OXTR, but the OXTR protein could be on axon terminals of those cells in distant brain regions as has been previously shown in mice (Dölen, Darvishzadeh, Huang, & Malenka, 2013).”

“Indeed, when these projections have been optogenetically stimulated, rats showed decreased freezing responses in a fear-conditioning paradigm (Knobloch et al., 2012).”

“This pattern of inputs may account for the value-related response properties of neuron in these nuclei (Paton, Belova, Morrison, & Salzman, 2006).”

“Furthermore, optogenetically stimulating fibers projecting from the amygdala to the NAc increases behavioral responding to reward (Stuber et al., 2011).”

“For example,virgin female rats normallyignoreorattackpups,yetwhentheyreceiveanintra-ventricular infusionofOTintothebraintheydisplaymaternalbehaviors(Pedersen& Prange, 1979).”

“Both functional magnetic resonance imaging (fMRI) in healthy humans and behavioral studies of patients with selective calcifications of the amygdala (Urbach-Wiethe disease) have implicated the amygdala as an anatomical substrate of OTmediated behavioral changes (Domes, Steiner, Porges, & Heinrichs, 2013; Gamer, 2010;…”

“Thus, Ach effectively increases the signal/noise ratio in the basolateral amygdala (Hasselmo & Sarter, 2011), an effect that could be enhanced by OT.”

“This mapping enabled subsequent rodent studies to perform site-specific pharmacological manipulations in regions where OXTRs were expressed to delineate circuits where OT affects behavior (Bosch et al., 2016; Burkett et al., 2016).”

“Importantly cholinergicmechanismsareinvolvedinvisualattentionandvigilancein general (Bentley, Vuilleumier, Thiel, Driver, & Dolan, 2003; Gill, Sarter, & Givens, 2000; Robbins, 1997; Sarter & Bruno, 1997).”

“For example, both species prefer looking more at the eyes than at any other facial feature (Gothard, Brooks, & Peterson, 2009; Gothard, Erickson, & Amaral, 2004; Keating & Keating, 1982; Mackworth & Morandi, 1967; Mosher, Zimmerman, & Gothard, 2011; Walker-Smith, Gale, & Findlay, 1977).”

“In rodents, OT exerts anxiolytic effects through activation of OXTR-expressing serotonergic neurons in the raphe nuclei (Yoshida et al., 2009).”

“Furthermore, inmice, the optogenetically induced release of OT in the ventral tegmental area not only increased pro-social behaviors, but also increased excitatory drive to dopamine neurons as part of reward specific responses (Hung et al., 2017).”

“Taken together with similar results from studies performed in humans (Gossen et al., 2012; Striepens et al., 2013), these results clearly suggest that OT enters the CSF of primates and elevates OT levels in the brain when peripherally administered at appropriate doses.”

“…with specific social-behavioral functions emerged from pharmacological or genetic manipulations of central OT levels in rodents, beginning with studies investigating its role in regulating the onset of maternal behaviors in rats and mother-infant bonding insheep (Rilling & Young, 2014).”

“Particularly interesting are the NBM and PPT, which serveasmajorsourcesofcholinergicinputtowiderangeofstructurein the brain including the amygdala (Kitt, Mitchell, DeLong, Wainer, & Price, 1987; Mesulam, Mufson, Levey, & Wainer, 1983).”

“Early attempts to localize OXTRs in NHPs were inconclusive (Toloczko, Young, & Insel, 1997) due to the cross-reactivity of the OT radioligand used for OXTR autoradiography and structurally similar arginine vasopressin receptor (AVPR1A) (Manning et al., 2012).”

“The NBM sends dense cholinergic projections to the basal and accessory basal nucleus of the amygdala in primates (Jones, Burton, Saper, & Swanson, 1976; Mesulam et al., 1983) and these projections may be ideally positioned to influence the process of stimulus evaluation that takes place in the…”

“…primate species, including Titi monkeys ( Callicebus cupreus ) (Freeman, Walum, et al., 2014), marmosets ( Callithrix jacchus ) (Schorscher-Petcu, Dupré, & Tribollet, 2009), and humans (Loup, Tribollet, Dubois-Dauphin, & Dreifuss, 1991; Loup, Tribollet, Dubois-Dauphin, Pizzolato, & Dreifuss, 1989).”

“This, and similar experiments in rodents examining olfactory processing (Oettl et al., 2016)have ledtothe hypothesis that OT tunes inhibitory circuits to increase the salience (signal/noise ratio) of important social stimuli (Marlin & Froemke, 2017; Mitre, Minder, Morina, Chao, & Froemke, 2017).”

“…the primate Amy does not contain detectable OXTRs it receives strong cholinergic innervation from the NBM. Note that OT could be acting on any of the terminal fields projecting from the NBM or PPN, despite these receptors not being detectable by autoradiography Young, 2011; Numan & Young, 2016).”

“…al., 2012), promoted trust (Kosfeld, Heinrichs, Zak, Fischbacher, & Fehr, 2005), and improved socially reinforced learning (Hurlemann et al., 2010), although the robustness of these pharmacological studies in healthy subjects has recently been called into question (Walum, Waldman, & Young, 2015).”

“…as well as many others, have fueled enthusiasm for targeting the OT system to improve various aspects of social cognition in psychiatric disorders such as autism (Shamay-Tsoory & Young, 2016; Tully et al., 2018; Watanabe et al., 2015; Yatawara,Einfeld,Hickie,Davenport,&Guastella,2016;Young,2015).”

“…In primates OT may modulate amygdala activity by binding to OXTR-containing neurons in the NBM that project to the amygdala (the activated OXTR may be located either on the soma of cholinergic neurons in the NBM, or on the axons of the amygdala-projecting NMB cholinergic neurons) (Figure 6).”

“Prairievolesexpress higher densities of OT receptors (OXTR) in regions of the brain involved in reward and reinforcement than other species of voles that do not form long-term, socially monogamous relationships (McGraw & Young, 2010; Young & Wang, 2004).”

“Inthefollowing paragraphs we review the outcome of experimental work with NHPs, and highlight possible future directions that either fill gaps in, or expand, our current understanding of OT.”

“These nuclei are also the source of glutaminergic excitatory projections to numerous cortical areas, including primary sensory areas such as V1 (Freese & Amaral, 2005, 2006), where OT receptors are also abundant.”

“They concluded that IN treatment of OT does not lead to central release of endogenous OT, instead the administered deuterated-OT penetrates into the CSF (Lee et al., 2018) crossing the blood-brain barrier via a yet unknown mechanism.”

“The innate preference for the eyes is further enhanced by IN OT in both species (Auyeung et al., 2015; Dal Monte, Noble, Costa, et al., 2014; Guastella et al., 2008).”

“Importantly cholinergicmechanismsareinvolvedinvisualattentionandvigilancein general (Bentley, Vuilleumier, Thiel, Driver, & Dolan, 2003; Gill, Sarter, & Givens, 2000; Robbins, 1997; Sarter & Bruno, 1997).”

“Subsequent studies found that administration of the marmoset-specific variant of the OT ligand (Pro(8)-OT) reduced time that marmosets spent in close proximity to opposite-sex strangers (Cavanaugh, Mustoe, Taylor, & French, 2014).”

“These nuclei are also the source of glutaminergic excitatory projections to numerous cortical areas, including primary sensory areas such as V1 (Freese & Amaral, 2005, 2006), where OT receptors are also abundant.”

“…& Dadds, 2008), enhanced the ability of subjects to discriminate facial expressions in others (Domes, Heinrichs, Michel, Berger, & Herpertz, 2007; Lischke et al., 2012), promoted trust (Kosfeld, Heinrichs, Zak, Fischbacher, & Fehr, 2005), and improved socially reinforced learning (Hurlemann et…”

“The distribution of OXTRs has been well characterized across numerous rodent species, where generally OXTRs are widely distributed across the brain, particularly in areas that process olfactory information (Freeman & Young, 2016).”

“Indeed, neurons in the BLA can be strongly activated by external stimuli, such as neurons that respond to faces or eye contact (Gothard, Battaglia, Erickson, Spitler, & Amaral, 2007; Mosher, Zimmerman, & Gothard, 2014).”

“For example, OXTR density is highly variable among prairie voles and is tightly regulated by genetic polymorphisms in the OXTR gene (King, Walum, Inoue, Eyrich, & Young, 2016).”

“For example, OXTR density is highly variable among prairie voles and is tightly regulated by genetic polymorphisms in the OXTR gene (King, Walum, Inoue, Eyrich, & Young, 2016).”

“Taken together with similar results from studies performed in humans (Gossen et al., 2012; Striepens et al., 2013), these results clearly suggest that OT enters the CSF of primates and elevates OT levels in the brain when peripherally administered at appropriate doses.”

“For example, both species prefer looking more at the eyes than at any other facial feature (Gothard, Brooks, & Peterson, 2009; Gothard, Erickson, & Amaral, 2004; Keating & Keating, 1982; Mackworth & Morandi, 1967; Mosher, Zimmerman, & Gothard, 2011; Walker-Smith, Gale, & Findlay, 1977).”

“The innate preference for the eyes is further enhanced by IN OT in both species (Auyeung et al., 2015; Dal Monte, Noble, Costa, et al., 2014; Guastella et al., 2008).”

“Pair-bonding in these monogamous voles is critically dependent on the action of OT in specific brain circuits, including the nucleus accumbens and prefrontal cortex (Donaldson & Young,2008;Johnson&Young,2015,2017;Johnsonetal.,2016;Young & Wang, 2004).”

“Importantly cholinergicmechanismsareinvolvedinvisualattentionandvigilancein general (Bentley, Vuilleumier, Thiel, Driver, & Dolan, 2003; Gill, Sarter, & Givens, 2000; Robbins, 1997; Sarter & Bruno, 1997).”

“The innate preference for the eyes is further enhanced by IN OT in both species (Auyeung et al., 2015; Dal Monte, Noble, Costa, et al., 2014; Guastella et al., 2008).”

“These hypothetical mechanisms could account for many of the behavioral effects of OT, for example, increased attention to the eyes is a resultofincreased saliencefor eyestimuli whichare represented in the amygdala (Mosher et al., 2014).”

“Intra-amygdala injections of OT might be more likely to replicate the effect of endogenous OT, as focal increases of OT may better represent the natural mechanisms of OT release in the brain (Chini, Verhage, & Grinevich, 2017).”

“Striatal OT receptors also mediate the onset of depressive-like “grieving” behavior in prairie voles following loss of a partner (Bosch et al., 2016), a phenomenon that has been proposed to maintain social bonds (Bosch & Young, 2017; Pohl, Young, & Bosch, 2018).”

“…calcifications of the amygdala (Urbach-Wiethe disease) have implicated the amygdala as an anatomical substrate of OT-mediated behavioral changes (Domes, Steiner, Porges, & Heinrichs, 2013; Gamer, 2010; Hurlemann et al., 2010; Kirsch et al., 2005; Tully, Gabay, Brown, Murphy, & Blackwood, 2018).”

“It appears that in primates AVPRs are expressed more widely, or at least more easily detectable, and in areas where OXTR is not abundantly detectable, notably the amygdala, and throughout the cortex (Freeman et al., 2017; Schorscher-Petcu et al., 2009; Young, Toloczko, & Insel, 1999).”

“…primate species, including Titi monkeys ( Callicebus cupreus ) (Freeman, Walum, et al., 2014), marmosets ( Callithrix jacchus ) (Schorscher-Petcu, Dupré, & Tribollet, 2009), and humans (Loup, Tribollet, Dubois-Dauphin, & Dreifuss, 1991; Loup, Tribollet, Dubois-Dauphin, Pizzolato, & Dreifuss, 1989).”

“Inthefollowing paragraphs we review the outcome of experimental work with NHPs, and highlight possible future directions that either fill gaps in, or expand, our current understanding of OT.”

“This,andsimilarexperimentsin rodentsexaminingolfactoryprocessing(Oettletal.,2016)haveledtothe hypothesis that OT tunes inhibitory circuits to increase the salience (signal/noise ratio) of important social stimuli (Marlin & Froemke, 2017; Mitre, Minder, Morina, Chao, & Froemke, 2017).”

“The first study examining female rhesus monkeys also found that IN treatments (as well as intravenous administration) of OT significantly raised CSF OT levels (Freeman et al., 2016).”

“It is known, however, that the impact of Ach on cells in the basolateral amygdala depends on how strongly these cells are activated (Unal, Pare, & Zaborszky, 2015).”

“For example, both species prefer looking more at the eyes than at any other facial feature (Gothard, Brooks, & Peterson, 2009; Gothard, Erickson, & Amaral, 2004; Keating & Keating, 1982; Mackworth & Morandi, 1967; Mosher, Zimmerman, & Gothard, 2011; Walker-Smith, Gale, & Findlay, 1977).”

“This variation in density has been linked to individual differencesinalloparentalbehavior (Olazábal& Young,2006a,2006b), pair-bonding (King et al., 2016; Ross, Cole, et al., 2009; Ross, Freeman, et al., 2009), and resilience to early-life social neglect (Barrett, Arambula, & Young, 2015).”

“These include the orbitofrontal cortex (OFC), the anterior cingulate cortex (ACC), and the amygdala (Amy).”

“…during mating, facilitating the flow of social information across the network in prairie voles, and nucleus accumbens OXTRs appear to serve as a hub for facilitating coordinated activity across the social salience network (Johnson et al., 2016; Johnson, Walum, Xiao, Riefkohl, & Young, 2017).”

“It appears that in primates AVPRs are expressed more widely, or at least more easily detectable, and in areas where OXTR is not abundantly detectable, notably the amygdala, and throughout the cortex (Freeman et al., 2017; Schorscher-Petcu et al., 2009; Young, Toloczko, & Insel, 1999).”

“More recent transcriptomicanalysisofOXTR mRNAdistribution inthehuman brain has revealed more distributed OXTR expression, perhaps due to the increased sensitivity of this technology, with the nucleus accumbens showing some of the highest levels of expression, resembling that of prairie voles and…”

“Likewise, both OT and opioid mechanism are involved in partner preference formation inmonogamous voles (M. ochrogaster) (Resendez et al., 2013).”

“The more socially engaging the partners in a dyadic interaction, the more likely it is that they coordinate their blinks—that is, the more likely they blink within 500 ms after the partner blinks (Ballesta et al., 2016; Cummins, 2012).”

“For example, both species prefer looking more at the eyes than at any other facial feature (Gothard, Brooks, & Peterson, 2009; Gothard, Erickson, & Amaral, 2004; Keating & Keating, 1982; Mackworth & Morandi, 1967; Mosher, Zimmerman, & Gothard, 2011; Walker-Smith, Gale, & Findlay, 1977).”

“Striatal OT receptors also mediate the onset of depressive-like “grieving” behavior in prairie voles following loss of a partner (Bosch et al., 2016), a phenomenon that has been proposedtomaintain socialbonds (Bosch& Young,2017; Pohl,Young, & Bosch, 2018).”

“If indeed OT has much of its effects through modulating ACh activity, the therapeutic potential of OT or drugs that evoke OT release (Modi et al., 2015) will go well beyond autism and may include disorders associated with cholinergic deficits such as cognitive decline.”

“The innate preference for the eyes is further enhanced by IN OT in both species (Auyeung et al., 2015; Dal Monte, Noble, Costa, et al., 2014; Guastella et al., 2008).”

“Furthermore, many neuroanatomical differences exist between rodents and primates (Murray, Wise, & Graham, 2017; Phillips et al., 2014; Wise, 2008), providing additional obstacles in translating results obtained in rodents to primates.”

“Natural variation in OXTR expression contributes to individual variation in social behavioral phenotypes as well.”

“Indeed, peer-reared infants, compared to their mother-reared counterparts, showed altered epigenetic regulation of the OXTR gene (resulting in decreased OXTR mRNA in the hippocampus), and higher levels of separation anxiety and arousal (Baker et al., 2017).”

“…of individuals, and most importantly, the discrimination of social signals such as facial expression, gestures, and postures is perfected (Dettmer et al., 2016; Harlow, 1962; Ruppenthal, Harlow, Eisele, Harlow, & Suomi, 1974; Sclafani et al., 2016; Simpson, Miller, Ferrari, Suomi, & Paukner, 2016).”

“Marmosets will typically form and maintain monogamous socio-sexualrelationships(Evans,1983;French,Cavanaugh,Mustoe,Carp,& Womack, 2018), however exhibit flexibility in their willingness to interact with opposite-sex strangers in the absence of their pair-mate much like humans (Buss & Schmitt, 1993).”

“Inthefollowing paragraphs we review the outcome of experimental work with NHPs, and highlight possible future directions that either fill gaps in, or expand, our current understanding of OT.”

“…ventricle of rhesus monkeys, combined with radiotracers marking the serotonin transporter and the serotonin 1A receptor, revealed a release of serotonin in the amygdala, insula, and hippocampus, and an increase in the availability of 5-HT1AR receptors in the same regions (Lefevre et al., 2017).”

“Interestingly IN treatment of Pro(8)-OT also decreased latencies to respond to infant stimuli in males (Taylor & French, 2015).”

“Videos are known to engage monkeys in the reciprocation of facial expressions and in reciprocating or soliciting eye contact (Mosher et al., 2011).”

“…rhesus infants form bonds not only with their mothers but also with other adult females in the matriline and develop social skills that will support social bonding with peers later in life (Corcoran et al., 2012; Dettmer et al., 2016; Simpson, Sclafani, et al., 2017; Vanderwert et al., 2015).”

“Marmosets will typically form and maintain monogamous socio-sexualrelationships(Evans,1983;French,Cavanaugh,Mustoe,Carp,& Womack, 2018), however exhibit flexibility in their willingness to interact with opposite-sex strangers in the absence of their pair-mate much like humans (Buss & Schmitt, 1993).”

“Likewise in rhesus monkeys, IN OT reduced the functional coupling between the amygdala and areas in the occipital and inferior temporal cortices but only when the subjects viewed aggressive or fearful faces (Liu et al., 2015).”

“This variation in density has been linked to individual differencesinalloparentalbehavior (Olazábal& Young,2006a,2006b), pair-bonding (King et al., 2016; Ross, Cole, et al., 2009; Ross, Freeman, et al., 2009), and resilience to early-life social neglect (Barrett, Arambula, & Young, 2015).”

“…rhesus infants form bonds not only with their mothers but also with other adult females in the matriline and develop social skills that will support social bonding with peers later in life (Corcoran et al., 2012; Dettmer et al., 2016; Simpson, Sclafani, et al., 2017; Vanderwert et al., 2015).”

“Similar interactions regulate resident-intruder aggression in male mice (Pagani et al., 2015) and are crucial for social interactions to be rewarding (as demonstrated by a conditioned place preference) (Dölen et al.”

“Vigilance and attention to visual signals is under cholinergic control in primates (Monosov, Leopold, & Hikosaka, 2015) and this may be potentiated for social stimuli by OT (Freeman & Young, 2016).”

“When AE OT was paired with a µ-opioid receptor antagonist, rhesus monkeys increased the number of fixations on a partner monkey, beyond the effect of either OT or the antagonist alone (Dal Monte et al., 2017).”

“The effect of OT on blinking should also be quantified, as blinking is an integral component of a gaze-mediated social interactions (Ballesta & Duhamel, 2015; Ballesta, Mosher, Szep, Fischl, & Gothard, 2016; Cummins, 2012).”

“Rhesus monkeys that received AE OT before they freely viewed videos of conspecifics, showed a robust increase in the frequency of gaze following saccades, abehaviorthatindicatesanexplicitinterestinwhereothersarelooking (Putnam, Roman, Zimmerman, & Gothard, 2016) (Figure 4).”

“It appears that in primates AVPRs are expressed more widely, or at least more easily detectable, and in areas where OXTR is not abundantly detectable, notably the amygdala, and throughout the cortex (Freeman et al., 2017; Schorscher-Petcu et al., 2009; Young, Toloczko, & Insel, 1999).”

“Future research in NHPs could employ techniques such as fast-scan cyclic voltammetry to monitor real-time dopamine concentrations in vivo in response to OT manipulations (Schluter, Mitz, Cheer, & Averbeck, 2014).”

“…of individuals, and most importantly, the discrimination of social signals such as facial expression, gestures, and postures is perfected (Dettmer et al., 2016; Harlow, 1962; Ruppenthal, Harlow, Eisele, Harlow, & Suomi, 1974; Sclafani et al., 2016; Simpson, Miller, Ferrari, Suomi, & Paukner, 2016).”

“The ability to recognize others is an essential social behavior inprimates (Gothard & Hoffman, 2009; Leonard, Blumenthal, Gothard, & Hoffman, 2012), and deficits in facial processing are early predictors of social deficits later in life (Sclafani et al., 2016).”

“The ability to recognize others is an essential social behavior inprimates (Gothard & Hoffman, 2009; Leonard, Blumenthal, Gothard, & Hoffman, 2012), and deficits in facial processing are early predictors of social deficits later in life (Sclafani et al., 2016).”

“…as well as many others, have fueled enthusiasm for targeting the OT system to improve various aspects of social cognition in psychiatric disorders such as autism (Shamay-Tsoory & Young, 2016; Tully et al., 2018; Watanabe et al., 2015; Yatawara,Einfeld,Hickie,Davenport,&Guastella,2016;Young,2015).”

“When males were treated with OT the untreated female partners approached them more frequently (Cavanaugh, Huffman, Harnisch, & French, 2015).”

“Thesedynamicsmaybedifferentduringface-to-face interactions with social partners and even when watching videos, where the social stimulus behaves more naturally (Gothard et al., 2018).”

“Early attempts to localize OXTRs in NHPs were inconclusive (Toloczko, Young, & Insel, 1997) due to the cross-reactivity of the OT radioligand used for OXTR autoradiography and structurally similar arginine vasopressin receptor (AVPR1A) (Manning et al., 2012).”

“The relationship between the number of reciprocal friendships and plasma OT was best described by a U-shaped quadratic function (middle-and high-ranking juveniles with either low or high numbers of reciprocal friendships had higher OT levels) (Weinstein et al., 2014).”

“The more socially engaging the partners in a dyadic interaction, the more likely it is that they coordinate their blinks—that is, the more likely they blink within 500 ms after the partner blinks (Ballesta et al., 2016; Cummins, 2012).”

“Subcutaneous injections of a selective 5-HTP 1A agonist in male Titi monkeys decreased the social behaviors directed at a female pair-mate (Larke, Maninger, Ragen, Mendoza, & Bales, 2016), further implicating serotonergic activity in the regulation of primate social behavior.”

“Moreover, NHPs are the species of choice for certain invasive procedures, not feasible in healthy human subjects, such as recording both extracellular single unit activity and local field potentials in the context of primate-specific social behaviors (Chang, 2017).”

“Similar links between the dopaminergic system and OT in NHPs have been evidenced by IV administration of a non-selective dopamine agonist that resulted in peripheral OT secretion (Amico, Layden, Pomerantz, & Cameron, 1993).”

“…calcifications of the amygdala (Urbach-Wiethe disease) have implicated the amygdala as an anatomical substrate of OT-mediated behavioral changes (Domes, Steiner, Porges, & Heinrichs, 2013; Gamer, 2010; Hurlemann et al., 2010; Kirsch et al., 2005; Tully, Gabay, Brown, Murphy, & Blackwood, 2018).”

“They concluded that IN treatment of OT does not lead to central release of endogenous OT, instead the administered deuterated-OT penetrates into the CSF (Lee et al., 2018) crossing the blood-brain barrier via a yet unknown mechanism.”

“, 2018); linking cortical and subcortical regions, it coordinates social and affective behavior (Putnam et al., 2018).”

“…(i) by directly depolarizing projection neurons, (ii) by affecting the activity of interneurons that regulate local circuit activity, and (iii) by modulating the activity of other neuromodulator systems like dopamine, acetylcholine, and serotonin (Froemke & Young, 2021; Putnam et al., 2018).”

“Finally, the null effect of oxytocin administration adds to the growing evidence that the behavioral and neural effects of intranasal oxytocin in primates has not been unequivocally established (recently reviewed by (Putnam et al., 2018).”

“Existing reviews have done an excellent job summarizing known behavioural effects of oxytocin [43,48,50,52,58,71,82,83], the neuralmechanisms underlying these effects [15–17,84,85] and potential hypotheses about the role of oxytocin in the brain and social behaviour [20,22,24].”

“Here, though, stranger touch activated the amygdala in a general fashion (Fig 3C; Table S5), supporting the proposal that its prominent role in human and nonhuman primate OT studies may be indirect (93, 94).”

“, the region-specific receptor expression level), including humans’,(26) have widely been studied and relatively wellcharacterized.(27,28) Second, only small variations in the promotor”

“14 In baboons and squirrel monkeys, direct cooling or warming of the preoptic/anterior hypothalamus alters body temperature.”

“Recent studies suggest that oxytocin influences cognitive functions such as memory, attention and emotional regulation, particularly in the context of social and communicative behaviour [4,37,49].”

“The co-localization of key neurotransmitters for reward and social behavior, particularly DA, OT, and opioid receptors (Freeman et al., 2014; Ragen et al., 2015a; Putnam et al., 2018), further support this role.”

“Substantial differences between rodents and primates in the mechanisms that regulate these processes require utilizing nonhuman primates for bridging rodent to human research [13, 14].”

“Importantly, rhesus and humans both rely on audio-visual social cues in contrast to rodents, which depend more heavily on olfaction (Freeman and Young, 2016; Putnam et al., 2018).”

“Hundreds of studies on rodent fauna have been performed worldwide which have increased our knowledge about distributional patterns of rodents (Du et al. 2017, Putnam et al. 2018).”

“Although monkeys provide a crucial bridge between rodent and human research 28,29 , OT studies in non-human primates have largely relied on the same approaches used in human research 30 , emphasizing the need for more targeted methods 31 .”