Dopamine in the medial amygdala network mediates

human bonding
Shir Atzila, Alexandra Touroutogloua, Tali Rudya,b, Stephanie Salcedoa, Ruth Feldmanc,d, Jacob M. Hookera,
Bradford C. Dickersona,e, Ciprian Catanaa,1, and Lisa Feldman Barretta,b,1,2
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129; bDepartment
of Psychology, Northeastern University, Boston, MA 02115; cYale Child Study Center, New Haven, CT 06520; dGonda Brain Research, Bar Ilan University,
Ramat Gan 5290002, Israel; and eDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114

Edited by Linda M. Bartoshuk, University of Florida, Gainesville, FL, and approved January 6, 2017 (received for review July 26, 2016)

Research in humans and nonhuman animals indicates that social area, which sends dopaminergic projections to the NAcc as part of
affiliation, and particularly maternal bonding, depends on reward the mesolimbic system, in response to infant stimuli (5).
circuitry. Although numerous mechanistic studies in rodents demon- In this study, we extend our knowledge of the neural basis of
strated that maternal bonding depends on striatal dopamine trans- bonding by demonstrating that dopamine is associated with human
mission, the neurochemistry supporting maternal behavior in bonding. Bonding behavior was assessed in this study using indices
humans has not been described so far. In this study, we tested the of mother–infant synchrony. We also examined dopamine re-
role of central dopamine in human bonding. We applied a combined sponses and intrinsic connectivity of the striatum with the broader
functional MRI-PET scanner to simultaneously probe mothers’ dopa- medial amygdala network (Fig. 1) that connects the NAcc to the
mine responses to their infants and the connectivity between the medial amygdala, rostral hypothalamus, ventromedial prefrontal
nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (vmPFC), subgenual anterior cingulate cortex (sgACC), and
cortex (mPFC), which form an intrinsic network (referred to as the

posterior cingulate cortex (PCC). This network’s hubs were con-
“medial amygdala network”) that supports social functioning. We sistently linked to human maternal bonding (for review, see ref. 3;
also measured the mothers’ behavioral synchrony with their infants also see refs. 4 and 6). Moreover, atypical maternal behavior, as
and plasma oxytocin. The results of this study suggest that synchro- seen in patients with postpartum depression (PPD), is associated
nous maternal behavior is associated with increased dopamine re- with attenuated maternal responses in the striatum (7), rapid
sponses to the mother’s infant and stronger intrinsic connectivity striatal attenuation to reward (8), and disrupted connectivity
within the medial amygdala network. Moreover, stronger network
between the right amygdala and the PCC (9). We examined the

connectivity is associated with increased dopamine responses within

connectivity within the medial amygdala network using blood
the network and decreased plasma oxytocin. Together, these data
oxygenation level-dependent (BOLD) signals acquired during
indicate that dopamine is involved in human bonding. Compared
fMRI and examined dopamine function with the radiolabeled
with other mammals, humans have an unusually complex social life.
ligand [11C]raclopride during PET imaging while a mother
The complexity of human bonding cannot be fully captured in non-
watched a film of her own infant and a film of an unfamiliar
human animal models, particularly in pathological bonding, such as
that in autistic spectrum disorder or postpartum depression. Thus,
infant. Whole-brain network investigation during real experi-
investigations of the neurochemistry of social bonding in humans, ences, using simultaneous probing of PET and fMRI, facilitates
for which this study provides initial evidence, are warranted. the mechanistic understanding of how multifaceted brain
function relates to complex human behavior.
dopamine | maternal behavior | social affiliation | network connectivity |
humans Significance

Early life bonding in humans has critical long-term implications
E arly social bonding with a primary caregiver is necessary for
mental and physical health, whereas the absence of such bonding
is a clear risk factor for adult illness (1). However, despite potentially
for health, productivity, and well-being in society. Nonetheless,
neural mechanisms of bonding are typically studied in rodents,
and no studies to date had examined the neurochemistry of
enormous implications, to date the science of mother–infant bonding
human social affiliation. This study utilizes a state-of-the-art
relies mostly on nonhuman animal models.
technology to demonstrate that human maternal bonding is
Research on nonhuman animals indicates that maternal bonding
associated with striatal dopamine function and the recruitment
involves the nucleus accumbens (NAcc), amygdala, and medial of a cortico–striatal–amygdala brain network that supports af-
prefrontal cortex (mPFC). In rodents, oxytocin and dopamine act filiation. The simultaneous probing of neurochemical responses
in the amygdala and NAcc (2) to regulate maternal appetitive be- and whole-brain network function in mothers watching their
haviors. In humans, functional MRI (fMRI) studies have verified infants provides a unique observation into an “affiliating brain.”
that NAcc activity increases consistently when mothers gaze at their These results advance the mechanistic understanding of human
infants (3). Moreover, the NAcc and amygdala activity have been social bonding and promote basic and clinical research in social
linked to the quality of maternal behavior (4). Mothers who were neuroscience, development, and psychopathology.
sensitive to their infants’ cues for social engagement and who ad-
Author contributions: S.A., B.C.D., C.C., and L.F.B. designed research; S.A., T.R., S.S., and J.M.H.
justed their own behavior to meet those needs (referred to as performed research; S.A., A.T., T.R., R.F., B.C.D., C.C., and L.F.B. analyzed data; and S.A., T.R.,
“mother–infant synchrony”), showed greater activations in the left C.C., and L.F.B. wrote the paper.
NAcc and lower activation in the right amygdala when viewing films The authors declare no conflict of interest.
of their infants than did nonsynchronous mothers (4). In agreement This article is a PNAS Direct Submission.
with the animal studies, oxytocin has been implicated in human Freely available online through the PNAS open access option.
maternal behavior, so that synchronous mothers show a stronger 1
C.C. and L.F.B. contributed equally to this work.
link between levels of circulating plasma oxytocin and NAcc fMRI 2
To whom correspondence should be addressed. Email:
activations when viewing films of their infants (4). Moreover, oxy- This article contains supporting information online at
tocin administration increased activations of the ventral tegmental 1073/pnas.1612233114/-/DCSupplemental. PNAS Early Edition | 1 of 6

. 1.4. such as infants’ arousal levels and social engagement. with a mean of 4% and median of 2. In our sample. or attunement (r = 0.03) and right amygdala (r = the percentage of time during a 2-min unconstrained interaction in 0. P < 0. P < 0. P < 0. a mother needs to be sensitive to her infant mine responses. P < 0. the amygdala along with a set of connected regions in the NAcc. medial amygdala network (r = −0. see Table S1 for a complete list of regions and effects). 2 B and C show the correlation between the in- Results dividual differences in dopamine responses in the right pallidum Behavioral Results. pallidum (r = 0. rostral [11C]raclopride binds specifically to free D2 receptors that are not hypothalamus. In our sample. Maternal attunement is a broader measure of synchrony that traces how well the mother accommodates her vocal stimulation to the infant’s affect and social engagement. the order was counterbalanced. unfamiliar infant (for individual data see Fig.” Maternal attunement measured the time in which mothers provided vocal stimulation while the infant was showing signs of positive affect (the infant is content and socially engaging).5).2). Mothers then participated in two simultaneous PET- pallidum (F = 11.6.36%.7% and a median of 10. At the associated with maternal dopamine responses and that high-syn- outset. Using the median.3. bonding behavior. Mother–infant synchrony is tivity within the medial amygdala network and maternal attunement. We then measured task-independent changes in BOLD mothers. maternal attunement ranged from 0–27% of the time in the 2-min unconstrained in- PCC teraction. Mothers Mother–infant vocalization synchrony measures the temporal who were more attuned to their infants had a more cohesive matching of mother–infant vocalizations. We hypothesized that dopamine secretion within the versa (12). To assess mothers’ endog- enous dopamine response in each condition. with a mean of maternal attunement was strongly associated with and adjust her behavior dynamically according to the infant’s cues. Age. Once injected. The interaction films infants.3.8). Imaging Results.49. F = 4.pnas. we injected to the Fig. P < 0. vocalization mothers and infant synchronized vocalizations for 0–13% of the synchrony (r = 0.5. mothers and infants tend to synchronize their Infants’ ages were correlated with the dopamine responses in vocal communication (1).1073/pnas. n = 19. S1. Just before the onstrates that mothers with a dopaminergic preference in the right brain imaging session. most mothers had a stronger dopamine response to the signal. Our primary out- adults and reflects a whole-brain intrinsic connectivity analysis seeded in the right medial amygdala. we visited families at home.1612233114 Atzil et al.1. time. NAcc or education level did not predict maternal attunement or mother– mPFC Hypothalamus infant vocalization synchrony. relative dopamine were behaviorally coded to evaluate mother–infant synchrony. Maternal voice helps regulate the infant’s attention and affect (10). P < 0. To synchronize. Analyses with behavior and PET: Association between mother–infant vocalization synchrony and dopamine response. We predicted that synchronous mothering would be own-infant condition compared with the unfamiliar-infant condition associated with an enhanced dopamine response within the network that using the formula −[raclopride BPnd(own infant) − raclopride specifically signifies the own-infant over the unfamiliar-infant condition. In a multivariate general linear model. Fig. P < 0. We refer to this broader as- pect of synchrony as “maternal attunement. and vice plasma oxytocin levels. Bonding behavior was evaluated with two in. BPnd indirectly indexes the levels of endogenous social networks (25). pallidum to their own infants are more synchronous). P < 0. vocalization synchrony was still we divided the sample into two groups: high and low vocalization correlated significantly with dopamine responses in the right synchrony groups. and NAcc and vocalization synchrony scores. After controlling for infant age. P < 0.03). with greatest effects in the right imaging (4).004) and right NAcc (F = 9. intrinsic connectivity in the medial amygdala network. the temporal contingency of behavior between a mother and her Unlike vocalization synchrony. As part of typical human medial amygdala network (Fig. dices of mother–infant synchrony: mother–infant vocalization Analyses with behavior and fMRI: Association between intrinsic connec- synchrony and maternal attunement. In the low-synchrony as control.2.04. The scat- terplots in Fig. We also confirmed that infants’ age 2 of 6 | www. The medial amygdala network (in red) includes the medial sector of mothers with [11C]raclopride 10 min into each film. Previous research shows that stronger intrinsic con- come measure was [11C]raclopride-nondisplaceable binding poten- nectivity within this network is associated with larger and more complex tial (BPnd) (11). and sgACC (25). The map is based on 150 healthy occupied by endogenous dopamine molecules. Each mother viewed a film of her own infant during one scan (own-infant condition) and a film of an un- familiar infant during another scan (unfamiliar-infant condition) as a control. BPnd(unfamiliar infant)] × 100/raclopride BPnd(unfamiliar infant). Our results showed that mother–infant synchrony scores are Nineteen mother–infant dyads completed the study. mothers attune their vocal communication not only to the infants’ vocali- zations but also to a broader set of affective cues. The imaging paradigm included two scans. from which we estimated the degree of intrinsic connec. PCC. As such.01) but were not correlated with the connectivity in the which mothers and infants were vocally synchronized. race.02). blood was collected for oxytocin analysis. We calculated vocalization synchrony as the right pallidum (r = 0. S2 dem- tivity of each mother’s medial amygdala network. 2A. [11C]raclopride to D2-type dopamine receptors while mothers The left hemisphere contralateral regions did not display such a viewed films of their own infant and films of an unfamiliar infant group difference in [11C]raclopride BPnd. vmPFC. The connectivity and dopamine response within the neural dopamine response: A decrease in [11C]raclopride BPnd network were tested for association with maternal bonding behavior and signifies a proportional increase in endogenous dopamine.8%. and responses in the high vocalization synchrony group were signifi- cantly higher in the right hemisphere regions of interest (main the infant solitary play films were used as stimuli during brain effect. We filmed their unconstrained chrony mothers have a dopaminergic preference for their own interactions and the infant’s solitary play. Each mother’s relative dopamine response was calculated medial amygdala network recruits the network to support human bonding as the percentage change in endogenous dopamine response in the (green arrowheads).007) fMRI scannings in which we tracked the change in the binding of (Fig. which was linked to PET dopa- infant. 3).

Mothers were assigned to a high. Evidence that behavioral synchrony between mothers and infants is associated with maternal striatal dopamine responses to the infant. A B C NEUROSCIENCE PSYCHOLOGICAL AND COGNITIVE SCIENCES Fig. P < 0. the blood circulation as a hormone. pallidum and with the strength of intrinsic connectivity within the Analyses with plasma oxytocin levels. Mothers with stronger medial amygdala network was positively correlated with vocalization synchrony (r = 0.5. unfamiliar- infant comparison (indexed by percent [11C]raclopride BPnd change). across infants’ ages. with a negative correlation coefficient (Fig. Regions of interest are presented according to their effect size (see the full list of regions in Table S1).055. Levels of connectivity and dopamine responses in mothers.07). Central oxytocin is within-network dopamine levels tested simultaneously and with secreted as a neurotransmitter via axon terminals in the brain. between plasma oxytocin and human behavior (for review see ref. PNAS Early Edition | 3 of 6 . Plasma for oxytocin analysis was available for 17 subjects and Analyses with fMRI and PET: Association between medial amygdala network ranged from 43–370 pg/mL with a mean of 195 pg/mL. Moreover.012) (B) and right NAcc (one-tailed. z = 1.06). n = 19. while watching their own infants but not while watching an un- familiar infant. Connectivity within the plasma oxytocin predicted medial amygdala network connectivity medial amygdala network was associated with in-network dopa.378. medial amygdala network. (Fig. P < 0.vs. Error bars represent the SEM. r = 0.or low-synchrony group based on the vocalization synchrony median (2. These analyses confirm that mother–infant vocalization 15). 5). trending) (C). (A) A general linear model analysis demonstrates that high-synchrony mothers have higher relative dopamine responses than low-synchrony mothers in the own.517. stronger intrinsic connec- sured in circulating plasma because there is still no reliable specific tivity in the medial amygdala network is associated with increased radiotracer for human oxytocin receptors (13). did not mediate the relationship between vocalization synchrony central oxytocin. Dopamine responses in the contralateral The results of this study demonstrate that human maternal left regions were not correlated with intrinsic connectivity in the bonding is associated with dopamine responses in the NAcc and left hemisphere medial amygdala network.36%). 2.36. their appetitive behaviors synchronize (14) showed no direct correlation between levels of peripheral and (1). numerous studies reported a link and right pallidum dopamine (Sobel test not significant. Peripheral oxytocin was mea. In this study peripheral oxytocin and its relations to central synchrony is associated with maternal dopamine responses dopamine and behavior were evaluated in an exploratory way. Nonetheless.3). and right NAcc in the left NAcc in the own-infant condition (r = 0. A trend of correlation also was evident for Discussion the right PCC (P < 0. Synchrony has been shown to improve prosocial behavior in Atzil et al. lower plasma oxytocin levels. these data provide evi- whereas peripheral oxytocin is secreted via the pituitary gland into dence indicating that dopamine is involved in human bonding. r = 0. P < 0. (B and C) Individual differences in vocalization synchrony in mothers are positively correlated with dopamine responses (indexed by the percent [11C]raclopride BPnd change) in the right pallidum (one-tailed. Together.03) and showed a trend of correlation with dopamine responses responses in the right sgACC. Studies in nonhuman animals When humans interact. P < 0. 4). n = 19. Plasma oxytocin mine responses. right amygdala. P < connectivity showed increased in-network endogenous dopamine 0.03.

In rodents. In the work connectivity is represented as Fisher’s r-to-z transformed Pearson corre- lation coefficients between the right medial amygdala seed and the rest of the clinical realm.03). Instead. In our sample none of the mothers had a psychi- atric diagnosis. among healthy children (1). Medial amygdala net- the mother’s own infant is extremely salient to her (1). P < 0. unlike high-synchrony mothers. according to FreeSurfer segmentation atlases (34)] in which [11C]raclopride BPnd is correlated with the network connectivity. Behavioral synchronization demands dynamic adjustment might represent the selectivity of maternal attachment. focus on her infant while disregarding all distractions (23). However.1073/pnas. one-tailed). low-synchrony mothers did not show infant macaques (16. Maternal attunement was measured as the percent of time ternal preoccupation”’ (23). Lower) The Pearson one-tailed correlation graphs (n = 19).455. . (C) Right NAcc (r = 0. an increase in dopamine responses during the own-infant condition is indexed by a decrease in [11C]raclopride BPnd. linking human behavioral synchronization to dopamine.02). overlaid with regions of interest for PET analysis [manually illustrated in green. possibly because to their infants (n = 19. beyond evidence that dopamine is involved in the prosocial effects of syn. join the rodent literature and mark dopaminergic function in the NAcc and pallidum as a regulatory pathway of appetitive bonding be- havior in humans. Additionally.46. P < 0.1612233114 Atzil et al. medial amygdala network connectivity is represented as Fisher’s r-to-z transformed Pearson correlation coefficients between the right medial amygdala seed and the rest of the network’s nodes. maternal preoccupation is linked to PPD and nonsynchronous parenting (23). 17).02. 4. (A) Right sgACC (r = 0. In the y axis. provides initial their infant saliency with regard to other infants. 3. In this study. The results of this study. differential dopamine responses that favor their own infants. P < 0. The evidence pre. (A–C. increased saliency. P < 0. r = 0. (A–C. lack of a differential response could represent a relative deficit in sented here. Primate of one’s behavior to the dyadic partner. in synchronous mothers dopamine responses to the mother’s own Fig. the NAcc and pallidum. Mothers with a stronger medial amygdala network are more attuned infant are stronger than those to a novel infant. which links synchrony to dopamine. dopamine in the NAcc reg- ulates appetitive maternal behaviors (2). which describes a mother’s complete during a 2-min interaction in which mothers provided positive vocal stimula.pnas. low-synchrony mothers showed increased dopamine responses in the unfamiliar-infant condition. Low tion to their infants while the infants were content and socially engaged. (B) Right amygdala (r = 0. This dren with autistic spectrum disorder (18–21).45.38. D2 receptors in the NAcc are important for the A B C Fig. 4 of 6 | www. However. In response to a salient event. In the x axes.05). the dopaminergic patterns measured here chrony. One possible explanation for this finding could be the novelty of the unfamiliar infant (22). and in chil. Stronger intrinsic connectivity in the medial amygdala network is predicted by increased in-network dopamine responses during the own-infant condition. dopamine in the NAcc releases the pallidum from GABA inhibition to disinhibit (or activate) motor pathways that execute appetitive behavior toward the pups (2). synchronous mothers and sheep show a selective bonding to their own young mothers had stronger dopamine responses to their own infant in (24). The infants’ films are salient social stimuli that elicit striatal dopamine responses. Upper) Intrinsic connectivity maps of the medial amygdala network (in red). such salience-specificity is known as “primary ma- network’s nodes.

mother’s selective attachment to her own child. The human medial–rostral medial amygdala network includes the medial–rostral hypothala. was negatively correlated to the medial amygdala network. Previous studies involvement in maternal synchronization. Recent studies suggest a role for D2 asym- amygdala network is a reliable predictor for social affiliation (25). In the x axis. hypothalamus. using neuroimaging with improved spatial resolution. Future studies should administer an additional condition may reflect the involvement of D2 receptors in a control condition measuring baseline levels of raclopride BPnd. Participants had no psychiatric history needed for human bonding. The analysis of plasma oxytocin yielded intriguing results. is medially adjacent mus (6). Moreover. amygdala network potentially promotes human bonding and thus tical circuitry that supports mentalization to striatal reward circuitry could play a considerable role in optimal human development. metry in motivation. hypothalamus. our Future mechanistic studies should evaluate a possible lateralization results extend previous studies on the neural basis of maternal in striatal function. r = −0. In healthy humans. Moreover. these methods are inherently correlational and include broader neural connections with the human cortex. Moreover. have abnormal default-mode network connectivity. but discrete function of the NAcc. Furthermore. This finding could have important implications for neuropathologies of the dopaminer- gic system. is of This evidence helps integrate animal and human studies concep. so it is possible that the pallidal dopamine observed The MPOA has a dominant role in maternal behavior in every here actually reflects dopamine transmission into the rostral hypo- mammalian species examined experimentally (24). 5.049). Additionally. L-dopa increased the connectivity in several networks. who suffer from a dopaminergic deficiency. which is considered a prosocial network (25). addic- tion (30). our includes cortical regions. previous studies have observed both left and right NAcc This study reports a finding for a second key element in human maternal bonding: the medial amygdala network. Dopamine within the medial between them. animal models do not show that bonding (4. that supports behavioral regulation.. n = 17. including additional neuro- important for motivating and regulating behavior. Linking behavior to dopamine in cortical regions of the medial amygdala network extends the Materials and Methods contribution of this study beyond the rodent literature because it Participants. Importantly. synchrony relies on mentalization (i. the ability to rep. and mPFC (3) but in. Our study pro. and possibly social dysfunction and PPD. This evidence converges with the results of this report to support a possible role for dopamine in network reg- ulation and thus in human cognition. which contains the medial preoptic area (MPOA) (26). Future investigation of the rostral hypothalamus in human vides evidence for the involvement of this region in human bonding. For example. amygdala. Nineteen mothers (age range 21–42 y) and their infants (age marks a possible role for dopamine in the higher social cognition range 4–24 mo) completed the study. The stimulate rodent maternal behavior (31). to the pallidum. P < 0. age could account for some neural variability resent the partner’s intentions and anticipate behavior) (4). inhibitory and excitatory pathways affecting dopaminergic receptors medial amygdala network connectivity is represented as Fisher’s r-to-z in the NAcc and amygdala [summarized in figure 3 from Numan transformed Pearson correlation coefficient values between the right medial and Young (2)]. 6) by showing that bonding behavior relies not on the dopamine acts in the pallidum to regulate maternal behavior. where the MPOA is located (26). bonding. Accordingly. The Massachusetts General Hos- Previous findings have suggested a possible mechanistic role pital Institutional Review Board approved the study. although primates and to activate reward circuitry (27. and amygdala. which is considered a “prosocial” hormone (2). but this study only ob- PSYCHOLOGICAL AND COGNITIVE SCIENCES have shown that the strength of connectivity within the medial served the right NAcc. in humans the digm involved some limitations. The and may be an important aspect to consider in future research. studies showed that patients with Parkinson’s disease. Synchrony behavior and did not model maternal dopamine responses to an appeared to be intrinsically rewarding to humans and nonhuman infant’s distress. schizophrenia. Both of dopamine and the medial amygdala network in PPD and the subcortical and cortical regions. which is restored after treatment with the dopaminergic precursor L-dopa (29). which is important for synchrony. and PCC. 28). The cannot provide information about the causal nature of the reported medial amygdala network possibly supports synchronous affiliation relationships. Atzil et al. and the dopami- nergic antagonist haloperidol decreased the connectivity in those networks (30). our study focused on positive interactive by coordinating two functions: reward and mentalization. The negative correlation between oxytocin and the amygdala seed and the rest of the network’s nodes. Oxy- tocin. thalamus. Mothers’ responses to their own increased D2-mediated dopaminergic responses in the NAcc in infants were compared with their responses to unfamiliar infants and the own-infant condition as compared with an unfamiliar-infant are thus relative. which are potentially neurochemistry of human bonding. The network also transmitters such as central oxytocin and opioids. Animal models revealed that central oxy- Fig. medial amygdala network requires further investigation of the oxytocin–dopamine interplay in humans. high importance because of this brain area’s homology to rodents’ tually and suggests that homologous striatal circuitry has evolved to MPOA. PNAS Early Edition | 5 of 6 . including Parkinson’s disease. there is strong evidence that dopamine acts on the MPOA to stead on the synchronous firing in these regions as a network. such The evidence reported here encourages future research on the as the NAcc. promote synchronous bonding by coordinating cor. sponses across ages. Moreover. Plasma oxytocin negatively predicts connectivity in the medial tocin projections from the hypothalamus to the striatum have both amygdala network (two-tailed. with D2 receptors in the right hemisphere Our results extend those findings by demonstrating that the net. results may be useful for clinical research testing the involvement which are consistently reported to support mentalization (9). involved in behavioral regulation. Studying postpartum mothers in a behavioral PET-fMRI para- NEUROSCIENCE formation of selective social bonds (2).415. and all mothers signed for dopamine in intrinsic network function. work is specifically involved in maternal bonding. several an informed consent before participating. a subject for future research. In addition to mother–infant synchrony associated with maternal dopamine re- reward.e. medial amygdala network includes subcortical reward regions. such as the vmPFC. sgACC. and were not breastfeeding or pregnant. and particularly the connectivity developmental psychopathology.

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