"hole in the soul"

What is Missing in the “Hole in the Soul”?


Following directly on from our Previous blog on  Maternal Neglect: Oxytocin, Dopamine and the Neurobiology of Attachment

Fig 2

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“Infants of caregivers who are available, responsive and sensitive to their emotional and physical needs tend to manifest patterns of “secure attachment”. However, if the care provided is chaotic, unpredictable, rejecting, or neglectful, infants develop self-protective strategies manifest as various “insecure” patterns of attachment.

“dismissing” adults tend to minimize affective information, dismiss their own feelings, intentions and perspectives  (25). Studies have also shown that “dismissing” mothers score much lower on measures of parental warmth and responsivity (35, 36), suggesting that this pattern of attachment may be associated with emotional neglect (23).“Preoccupied” adults, in contrast, organize their behavior around affective information, such as fear, anger, or desire for comfort. They tend to be preoccupied with their own feelings and perspectives.

“Adult attachment has been shown to reliably predict maternal behavior patterns, and through this, infant social/emotional development (37) and attachment (38, 39). It is hypothesized that the intergenerational transmission of attachment may be mediated by differences in maternal neuroendocrine responses to infant cues, which translate into differences in maternal caregiving behavior (29, 40) (Figure 2). This, along with individual genetic variation, may help to shape the infant’s neuroendocrine development and subsequent behavioral patterns.

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Biological mechanisms underlying maternal caregiving and neglect

Maternal neglect represents a fundamental breakdown in the most primal of human relationships, defying multiple biological mechanisms designed to ensure the optimal development of the offspring (41). Bowlby first proposed that attachment between a mother and her child was a biologically driven process which could, however, like most biological systems, be adapted or modified by experience (30). Since that time, numerous studies have confirmed that social and parenting behaviors are dependent on genetically programmed biological mechanisms—such as the oxytocinergic and dopaminergic neuroendocrine systems (42, 43)—but are also influenced by environmental factors, such as stress during pregnancy, early caregiving experience and relationships throughout the lifespan (37, 4446).

From the emerging field of epigenetics, we are beginning to understand how the caregiving environment may influence the development of biological systems and behavioral phenotypes, via stable changes in the regulation of gene expression (47) (Figure 2).

For example, from rodent models we learn that lower levels of maternal licking and grooming (LG) of pups results in increased DNA methylation of the estrogen receptor-α (ERα) gene promoter, which inhibits the development of the oxytocin system (48, 49).

Furthermore, stress during pregnancy may reduce oxytocin receptor binding in key brain areas involved in maternal behavior, with associated increases in maternal anxiety and decreased maternal LG behavior postnatally (50). This may then result in decreased oxytocin receptor binding in the offspring (44).

Environmental enrichment later in life may compensate for, but not reverse, some of these stress-related effects in the offspring (51, 52). Human research has also demonstrated that a mother’s own attachment history, as well as psychosocial stress, may influence the development of secure attachment in her own infant, as assessed by the Strange Situation Procedure (39, 53).

Oxytocinergic and dopaminergic systems

Two neuroendocrine systems critically involved in maternal caregiving behavior are the oxytocinergic and dopaminergic systems (see review, 54). The oxytocinergic system is important in the formation of social and spatial memories, affiliative behavior and emotion regulation (55). The dopaminergic system is involved in reinforcement stimulus-reward learning, and in decision-making based on future predicted reward (56).

a) Oxytocinergic System


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In several mammalian species, oxytocin facilitates physical proximity and nurturant care between the mother and infant (41). For example, in estrogen-primed virgin rats that normally exhibit aversive behavior toward rat pups, an intraventricular injection of oxytocin stimulates a broad range of maternal behaviors, including pup grouping, retrieval of separated pups, nest building, and licking (59). Infusion of an oxytocin antagonist into the VTA blocks many of these behaviors in parturient rat dams, who then leave the pups scattered and “neglected” (60). In the amygdala, oxytocin has an anxiolytic effect and is critical for social recognition (61).

Oxytocin is also important in the development of long-term spatial memories via the hippocampus (18), which supports maternal behaviors such as pup retrieval and foraging. In sheep, which are normally aversive toward newborn lambs, vaginocervical stimulation causes a release of central oxytocin, which facilitates proceptive maternal behaviors and minimizes rejection of lambs (63).

While oxytocin plays a role in stimulating the onset and maintenance of maternal behavior, maternal behavior may also program the development of the oxytocin system in female offspring, as well as the quality of maternal behavior in adulthood (see Figure 2) (51, 64, 65). In rodents, natural variation in pup LG behavior is associated with the offspring’s oxytocin receptor (OTR) expression in the hypothalamus, and maternal caregiving behavior in subsequent generations (45, 58, 66).

Changes in OTR expression in the rodent appear to be mediated via changes in DNA methylation within the ERα gene promoter (48), with low LG associated with increased DNA methylation, down-regulation of ERα gene, estrogen-insensitivity, reduced OTR expression, and diminished LG behavior in the offspring.

In both human and non-human primates, early maternal caregiving has also been associated with the development of the oxytocinergic system. In rhesus monkeys, non-maternal (or nursery) rearing was associated with reduced levels of cerebrospinal fluid (CSF) oxytocin over the first 3 years of life (68). Similarly, women who reported childhood emotional neglect showed significantly reduced levels of CSF oxytocin, as was also seen for other types of maltreatment but not for physical neglect (69). CSF concentrations were inversely correlated with scores for emotional neglect on the Childhood Trauma Questionnaire.

b) Dopaminergic System

Dopamine is a neurotransmitter associated with motivated behavior in both mother and offspring (19). Dopamine production in the nucleus accumbens of the VS appears to stimulate responsive maternal caregiving in the rat (64, 71). Pharmacologic blocking of dopamine D1 receptors in the nucleus accumbens results in disrupted pup retrieval and LG, and selective pharmacologic destruction of monoamine cells in the VTA also blocks maternal behavior (72, 73). Likewise, maternal behavior is severely impaired in dopamine-transporter knockout mice (74).

Dopaminergic neurons respond to temporally ordered prediction errors signals, facilitating stimulus-reward learning in the brain (75). These signals generally originate in the VTA and substantia nigra (SN) of the midbrain and project to a variety of regions throughout the brain, including the VS, dorsal striatum, prefrontal and anterior cingulate cortex (75) (Figure 3). In humans, unpredictable randomly delivered reward stimuli activate the mesocorticolimbic system (VS and medial prefrontal cortex) (76)

There are corresponding connections between the striatum and the forebrain, including those involved in affect processing (medial prefrontal, anterior cingulate) and cognition (dorsolateral prefrontal). Thus, the striatum is believed to be an important relay station between the limbic and motor systems, integrating affective information from limbic regions with cognitive information from the prefrontal cortex, in shaping motor/behavioral responses (Figure 3).

There is evidence to suggest that the development of these dopaminergic circuits is influenced by early developmental stimulation. For example, prolonged maternal separation and isolation rearing of rat pups results in reduced dopamine transporter binding in the VS, elevated baseline dopamine levels and increased dopamine release in response to acute stress in adulthood (79, 80). These animals also show enhanced sensitivity to psychostimulants such as cocaine, which activate dopaminergic neurons, and this may lead to increased vulnerability to addiction (80).

A human PET study likewise showed that low self-reported maternal care was associated with an elevated dopamine response to stress in the VS (46). High LG dams (who received high levels of maternal care in infancy (64)) also demonstrate enhanced dopamine release—but in response to infant cues rather than stressors (71), while their physiological stress response is dampened (45).

Thus, early maternal caregiving appears to play an important role in programming both the oxytocinergic and dopaminergic neuroendocrine systems in infancy, which then supports maternal behavior in adulthood (Figure 2). A disruption in these systems at any point in the lifespan may predispose to maternal neglect.

c) How oxytocin and dopamine connect

Understanding how these two systems interact and communicate is also important in understanding possible etiologies of maternal neglect.

From animal studies, we learn that oxytocinergic circuits are directly linked with the mesocorticolimbic dopamine pathway, with oxytocinergic neurons projecting from the hypothalamic PVN and MPOA to both the VTA and the VS (see Figure 3). The strength of these connections is associated with levels of maternal caregiving behavior, with high LG rat dams having an increased number of oxytocin neurons in the MPOA that project to the VTA (81). An oxytocin infusion in the VTA results in increased dopamine signal in the VS, which signal is blocked by an oxytocin antagonist (81). Maternal LG responses follow the rise in dopamine signal, suggesting that dopamine may trigger the onset of maternal behavior (71).

A direct oxytocinergic connection between the hypothalamus and the VS has also been demonstrated (82), and oxytocin receptor density in the VS is positively associated with levels of maternal behavior (83).

During pregnancy and lactation, oxytocin gene expression increases in areas associated with maternal behavior, including the dopaminergic SN (84), and both oxytocin and dopamine levels increase in the SN during suckling (85).

Addiction studies have also linked oxytocin with the mesocorticolimbic dopamine system. Chronic administration of drugs of abuse, such as cocaine, substantially reduces oxytocin levels in the hypothalamus, while acute administration decreases oxytocin in the VS (86).

Conversely, oxytocin may assist in ameliorating addiction and drug withdrawal effects via connections with mesocorticolimbic pathways (see reviews, 54, 87). These findings are significant in view of the strong association between addiction and maternal neglect (88).

Thus, infant cues, such as suckling, vocalization and tactile stimulation, stimulate oxytocin release in the hypothalamus, which may result in activation of the dopaminergic reward pathway and lead to behavioral reinforcement and long-term conditioned preference to social cues.

Exploring attachment in the human brain using functional MRI

Functional MRI (fMRI) is a non-invasive brain imaging technique that has enabled us to explore maternal brain responses in humans. Over the past decade, several fMRI studies have explored maternal brain responses to infant cues, including infant faces and cries (89). Lorberbaum and colleagues were the first to examine maternal brain response to a standard infant cry, which revealed activation of many of the same regions identified in rodent models of maternal behavior, including the hypothalamic region, SN, striatum and medial prefrontal cortex (90).

In our first study, 28 first-time normative mothers were shown 60 novel face images of their own infant, with happy, neutral or sad affect, and a matched unknown infant (93). When mothers viewed their own infant’s face, compared to an unknown infant face, key dopamine-associated reward processing regions of the brain were activated, including mesocorticolimbic pathways (VTA, VS and medial prefrontal cortex) and nigrostriatal pathways (SN, dorsal striatum and dorsolateral prefrontal cortex) (Figure 3).

Our next goal, therefore, was to test for individual and group differences in maternal neuroendocrine responses, in order to better understand differences that may occur in maternal neglect. We hypothesized that the mesocorticolimbic and nigrostriatal dopaminergic pathways would be differentially activated depending on the mother’s adult attachment classification (based on the AAI). We also looked for differences in peripheral oxytocin response, during mother-infant interaction. We compared 15 mothers with “secure” attachment and 15 with “insecure/dismissing” patterns.

Compared with “secure” mothers, those with an “insecure/dismissing”  pattern of adult attachment showed significantly less activation of the VS and medial prefrontal cortex bilaterally, when viewing their own infants’ happy faces (Figure 4A). While “secure” mothers also activated the ventral striatum on viewing their own infant’s crying faces, “insecure/dismissing” mothers showed more activation of the dorsolateral prefrontal cortex (Figure 4B) and the insula

Thus, compared to “secure” mothers, “insecure/dismissing” mothers showed relatively reduced activation of mesocorticolimbic pathways, but increased activation of the nigrostriatal pathway (Figure 3 and ​4).

Figure 4

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Furthermore, mothers with insecure/dismissing attachment, compared to “secure” mothers, showed reduced peripheral oxytocin production on interacting with their infant (Figure 5A), with oxytocin response correlated with brain activation in the hypothalamus and VS, key oxytocinergic and dopaminergic brain regions (Figure 5B). This suggests that mothers with an insecure/dismissing pattern of attachment may have impaired peripheral and central oxytocin production, which may help account for reduced activation of reward processing regions in the brain when presented with facial cues from their infant (Figure 3).

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These findings, although correlational, also suggest that oxytocin may help to drive activation of the mesocorticolimbic pathway in response to social cues in securely attached mothers, just as in high LG rodent dams (81)(Figure 3). Breastfeeding, which results in a surge of endogenous oxytocin, is also associated with increased activation of the striatum when mothers hear their own infant’s cry (97), as is suckling in rodents (21). In a large 15-year longitudinal follow-up study of over 7000 mother-infant dyads, the duration of breastfeeding was inversely associated with risk of subsequent state-reported maternal neglect (11).

Another currently funded study is examining maternal brain responses in a clinical population at high risk for maternal neglect—mothers with substance abuse disorders (88,98, 99). We are exploring how early attachment experience may increase vulnerability to addiction and how both insecure attachment and substance abuse may impact on maternal brain and behavioral responses to infant cues.

Thus, adaptation of the oxytocin and dopamine systems—whether through a mother’s own early childhood experience, stress during pregnancy or even breastfeeding experience—may lead to variation in infant and adult attachment, and maternal brain and endocrine responses (Figure 2). Understanding this cycle in humans may help us to better define and ultimately prevent maternal neglect.

Insecure/dismissing attachment, may involves an inherent deficit in affective information processing (25).


1. Strathearn, L. (2011). Maternal Neglect: Oxytocin, Dopamine and the Neurobiology of Attachment. Journal of Neuroendocrinology, 23(11), 1054–1065. doi:10.1111/j.1365-2826.2011.02228.x



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