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The transition to motherhood is marked by significant change at both biological and psychological levels, facilitating the development of maternal behavior. Interdisciplinary research converge to highlight the plasticity of the maternal brain, and the interplay of neurophysiology and postpartum experience, in shaping maternal brain and behavior. In this issue, new directions on the topic of the plasticity of the maternal brain is discussed by internationally renowned experts. Taking a lifespan developmental and crossspecies perspective, it highlights biological and environmental influences, including neuroendocrine events around parturition and offspring interactions, in shaping Maternal Brain Plasticity. This issue highlights the importance of maternal periods of neural plasticity as optimal temporal windows for targeted interventions in families to foster maternal behavior and child development. This provides a unique opportunity to synergistically bring together research scientists with clinical teams that routinely work with mothers and their children to support and prosper the dyadic relationship through innovative translational research programs. This is the 153rd volume in this Jossey-Bass series New Directions for Child and Adolescent Development. Its mission is to provide scientific and scholarly presentations on cutting edge issues and concepts in this subject area. Each volume focuses on a specific new direction or research topic and is edited by experts from that field.

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New Directions for Child and Adolescent Development

Elena L.Grigorenko EDITOR-IN-CHIEF

William Damon FOUNDING EDITOR

Maternal Brain Plasticity: Preclinical and Human Research and Implications for Intervention

Helena J. V. Rutherford Linda C. Mayes EDITORS

Number 153 • Summer 2016

Jossey-Bass

San Francisco

MATERNAL BRAIN PLASTICITY: PRECLINICAL AND HUMAN RESEARCH AND IMPLICATIONS FOR INTERVENTION

Helena J. V. Rutherford, Linda C. Mayes (eds.) New Directions for Child and Adolescent Development, no. 153Elena L. Grigorenko, Editor‐in‐Chief

© 2016 Wiley Periodicals, Inc., A Wiley Company. All rights reserved.

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NEW DIRECTIONS FOR CHILD AND ADOLESCENT DEVELOPMENT is part of The Jossey-Bass Education Series and is published quarterly by Wiley Subscription Services, Inc., a Wiley company, at Jossey-Bass, One Montgomery Street, Suite 1200, San Francisco, CA 94104-4594. Postmaster: Send address changes to New Directions for Child and Adolescent Development, Jossey-Bass, One Montgomery Street, Suite 1200, San Francisco, CA 94104-4594.

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EDITORIAL CORRESPONDENCE should be e‐mailed to the editor‐in‐chief: Elena L. Grigorenko (elena.grigorenko@yale.edu).

Jossey‐Bass Web address: www.josseybass.com

Elena L. Grigorenko, Editor-in-Chief Yale University, USA

Editorial Board

Baptiste Barbot, PhD

David D. Preiss, PhD

Pace University, USA

Pontificia Universidad Católica de Chile, Chile

Linda Jarvin, PhD

Peggy McCardle, PhD, MPH

Paris College of Art, France

Peggy McCardle Consulting, LLC, USA

Fumiko Hoeft, MD, PhD

Jens F. Beckmann, Dr. rer. nat.

University of California San Francisco, USA

Durham University, UK

CONTENTS

Introduction to Maternal Brain Plasticity: Preclinical and Human Research and Implications for Intervention

1: Plasticity of the Maternal Brain Across the Lifespan

Introduction

Prenatal Influence on the Maternal Brain

Plasticity of the Juvenile Maternal Brain

Experiences in Adulthood and the Quality of Mother–Infant Interactions

Conclusions

References

2: Structural and Functional Plasticity in the Maternal Brain Circuitry

Introduction

Maternal (Brain) Plasticity: Interplay Between Maternal Hormones and Social Experience

Maternal Hormones and Plasticity

Social (Sensory) Experience and Plasticity

Dynamic Reorganization of the Maternal Circuitry

Neuroplasticity in Fathers

Conclusions and Implications

Acknowledgments

References

3: Human Maternal Brain Plasticity: Adaptation to Parenting

Psychological Adaptation to Parenting

Functional Plasticity of the Maternal Brain

Structural Plasticity of the Maternal Brain

Relations of Maternal Neural Plasticity With Parenting Behaviors

Conclusion and Implications for At-Risk Mothers

Acknowledgments

References

4: Oxytocin and Maternal Brain Plasticity

Overview of the Oxytocin System

Oxytocin-Related Plasticity During Pregnancy and the Postpartum Period

Factors Influencing Oxytocin-Related Maternal Brain Plasticity

Variations in Oxytocin Function and Adaptation to Motherhood

Pharmacological Effects of Oxytocin: A Novel Treatment for Adaptation to Motherhood?

Author Note

References

5: A Preliminary Review of Whether Prior Reproductive Experience Influences Caregiving

Maternal Caregiving Behavior and Response to Infants

Neurobiological Changes

Hormonal Changes

Limitations and Future Directions

Summary and Implications

References

6: Sensitive Periods of Emotion Regulation: Influences of Parental Care on Frontoamygdala Circuitry and Plasticity

Sensitive Periods and Development of Frontoamygdala Circuitry

Impact of Parental Buffering on Emotional Reactivity and Frontoamygdala Circuitry

Impact of Parental Deprivation on the Development of Frontoamygdala Circuitry and Function

Potential Benefits and Consequences of Accelerated Development Following Parental Deprivation

Conclusions

References

7: Translational Neuroscience as a Tool for Intervention Development in the Context of High-Adversity Families

The Social Learning Model as an Application of an Experimental Approach to Family-Based Interventions

Extension of the Coercion Model to Incorporate Neurobiological Domains

Adequacy of the Evidence for Translational Neuroscience and Practice, and Implications for the Field

Notes

References

Order Form

Index

End User License Agreement

List of Illustrations

Chapter 1

Figure 1.1

The maternal brain

Chapter 4

Figure 4.1

Oxytocin-related maternal brain plasticity

Chapter 6

Figure 6.1

Developmental switch in frontoamygdala connectivity (adapted from Gee, Humphreys et al., 2013). A developmental switch from positive to negative functional connectivity between the amygdala and mPFC was observed during the transition from childhood to adolescence in typically developing youth. Younger children displayed positive functional connectivity, which became more strongly negative from adolescence to young adulthood.

Figure 6.2

Parental buffering of frontoamygdala circuitry specific to childhood (adapted from Gee et al., 2014). (A) Presence of the maternal stimulus phasically buffered right amygdala reactivity in children but not adolescents. Specifically, children showed lower activation of the right amygdala to their mother compared with a stranger. (B) Adolescents showed a pattern of negative amygdala–mPFC functional connectivity to both their mother and the stranger. In contrast, children exhibited the negative pattern of functional connectivity (typically only observed at older ages) to their mother but not the stranger.

Figure 6.3

Social buffering of emotional reactivity across the lifespan. Parental buffering has unique regulatory effects on emotional reactivity during infancy (rodents) and childhood (humans). Social buffering continues across the lifespan, with different relationships serving a regulatory function at distinct developmental timepoints (e.g., peer influences in adolescence, partner influences in adulthood). Due to heightened plasticity to caregiving influences early in life, parental care is especially likely to play a strong role in shaping the development of frontoamygdala circuitry and function.

Figure 6.4

Accelerated development of frontoamygdala functional connectivity following parental deprivation (adapted from Gee, Gabard-Durnam et al., 2013a). Left) A group by emotion interaction was observed in the mPFC, such that group differences emerged when participants viewed fearful faces. Right) Unlike comparison children who showed immature (positive) amygdala-mPFC connectivity, children with a history of early-life stress (previous institutionalized care) exhibited negative amygdala-mPFC coupling, such that the stressed children resembled adolescents. The results suggest an early closure of a sensitive period in frontoamygdala development following parental deprivation.

Chapter 7

Figure 7.1

Extension of the experimental medicine approach for family-based interventions to translational neuroscience research

Figure 7.2

The conceptual model guiding TFCO-P

Figure 7.3

Evidence for the TFCO-P Conceptual Model (thicker arrows denote stronger evidence of associations

Guide

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INTRODUCTION TO MATERNAL BRAIN PLASTICITY: PRECLINICAL AND HUMAN RESEARCH AND IMPLICATIONS FOR INTERVENTION

The transition to motherhood is a period accompanied by significant change at both biological and psychological levels that facilitate the onset and development of maternal behavior. Interdisciplinary programs of research converge in highlighting the plasticity of the maternal brain, and the interplay of neurophysiology and postpartum experience, in shaping maternal brain and behavior. In this issue, Champagne and Curley begin by describing developmental changes in the hypothalamic and dopaminergic systems relevant to maternal behavior across the lifespan. This lifespan developmental perspective highlights the importance of considering biological and environmental influences on shaping female brain development in the periods before, during, and after the transition to motherhood. Pereira advances this work by highlighting how neuroendocrine events around parturition first influence gene expression important to maternal brain and behavior, with ongoing offspring interactions shaping maternal brain plasticity in the postpartum.

With respect to human research, Kim presents an overview of the structural and functional changes in the maternal brain that have been observed in human mothers during pregnancy and the postpartum period. The research discussed focuses primarily on maternal behavioral and neural responses to infant socio-emotional signals (e.g., facial expressions, cries), and also documents the increasing vigilance to threat measured during pregnancy that slowly diminishes during the postpartum period—perhaps offering an adaptive significance to offspring survival during the very vulnerable first weeks and months. Kim and Strathearn focus on the role of the oxytocin system in regulating maternal brain plasticity, considering the apparent reorganization of the oxytocin system during pregnancy and the postpartum period that has been observed across species. The authors consider data from studies examining both circulating levels of oxytocin and recent work examining the administration of oxytocin in human subjects. Notably, many studies of human and nonhuman caregiving overlook the potential role of prior reproductive experience in shaping maternal brain and behavior. Maupin and colleagues review the literature across species that evidences the importance of parity, and argue that the first pregnancy and postpartum period may lay the foundation for subsequent reproductive experiences. Therefore, the period of neural plasticity for primiparous mothers may be a uniquely sensitive time for parenting interventions to harness the changing maternal neurobiology, and for these intervention approaches to recognize the importance of prior reproductive experiences in shaping maternal brain and behavior when engaging multiparous mothers.

Although this period of plasticity may be advantageous, for mothers in whom plasticity may be compromised and/or the postpartum experience negative, there may be detrimental consequences for both members of the dyad. Gee describes plasticity of the emerging frontolimbic circuitry in offspring across species that may be sensitive to caregiver influence. This neurocircuitry plays a critical role in affect regulation, with disruption during early development having lasting detrimental consequences for the child. Therefore recognizing critical periods of plasticity for both mother and child is warranted, highlighting the importance of these neurobiological studies to intervention efforts. Consistent with this notion, Fisher describes translational strategies in advancing our understanding of how early adversity can impact the child's neurobiology, and how this knowledge can be utilized in intervention work with children and families.

In sum, maternal periods of neural plasticity may identify optimal temporal windows for targeted interventions in families to foster maternal behavior and child development. This provides a unique opportunity to synergistically bring together the research scientists with the clinical teams that routinely work with mothers and their children to support and prosper the dyadic relationship through innovative translational programs of research.

Helena J. V. RutherfordLinda C. Mayes

 

 

 

Helena J. V. Rutherford, PhD

,

Assistant Professor, Yale Child Study Center.

Linda C. Mayes, MD

,

Arnold Gesell Professor of Child Psychiatry, Pediatrics, and Psychology, Director, Yale Child Study Center; Special Advisor to the Dean, Yale School of Medicine; Distinguished Visiting Professor of Psychology, Sewanee: The University of the South.

Champagne, F. A., & Curley, J. P., (2016). Plasticity of the maternal brain across the lifespan. In H. J. V. Rutherford & L. C. Mayes (Eds.), Maternal brain plasticity: Preclinical and human research and implications for intervention. New Directions for Child and Adolescent Development, 153, 9–21.

 

1Plasticity of the Maternal Brain Across the Lifespan

Frances A. Champagne, James P. Curley

Abstract

Maternal behavior is dynamic and highly sensitive to experiential and contextual factors. In this review, this plasticity will be explored, with a focus on how experiences of females occurring from the time of fetal development through to adulthood impact maternal behavior and the maternal brain. Variation in postpartum maternal behavior is dependent on estrogen sensitivity within the medial preoptic area of the hypothalamus and activation within mesolimbic dopamine neurons. This review will discuss how experiences across the lifespan alter the function of these systems and the multigenerational consequences of these neuroendocrine and behavioral changes. These studies, based primarily on the examination of maternal behavior in laboratory rodents and nonhuman primates, provide mechanistic insights relevant to our understanding of human maternal behavior and to the mechanisms of lifelong plasticity. © 2016 Wiley Periodicals, Inc.

Introduction

Maternal behavior is dynamic and highly sensitive to experiential and contextual factors. This plasticity allows mothers to adapt to the changing developmental needs of offspring and promotes reproductive success. Maternal behavioral complexity is mediated by multiple neural and endocrine systems that promote hormone sensitivity, responsivity to offspring cues, and motivation to engaging in parental care (Jensen & Champagne, 2012). In particular, mammalian maternal behavior is dependent on estrogen sensitivity within the medial preoptic area of the hypothalamus (MPOA) and activation within mesolimibic dopamine (DA) neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (see Figure 1.1; see Numan, 2007). These systems account for the behavioral changes observed in females as they transition from pregnancy to the postpartum period (Brunton & Russell, 2008) and for individual differences between mothers in the frequency and quality of maternal care (Jensen & Champagne, 2012). Plasticity within these systems is evident across the lifespan and likely accounts for the sensitivity of maternal behavior to the quality of the environment. Here, research will be highlighted linking the experiences of females from the time of fetal development through to adulthood on maternal behavior and to changes within the MPOA and mesolimbic DA circuits. These studies, based primarily on the examination of maternal behavior in laboratory rodents and nonhuman primates, provide mechanistic insights relevant to our understanding of human maternal behavior and to the mechanisms of lifelong plasticity. This research also highlights the multigenerational consequences of environmentally induced changes in maternal behavior and the maternal brain.

Figure 1.1 The maternal brain

In the rodent brain, maternal behavior is regulated by hormone sensitive hypothalamic regions (medial preoptic area—MPOA) projecting to dopaminergic systems involved in motivated behavior (see Numan, 2007): midbrain dopamine (DA) neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). DRs, dopamine receptors; ERs, estrogen receptors; OT, oxytocinergic neurons; OTR, oxytocin receptors.

Prenatal Influence on the Maternal Brain

The prenatal period is a time of dynamic change within the brain of the fetus. Studies in female rodents suggest that expression of estrogen receptors within the MPOA emerge in mid to late gestation and reach adult-like levels at the time of birth (Vito & Fox, 1981). Midbrain DA neuron proliferation is also increasing during this stage of development and by the time of birth, the numbers of DA neurons projecting from the VTA in the female rodent brain is at the level observed in adulthood (Lieb et al., 1996). Thus, disruption to these systems prenatally (i.e., through exposure to stress or endocrine-disrupting chemicals), can result in long-term consequences for maternal behavior.

Prenatal Stress and the Developing Maternal Brain

Fetal exposure to stress in female rodents has consequences for motherhood, resulting in reductions in maternal behavior, reduced pup retrieval (Fride, Dan, Gavish, & Weinstock, 1985; Kinsley & Bridges, 1988), reduced nest-building (Kinsley & Svare, 1988), reduced contact and nursing of offspring (Bosch, Musch, Bredewold, Slattery, & Neumann, 2007), reduced pup licking/grooming (LG) (Champagne & Meaney, 2006), and increased infanticide (Perez-Laso et al., 2008). The mechanisms through which these behavioral outcomes are mediated are likely complex. Increased depression and anxiety-like behavior are also a consequence of prenatal stress and may inhibit the motivation to care for offspring or decrease sensitivity to offspring cues (Bosch et al., 2007; Coulon, Levy, Ravel, Nowak, & Boissy, 2014). Prenatal stress also impacts sexual dimorphism and the reduced maternal behavior exhibited by prenatally stressed female rodents may reflect a more masculinized pattern of parental behavior (Altman & Bayer, 1978; Kinsley & Svare, 1988). Though nonstressed female rodents typically provide more parental care toward offspring than nonstressed males, this sex difference is ablated following prenatal stress (Perez-Laso et al., 2008).

Stress-induced disruption to developing hypothalamic and DA circuits may be particularly relevant to our understanding of prenatal influence on the maternal brain. Levels of estrogen receptors within the MPOA are masculinized within the brain of prenatally stressed females (i.e., increased in stressed females) as are circulating levels of estrogen, which are decreased in prenatally stressed females (Del Cerro, Ortega, Gomez, Segovia, & Perez-Laso, 2015). Prenatal stress alters the activity of midbrain DA neurons (Hausknecht, Haj-Dahmane, & Shen, 2013; Kaiser, Kruijver, Swaab, & Sachser, 2003), increases levels of the DA transporter within striatal regions (Converse et al., 2013), and increases DA release in the nucleus accumbens (Alonso, Navarro, Santana, & Rodriguez, 1997). These outcomes in adulthood may be a consequence of prenatal stress-induced alterations in the developmental expression of transcription factors involved in DA neuron differentiation and survival, namely Nurr1 and Pitx3 (Baier, Katunar, Adrover, Pallares, & Antonelli, 2012; Sousa et al., 2007; Volpicelli et al., 2007). Expression of Nurr1 is increased in the VTA of prenatally stressed female rat offspring at postnatal day 7 and this effect persists through adolescence and into adulthood. Pitx3 expression in the VTA is decreased transiently in adolescence and then increases in the adult brain of prenatally stressed female offspring (Katunar, Saez, Brusco, & Antonelli, 2010). Collectively, these neuroendocrine effects of prenatal stress may reduce the activation of hormone-dependent systems within the brain that increase maternal motivation. Increasing the levels of circulating estrogen in prenatally stressed females restores motivated behavior and functioning within DA circuits (Reynaert et al., in press)—a finding that also highlights the interplay between hypothalamic/endocrine systems and DA neurons.

Prenatal Endocrine Disruption of the Maternal Brain

The hormonal environment experienced by the fetus can shape developing neural circuits with consequence for sexually dimorphic behaviors and social development. For example, in humans, elevated in utero testosterone levels are predictive of social relationships and may serve as a risk factor for the development of autism (Auyeung, Taylor, Hackett, & Baron-Cohen, 2010; Knickmeyer, Baron-Cohen, Raggatt, & Taylor, 2005). Studies of the impact of fetal exposure to endocrine-disrupting chemicals in rodents confirm the critical role of prenatal hormones in shaping social and reproductive behavior (Rosenfeld, 2015). In mice, gestational exposure to bisphenol A (BPA), an endocrine-disrupting chemical used in the manufacture of plastics, which likely acts as an antagonist/agonist at estrogen receptors (Wetherill et al., 2007), results in reduced contact with pups by adult female offspring (Palanza, Howdeshell, Parmigiani, & vom Saal, 2002). Similar to the case of prenatal stress, disruption to hypothalamic and DA circuits may mediate BPA-induced effects on maternal behavior. Midbrain DA projections are decreased in nonhuman primate offspring prenatally exposed to BPA (Elsworth, Jentsch, Vandervoort, Roth, & Leranth, 2013) and DA receptor binding within limbic regions of the mouse brain is decreased following prenatal exposure to BPA (Mizuo, Narita, Yoshida, Narita, & Suzuki, 2004). Expression of estrogen-receptor alpha (Esr1) and beta (Esr2) is altered in the neonatal hypothalamus in rats prenatally exposed to BPA (Cao et al., 2013) and nonlinear dose-dependent effects of prenatal BPA have been observed on both Esr1 and Esr2 mRNA levels within the hypothalamus of adult female mice (Kundakovic et al., 2013). These gene expression changes are associated with epigenetic variation—decreased DNA methylation—of the Esr1 gene in the female hypothalamus (Kundakovic et al., 2013), which may account for the stable maintenance of these hypothalamic changes into adulthood.

Postnatal Sensitivity of the Maternal Brain

Hypothalamic and dopaminergic pathways involved in the regulation of maternal behavior continue to develop following birth, extending the sensitivity of the maternal brain and behavior to the postnatal period. In humans, the quality of attachment relationships and parental bonding established during this period is predictive of the quality of caregiving observed in adulthood (Benoit & Parker, 1994; Miller, Kramer, Warner, Wickramaratne, & Weissman, 1997). In rodents, the quality of mother–infant interactions occurring during the postnatal period has long-term effects on the hypothalamic-pituitary-adrenal response to stress, cognition, and social/reproductive behavior (Meaney, 2001). Female rats that receive elevated levels of LG during the first week postpartum engage in higher levels of LG toward their own offspring (Champagne, Francis, Mar, & Meaney, 2003). In rats, brief periods of maternal separation, which stimulates maternal care, leads to increased maternal LG in female offspring (Francis, Diorio, Plotsky, & Meaney, 2002). Female mice reared in a communal nest receive elevated levels of LG and in adulthood exhibit elevated LG and nursing (Curley, Davidson, Bateson, & Champagne, 2009). In contrast, disruptions to the quality of care received during infancy are predictive of reduced maternal care in female offspring. Female rats reared under conditions of complete maternal deprivation (artificially reared: AR), engage in reduced pup retrieval and decreased frequencies of LG and nursing compared to mother-reared females (Gonzalez, Lovic, Ward, Wainwright, & Fleming, 2001). These observed deficits in maternal behavior can be partially ameliorated if females are provided with licking-like tactile stimulation during the postnatal period. In rhesus monkeys, postnatal maternal deprivation leads to impaired maternal behavior of offspring, with deprived females exhibiting reduced overall contact with offspring and reduced maternal competency (Seay, Alexander, & Harlow, 1964).

Prolonged postnatal maternal separation in rodents reduces frequency of nursing and LG exhibited by female offspring. Among rodent females that experience both reduced nurturing maternal care (i.e., nursing and LG) and increased abusive care (i.e., stepping on and dragging), there is an increased frequency of abusive care observed in adulthood (Roth, Lubin, Funk, & Sweatt, 2009)—a phenomenon also observed in abused nonhuman primates (Maestripieri, 2005). The impact of mothering on the maternal behavior of offspring leads to the multigenerational transmission of maternal behavior that has been observed in humans (Benoit & Parker, 1994; Miller et al., 1997), nonhuman primates (Fairbanks, 1989; Maestripieri, 2005; Maestripieri, Wallen, & Carroll, 1997), and rodents (Champagne et al., 2003; Fleming et al., 2002).

The modulating effects of maternal care received during infancy on the brain may account for the multigenerational effects of postnatal maternal behavior. Female offspring that experience elevated levels of LG (high LG compared to low LG) have increased expression of Esr1 in the MPOA in adulthood and increased estrogen sensitivity within this brain region (Champagne, Diorio, Sharma, & Meaney, 2001; Pena, Neugut, & Champagne, 2013). These changes in the MPOA emerge during the first week postnatal and are likely maintained through changes in DNA methylation within the Esr1 gene (Pena et al., 2013). Cross-fostering studies indicate that the expression of Esr1 within the MPOA is determined by the level of LG experienced prior to postnatal day 10, suggesting a sensitive period within postnatal development (Pena et al., 2013). Artificial rearing likewise impacts the MPOA, resulting in reduced c-fos activation following exposure to pups and decreased hormone sensitivity in AR-reared female offspring (Gonzalez & Fleming, 2002; Novakov & Fleming, 2005). Within developing mesolimbic DA pathways, high levels of LG lead to increased DA neuron projections from the VTA and elevated expression of DA receptors within the nucleus accumbens (Pena, Neugut, Calarco, & Champagne, 2014). During the postnatal period, females that receive high levels of LG have elevated levels of expression of Cdkn1c and the transcription factor Lmx1b within the VTA (Pena et al., 2014). These two factors may shape the DA system through effects on cell proliferation, survival, and interactions with other factors, such as Nurr1, that exert a developmental influence on DA neurons (Joseph et al., 2003; Smidt et al., 2000). Postnatal maternal deprivation (AR vs. MR) is associated with elevated basal DA release and reduced pup-associated DA elevations within the nucleus accumbens (Afonso, King, Novakov, Burton, & Fleming, 2011). Similar to the case of prenatal stress effects on DA function, the long-term effects of maternal deprivation on the DA system can be ameliorated following hormonal treatments (Afonso et al., 2011). This interplay between DA function and hormones is also evident following targeted manipulation of the levels of Esr1 within the MPOA. Increasing Esr1 in the MPOA of female offspring during the first week postnatal results in increased maternal behavior and increased numbers of DA neurons projecting from the VTA (Pena & Champagne, 2014). Thus, rather than developing independently, these systems are interacting throughout the postnatal period, and this interplay likely accounts for the hormonal influence on maternal motivation.

Plasticity of the Juvenile Maternal Brain

Adolescence is a period of hormonal change characterized by continued refinement of the nervous system and emergence of adult-like patterns of behavior. Neural systems regulating self-control and reward salience within the adolescent brain have yet to reach maturity resulting in functional consequences that may impact risk-taking behavior and response to social stimuli (Casey, 2015). Though experiences during this period can impact brain function and reverse the effects of early-life maternal separation (Francis et al., 2002; Vivinetto, Suarez, & Rivarola, 2013), less is known regarding the specific impact of this period on maternal behavior and associated neuroendocrine systems. Among female rats reared by low LG dams, the experience of social enrichment (social and environmental complexity) during the juvenile/post weaning period results in increased LG (Champagne & Meaney, 2007). In contrast, female rats that have experienced high levels of postnatal LG will engage in low levels of LG in adulthood following juvenile/post weaning social isolation. These juvenile experiences ameliorate postnatal rearing effects on later maternal behavior and lead to altered levels of oxytocin receptor (Otr) levels within the hypothalamus and amygdala (Champagne & Meaney, 2007). However, it is not known how these experiences shape dopaminergic function or hypothalamic expression of Esr1.

Experiences in Adulthood and the Quality of Mother–Infant Interactions

Despite an overall reduction in plasticity that is associated with progression into adulthood, the transition to motherhood is a time of heightened neuroendocrine and behavioral change. Childbirth and lactation involve restructuring of hypothalamic neurons and variation in circulating estrogens, progesterone, prolactin, and other hormones/neuropeptides that facilitate heightened sensitivity to infant cues (Brunton & Russell, 2008). This period of hormonal fluctuation can also lead to altered mood and an increased susceptibility to psychiatric disorder. Thus, mothers enter into a sensitive period during which time experiences may have both short- and long-term effects on maternal behavior and the brain. Similar to the prenatal period, stress and exposure to BPA during the prepartum period in adult mothers impacts the quality of mother–infant interactions. In rats, gestational stress results in reduced postpartum LG, particularly the frequency of LG directed at male offspring (Champagne & Meaney, 2006; Moore & Morelli, 1979). This influence of gestational stress on postpartum maternal behavior may account for many of the phenotypes observed in prenatally stressed offspring (Moore & Power, 1986). Moreover, female rats stressed during gestation continue to engage in reduced maternal care toward subsequent litters (i.e., following nonstressed pregnancies) (Champagne & Meaney, 2006). Exposure to elevated levels of BPA during gestation results in altered postpartum maternal behavior in adult female rats and mice, leading to reduced frequency of nursing and LG of offspring (Boudalia et al., 2014; Della Seta, Minder, Dessi-Fulgheri, & Farabollini, 2005; Palanza et al., 2002). Similar to the case of BPA-associated effects in prenatally exposed offspring, nonlinear dose-dependent effects of BPA have been observed in mothers on measures of postpartum nursing and LG, with lower BPA doses decreasing maternal behavior and higher doses increasing both nursing and LG (Kundakovic et al., 2013). A consideration in the effects of both gestational stress and BPA on maternal behavior is exposure-induced changes in the behavior of offspring. Altered sexual dimorphism and social development in offspring may result in a decrease or augmentation of cues typically used by offspring to solicit maternal care (Nakagami et al., 2009).

The quality of the rearing environment—a factor that contributes significantly to offspring development—also results in changes to the behavior of mothers. Brief maternal separations stimulate increased LG behavior toward pups, particularly among low LG mothers (Francis, Diorio, Liu, & Meaney, 1999), whereas prolonged maternal separations between mother and pups leads to reduced LG (Boccia & Pedersen, 2001). These alterations in postpartum maternal behavior are associated with changes in hypothalamic levels of estrogen receptors and oxytocin receptors in the brain, with brief separations leading to increased Esr1, Esr2, and Otr in the MPOA (Stamatakis et al., 2015). In rats, removal of bedding material from the home-cage leads to a reduced frequency of nursing/contact, decreased LG, increased frequency of abusive caregiving, and more fragmented patterns of maternal behavior (i.e., frequent shifts between contact and noncontact behaviors). This experience leads to increased adrenal weights and basal plasma corticosterone levels—suggesting a state of chronic stress, which may inhibit females from engaging in maternal care (Ivy, Brunson, Sandman, & Baram, 2008). In contrast, lactating adult female mice that are placed together in a communal nest engage in elevated levels of nursing and LG. This increase in maternal behavior is particularly evident in mice strains that typically display reduced frequency of mother–infant interactions (Curley et al., 2009).

The experience of motherhood in adulthood results in a broad change in the biology of mothers which includes but is not limited to changes in the brain (see Bridges, 2016). Neural complexity is increased within both the nucleus accumbens and MPOA following maternal experience (Shams et al., 2012) and may contribute to the impact of motherhood on the quality of subsequent mother–infant interactions. In rhesus monkeys reared under conditions of maternal deprivation, impaired maternal behavior is observed in first-time mothers (primiparous). However, over subsequent births, maternal competency is increased and level of abusive behavior is decreased (Ruppenthal, Arling, Harlow, Sackett, & Suomi, 1976). In laboratory mice, it has been observed that, in contrast to primiparous mothers, multiparous females engage in reduced frequency of nursing with no alterations in frequency of LG. Though this finding is counterintuitive, given evidence that maternal experience leads to increased maternal motivation and reduced rejection of offspring (Dwyer & Smith, 2008; Ruppenthal et al., 1976), it is likely that increased efficiency of energy usage and lactation by multiparous females accounts for these effects (Kunkele & Kenagy, 1997). In multiparous females, there are significant brain changes that may account for the altered nurturance displayed by experienced mothers, including increased DA release in response to neonates (compared to inexperienced females) (Afonso, Grella, Chatterjee, & Fleming, 2008) and increased expression of Esr1, Otr, and opiate receptors in the MPOA (Akbari et al., 2013; Meurisse et al., 2005; Munetomo, Ishii, Miyamoto, Sakuma, & Kondo, 2015). Moreover, the experience of elevated circulating estrogens occurring during pregnancy may alter the functioning of DA pathways resulting in amelioration of deficits in maternal care observed in inexperienced mothers. These effects may also account for the recovery of maternal behavior observed in maternally deprived nonhuman primates following repeated pregnancies (Ruppenthal et al., 1976).

Conclusions

Dynamic changes in mother–infant interactions coincide with plasticity within neuroendocrine circuits that regulate maternal behavior. Beyond the classic prenatal and postnatal sensitive periods for neural development, it is clear that the maternal brain can be modified by experiences during adolescence and adulthood with consequences for the quality of mother–infant interactions. Viewing motherhood as a sensitive period may promote the development of interventions that alter hypothalamic and DA circuits and increase maternal responsiveness. Targeting these systems may have lasting and multigenerational consequences for mothers and offspring. Though much of our understanding of these processes is derived from animal models, the perspective generated by these studies may guide hormonal and neuroimaging studies in humans aimed at determining the mechanisms of plasticity within the human maternal brain. These studies may provide critical insights into how both hormonal and nonhormonal (i.e., experience-associated and cognitive) processes interact to influence caregiving behavior.

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