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Neurobiology of Parental Regulation of the Infant and Its Disruption by Trauma Within Attachment

Graf, Nina; Zanca, Roseanna M; Song, Wei; Zeldin, Elizabeth; Raj, Roshni; Sullivan, Regina M
The complex process of regulating physiological functions and homeostasis during external and internal disruptions develops slowly in altricial species, with parental care functioning as a co-regulator of infant physiological and emotional homeostasis. Here, we review our current understanding of the infant's use of parental behaviors for neurobehavioral regulation and its disruption with harsh parental care. Taking a cross-species view, we briefly review the human developmental literature that highlights the importance of the caregiver in scaffolding the child's physiological and emotional regulation, especially under threat and stress. We then use emerging corresponding animal literature within the phylogenetically preserved attachment system to help define neural systems supporting caregiver regulation and its supporting causal mechanism to provide translational bridges to inform causation and mechanisms impossible to define in children. Next, we briefly review animal research highlighting the impact of specific sensory stimuli imbedded in parental care as important for infant physiological and emotion regulation. We then highlight the importance of parental sensory stimuli gaining hedonic value to go beyond simple sensory stimuli to further impact neurobehavioral regulation, with poor quality of care compromising the infant's ability to use these cues for regulation. Clinically, parental regulation of the infant is correlated with later-life neurobehavioral outcome and quality of life. We suggest an understanding of this parental regulation of the infant's immediate neurobehavioral functioning within the context of attachment quality, that may provide insights into the complex processes during early life, initiating the pathway to pathology.
PMID: 35464143
ISSN: 1662-5153
CID: 5217252

The Neurobiology of Infant Attachment-Trauma and Disruption of Parent-Infant Interactions

Naeem, Nimra; Zanca, Roseanna M; Weinstein, Sylvie; Urquieta, Alejandra; Sosa, Anna; Yu, Boyi; Sullivan, Regina M
Current clinical literature and supporting animal literature have shown that repeated and profound early-life adversity, especially when experienced within the caregiver-infant dyad, disrupts the trajectory of brain development to induce later-life expression of maladaptive behavior and pathology. What is less well understood is the immediate impact of repeated adversity during early life with the caregiver, especially since attachment to the caregiver occurs regardless of the quality of care the infant received including experiences of trauma. The focus of the present manuscript is to review the current literature on infant trauma within attachment, with an emphasis on animal research to define mechanisms and translate developmental child research. Across species, the effects of repeated trauma with the attachment figure, are subtle in early life, but the presence of acute stress can uncover some pathology, as was highlighted by Bowlby and Ainsworth in the 1950s. Through rodent neurobehavioral literature we discuss the important role of repeated elevations in stress hormone corticosterone (CORT) in infancy, especially if paired with the mother (not when pups are alone) as targeting the amygdala and causal in infant pathology. We also show that following induced alterations, at baseline infants appear stable, although acute stress hormone elevation uncovers pathology in brain circuits important in emotion, social behavior, and fear. We suggest that a comprehensive understanding of the role of stress hormones during infant typical development and elevated CORT disruption of this typical development will provide insight into age-specific identification of trauma effects, as well as a better understanding of early markers of later-life pathology.
PMID: 35935109
ISSN: 1662-5153
CID: 5286492

Bidirectional control of infant rat social behavior via dopaminergic innervation of the basolateral amygdala

Opendak, Maya; Raineki, Charlis; Perry, Rosemarie E; Rincón-Cortés, Millie; Song, Soomin C; Zanca, Roseanna M; Wood, Emma; Packard, Katherine; Hu, Shannon; Woo, Joyce; Martinez, Krissian; Vinod, K Yaragudri; Brown, Russell W; Deehan, Gerald A; Froemke, Robert C; Serrano, Peter A; Wilson, Donald A; Sullivan, Regina M
Social interaction deficits seen in psychiatric disorders emerge in early-life and are most closely linked to aberrant neural circuit function. Due to technical limitations, we have limited understanding of how typical versus pathological social behavior circuits develop. Using a suite of invasive procedures in awake, behaving infant rats, including optogenetics, microdialysis, and microinfusions, we dissected the circuits controlling the gradual increase in social behavior deficits following two complementary procedures-naturalistic harsh maternal care and repeated shock alone or with an anesthetized mother. Whether the mother was the source of the adversity (naturalistic Scarcity-Adversity) or merely present during the adversity (repeated shock with mom), both conditions elevated basolateral amygdala (BLA) dopamine, which was necessary and sufficient in initiating social behavior pathology. This did not occur when pups experienced adversity alone. These data highlight the unique impact of social adversity as causal in producing mesolimbic dopamine circuit dysfunction and aberrant social behavior.
PMID: 34706218
ISSN: 1097-4199
CID: 5033412

Basolateral amygdala to posterior piriform cortex connectivity ensures precision in learned odor threat

East, Brett S; Fleming, Gloria; Vervoordt, Samantha; Shah, Prachi; Sullivan, Regina M; Wilson, Donald A
Odor perception can both evoke emotional states and be shaped by emotional or hedonic states. The amygdala complex plays an important role in recognition of, and response to, hedonically valenced stimuli, and has strong, reciprocal connectivity with the primary olfactory (piriform) cortex. Here, we used differential odor-threat conditioning in rats to test the role of basolateral amygdala (BLA) input to the piriform cortex in acquisition and expression of learned olfactory threat responses. Using local field potential recordings, we demonstrated that functional connectivity (high gamma band coherence) between the BLA and posterior piriform cortex (pPCX) is enhanced after differential threat conditioning. Optogenetic suppression of activity within the BLA prevents learned threat acquisition, as do lesions of the pPCX prior to threat conditioning (without inducing anosmia), suggesting that both regions are critical for acquisition of learned odor threat responses. However, optogenetic BLA suppression during testing did not impair threat response to the CS+ , but did induce generalization to the CS-. A similar loss of stimulus control and threat generalization was induced by selective optogenetic suppression of BLA input to pPCX. These results suggest an important role for amygdala-sensory cortical connectivity in shaping responses to threatening stimuli.
PMID: 34741138
ISSN: 2045-2322
CID: 5038602

Neurobiology of infant attachment: Nurturing and abusive relationships

Chapter by: Sullivan, Regina M.; Sullivan-Wilson, Tristan; Raineki, Charlis
in: Encyclopedia of Behavioral Neuroscience by
[S.l.] : Elsevier, 2021
pp. 254-263
ISBN: 9780128196410
CID: 5059262

Oxytocin neurons enable social transmission of maternal behaviour

Carcea, Ioana; Caraballo, Naomi López; Marlin, Bianca J; Ooyama, Rumi; Riceberg, Justin S; Mendoza Navarro, Joyce M; Opendak, Maya; Diaz, Veronica E; Schuster, Luisa; Alvarado Torres, Maria I; Lethin, Harper; Ramos, Daniel; Minder, Jessica; Mendoza, Sebastian L; Bair-Marshall, Chloe J; Samadjopoulos, Grace H; Hidema, Shizu; Falkner, Annegret; Lin, Dayu; Mar, Adam; Wadghiri, Youssef Z; Nishimori, Katsuhiko; Kikusui, Takefumi; Mogi, Kazutaka; Sullivan, Regina M; Froemke, Robert C
Maternal care, including by non-biological parents, is important for offspring survival1-8. Oxytocin1,2,9-15, which is released by the hypothalamic paraventricular nucleus (PVN), is a critical maternal hormone. In mice, oxytocin enables neuroplasticity in the auditory cortex for maternal recognition of pup distress15. However, it is unclear how initial parental experience promotes hypothalamic signalling and cortical plasticity for reliable maternal care. Here we continuously monitored the behaviour of female virgin mice co-housed with an experienced mother and litter. This documentary approach was synchronized with neural recordings from the virgin PVN, including oxytocin neurons. These cells were activated as virgins were enlisted in maternal care by experienced mothers, who shepherded virgins into the nest and demonstrated pup retrieval. Virgins visually observed maternal retrieval, which activated PVN oxytocin neurons and promoted alloparenting. Thus rodents can acquire maternal behaviour by social transmission, providing a mechanism for adapting the brains of adult caregivers to infant needs via endogenous oxytocin.
PMID: 34381215
ISSN: 1476-4687
CID: 4972632

Neurobiology of Infant Fear and Anxiety: Impacts of Delayed Amygdala Development and Attachment Figure Quality

Sullivan, Regina M; Opendak, Maya
Anxiety disorders are the most common form of mental illness and are more likely to emerge during childhood compared with most other psychiatric disorders. While research on children is the gold standard for understanding the behavioral expression of anxiety and its neural circuitry, the ethical and technical limitations in exploring neural underpinnings limit our understanding of the child's developing brain. Instead, we must rely on animal models to build strong methodological bridges for bidirectional translation to child development research. Using the caregiver-infant context, we review the rodent literature on early-life fear development to characterize developmental transitions in amygdala function underlying age-specific behavioral transitions. We then describe how this system can be perturbed by early-life adversity, including reduced efficacy of the caregiver as a safe haven. We suggest that greater integration of clinically informed animal research enhances bidirectional translation to permit new approaches to therapeutics for children with early onset anxiety disorders.
PMID: 33109337
ISSN: 1873-2402
CID: 4661112

Maternal continuous oral oxycodone self-administration alters pup affective/social communication but not spatial learning or sensory-motor function

Zanni, Giulia; Robinson-Drummer, Patrese A; Dougher, Ashlee A; Deutsch, Hannah M; DeSalle, Matthew J; Teplitsky, David; Vemulapalli, Aishwarya; Sullivan, Regina M; Eisch, Amelia J; Barr, Gordon A
BACKGROUND:The broad use/misuse of prescription opioids during pregnancy has resulted in a surge of infants with Neonatal Opioid Withdrawal Syndrome (NOWS). Short-term irritability and neurological complications are its hallmarks, but the long-term consequences are unknown. METHODS:A newly-developed preclinical model of oxycodone self-administration enables adult female rats to drink oxycodone (∼10/mg/kg/day) before and during pregnancy, and after delivery, and to maintain normal liquid intake, titrate dosing, and avoid withdrawal. RESULTS:Oxycodone was detected in the serum of mothers and pups. Growth parameters in dams and pups and litter mass and size were similar to controls. There were no differences in paw retraction latency to a thermal stimulus between Oxycodone and Control pups at postnatal (PN) 2 or PN14. Oxycodone and Control pups had similar motor coordination, cliff avoidance, righting time, pivoting, and olfactory spatial learning from PN3 through PN13. Separation-induced ultrasonic vocalizations at PN8 revealed higher call frequency in Oxycodone pups relative to Control pups (p<0.031; Cohen's d=1.026). Finally, Oxycodone pups displayed withdrawal behaviors (p's<0.029; Cohen's d's>0.806), and Oxycodone males only vocalized more than Control pups in the first minute of testing (p's<0.050; Cohen's d's>.866). Significant effects were corroborated by estimation plots. CONCLUSIONS:Our rat model of oral oxycodone self-administration in pregnancy shows exacerbated affect/social communication in pups in a sex-dependent manner but spared cognition and sensory-motor behaviors. This preclinical model reproduces selective aspects of human opioid use during pregnancy, enabling longitudinal analysis of how maternal oxycodone changes emotional behavior in the offspring.
PMID: 33761428
ISSN: 1879-0046
CID: 4851142

Infant Attachment and Social Modification of Stress Neurobiology

Packard, Katherine; Opendak, Maya; Soper, Caroline Davis; Sardar, Haniyyah; Sullivan, Regina M
Decades of research have informed our understanding of how stress impacts the brain to perturb behavior. However, stress during development has received specific attention as this occurs during a sensitive period for scaffolding lifelong socio-emotional behavior. In this review, we focus the developmental neurobiology of stress-related pathology during infancy and focus on one of the many important variables that can switch outcomes from adaptive to maladaptive outcome: caregiver presence during infants' exposure to chronic stress. While this review relies heavily on rodent neuroscience research, we frequently connect this work with the human behavioral and brain literature to facilitate translation. Bowlby's Attachment Theory is used as a guiding framework in order to understand how early care quality impacts caregiver regulation of the infant to produce lasting outcomes on mental health.
PMID: 34483852
ISSN: 1662-5137
CID: 5011912

Defining Immediate Effects of Sensitive Periods on Infant Neurobehavioral Function

Sullivan, Regina M; Opendak, Maya
During a sensitive period associated with attachment, the infant brain has unique circuitry that enables the specialized adaptive behaviors required for survival in infancy. This infant brain is not an immature version of the adult brain. Within the attachment relationship, the infant remains close (proximity seeking) to the caregiver for nurturing and survival needs, but the caregiver also provides the immature infant with the physiological regulation interaction needed before self-regulation matures. Here we provide examples from the human and animal literature that illustrate some of these regulatory functions during sensitive periods, recent advances demonstrating the supporting transient neural mechanisms, and how these systems go awry in the absence of species-expected caregiving.
PMID: 33043102
ISSN: 2352-1546
CID: 4629992