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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

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.
PMCID:7543993
PMID: 33043102
ISSN: 2352-1546
CID: 4629992

Elevated infant cortisol is necessary but not sufficient for transmission of environmental risk to infant social development: Cross-species evidence of mother-infant physiological social transmission

Perry, Rosemarie E; Braren, Stephen H; Opendak, Maya; Brandes-Aitken, Annie; Chopra, Divija; Woo, Joyce; Sullivan, Regina; Blair, Clancy
Environmental adversity increases child susceptibility to disrupted developmental outcomes, but the mechanisms by which adversity can shape development remain unclear. A translational cross-species approach was used to examine stress-mediated pathways by which poverty-related adversity can influence infant social development. Findings from a longitudinal sample of low-income mother-infant dyads indicated that infant cortisol (CORT) on its own did not mediate relations between early-life scarcity-adversity exposure and later infant behavior in a mother-child interaction task. However, maternal CORT through infant CORT served as a mediating pathway, even when controlling for parenting behavior. Findings using a rodent "scarcity-adversity" model indicated that pharmacologically blocking pup corticosterone (CORT, rodent equivalent to cortisol) in the presence of a stressed mother causally prevented social transmission of scarcity-adversity effects on pup social behavior. Furthermore, pharmacologically increasing pup CORT without the mother present was not sufficient to disrupt pup social behavior. Integration of our cross-species results suggests that elevated infant CORT may be necessary, but without elevated caregiver CORT, may not be sufficient in mediating the effects of environmental adversity on development. These findings underscore the importance of considering infant stress physiology in relation to the broader social context, including caregiver stress physiology, in research and interventional efforts.
PMID: 33427190
ISSN: 1469-2198
CID: 4771102

Adverse caregiving in infancy blunts neural processing of the mother

Opendak, Maya; Theisen, Emma; Blomkvist, Anna; Hollis, Kaitlin; Lind, Teresa; Sarro, Emma; Lundström, Johan N; Tottenham, Nim; Dozier, Mary; Wilson, Donald A; Sullivan, Regina M
The roots of psychopathology frequently take shape during infancy in the context of parent-infant interactions and adversity. Yet, neurobiological mechanisms linking these processes during infancy remain elusive. Here, using responses to attachment figures among infants who experienced adversity as a benchmark, we assessed rat pup cortical local field potentials (LFPs) and behaviors exposed to adversity in response to maternal rough and nurturing handling by examining its impact on pup separation-reunion with the mother. We show that during adversity, pup cortical LFP dynamic range decreased during nurturing maternal behaviors, but was minimally impacted by rough handling. During reunion, adversity-experiencing pups showed aberrant interactions with mother and blunted cortical LFP. Blocking pup stress hormone during either adversity or reunion restored typical behavior, LFP power, and cross-frequency coupling. This translational approach suggests adversity-rearing produces a stress-induced aberrant neurobehavioral processing of the mother, which can be used as an early biomarker of later-life pathology.
PMID: 32111822
ISSN: 2041-1723
CID: 4324502

Consolidation of Adverse Memories is Differentially Modulated by MTOR and ERK Across Development [Meeting Abstract]

Woo, Joyce; Opendak, Maya; Sullivan, Regina
ISI:000535308201166
ISSN: 0006-3223
CID: 4560902

Early Life Trauma Has Lifelong Consequences for Sleep And Behavior

Lewin, Monica; Lopachin, Jenna; Delorme, James; Opendak, Maya; Sullivan, Regina M; Wilson, Donald A
Sleep quality varies widely across individuals, especially during normal aging, with impaired sleep contributing to deficits in cognition and emotional regulation. Sleep can also be impacted by a variety of adverse events, including childhood adversity. Here we examined how early life adverse events impacted later life sleep structure and physiology using an animal model to test the relationship between early life adversity and sleep quality across the life span. Rat pups were exposed to an Adversity-Scarcity model from postnatal day 8-12, where insufficient bedding for nest building induces maternal maltreatment of pups. Polysomnography and sleep physiology were assessed in weaning, early adult and older adults. Early life adversity induced age-dependent disruptions in sleep and behavior, including lifelong spindle decreases and later life NREM sleep fragmentation. Given the importance of sleep in cognitive and emotional functions, these results highlight an important factor driving variation in sleep, cognition and emotion throughout the lifespan that suggest age-appropriate and trauma informed treatment of sleep problems.
PMID: 31723235
ISSN: 2045-2322
CID: 4186942

During infant maltreatment, stress targets hippocampus, but stress with mother present targets amygdala and social behavior

Raineki, Charlis; Opendak, Maya; Sarro, Emma; Showler, Ashleigh; Bui, Kevin; McEwen, Bruce S; Wilson, Donald A; Sullivan, Regina M
Infant maltreatment increases vulnerability to physical and mental disorders, yet specific mechanisms embedded within this complex infant experience that induce this vulnerability remain elusive. To define critical features of maltreatment-induced vulnerability, rat pups were reared from postnatal day 8 (PN8) with a maltreating mother, which produced amygdala and hippocampal deficits and decreased social behavior at PN13. Next, we deconstructed the maltreatment experience to reveal sufficient and necessary conditions to induce this phenotype. Social behavior and amygdala deficits (volume, neurogenesis, c-Fos, local field potential) required combined chronic high corticosterone and maternal presence (not maternal behavior). Hippocampal deficits were induced by chronic high corticosterone regardless of social context. Causation was shown by blocking corticosterone during maltreatment and suppressing amygdala activity during social behavior testing. These results highlight (1) that early life maltreatment initiates multiple pathways to pathology, each with distinct causal mechanisms and outcomes, and (2) the importance of social presence on brain development.
PMID: 31636210
ISSN: 1091-6490
CID: 4175632

Corticosterone administration targeting a hypo-reactive HPA axis rescues a socially-avoidant phenotype in scarcity-adversity reared rats

Perry, Rosemarie E; Rincón-Cortés, Millie; Braren, Stephen H; Brandes-Aitken, Annie N; Opendak, Maya; Pollonini, Gabriella; Chopra, Divija; Raver, C Cybele; Alberini, Cristina M; Blair, Clancy; Sullivan, Regina M
It is well-established that children from low-income, under-resourced families are at increased risk of altered social development. However, the biological mechanisms by which poverty-related adversities can "get under the skin" to influence social behavior are poorly understood and cannot be easily ascertained using human research alone. This study utilized a rodent model of "scarcity-adversity," which encompasses material resource deprivation (scarcity) and reduced caregiving quality (adversity), to explore how early-life scarcity-adversity causally influences social behavior via disruption of developing stress physiology. Results showed that early-life scarcity-adversity exposure increased social avoidance when offspring were tested in a social approach test in peri-adolescence. Furthermore, early-life scarcity-adversity led to blunted hypothalamic-pituitary-adrenal (HPA) axis activity as measured via adrenocorticotropic hormone (ACTH) and corticosterone (CORT) reactivity following the social approach test. Western blot analysis of brain tissue revealed that glucocorticoid receptor levels in the dorsal (but not ventral) hippocampus and medial prefrontal cortex were significantly elevated in scarcity-adversity reared rats following the social approach test. Finally, pharmacological repletion of CORT in scarcity-adversity reared peri-adolescents rescued social behavior. Our findings provide causal support that early-life scarcity-adversity exposure negatively impacts social development via a hypocorticosteronism-dependent mechanism, which can be targeted via CORT administration to rescue social behavior.
PMID: 31704654
ISSN: 1878-9307
CID: 4186602

Neurobiology of maternal regulation of infant fear: the role of mesolimbic dopamine and its disruption by maltreatment

Opendak, Maya; Robinson-Drummer, Patrese; Blomkvist, Anna; Zanca, Roseanna M; Wood, Kira; Jacobs, Lily; Chan, Stephanie; Tan, Stephen; Woo, Joyce; Venkataraman, Gayatri; Kirschner, Emma; Lundström, Johan N; Wilson, Donald A; Serrano, Peter A; Sullivan, Regina M
Child development research highlights caregiver regulation of infant physiology and behavior as a key feature of early life attachment, although mechanisms for maternal control of infant neural circuits remain elusive. Here we explored the neurobiology of maternal regulation of infant fear using neural network and molecular levels of analysis in a rodent model. Previous research has shown maternal suppression of amygdala-dependent fear learning during a sensitive period. Here we characterize changes in neural networks engaged during maternal regulation and the transition to infant self-regulation. Metabolic mapping of 2-deoxyglucose uptake during odor-shock conditioning in postnatal day (PN)14 rat pups showed that maternal presence blocked fear learning, disengaged mesolimbic circuitry, basolateral amygdala (BLA), and plasticity-related AMPA receptor subunit trafficking. At PN18, when maternal presence only socially buffers threat learning (similar to social modulation in adults), maternal presence failed to disengage the mesolimbic dopaminergic system, and failed to disengage both the BLA and plasticity-related AMPA receptor subunit trafficking. Further, maternal presence failed to block threat learning at PN14 pups following abuse, and mesolimbic dopamine engagement and AMPA were not significantly altered by maternal presence-analogous to compromised maternal regulation of children in abusive relationships. Our results highlight three key features of maternal regulation: (1) maternal presence blocks fear learning and amygdala plasticity through age-dependent suppression of amygdala AMPA receptor subunit trafficking, (2) maternal presence suppresses engagement of brain regions within the mesolimbic dopamine circuit, and (3) early-life abuse compromises network and molecular biomarkers of maternal regulation, suggesting reduced social scaffolding of the brain.
PMID: 30758321
ISSN: 1740-634x
CID: 3656282