Corticotropin-Releasing Factor Receptor 1 in the Anterior Cingulate Cortex Mediates Maternal Absence-Induced Attenuation of Transport Response in Mouse Pups

A human infant initially shows non-selective sociality, and gradually develops selective attachment toward its caregiver, manifested as “separation anxiety.” It was unclear whether such sophistication of attachment system occurs in non-human mammals. To seek a mouse model of separation anxiety, we utilized a primitive attachment behavior, the Transport Response, in that both human and mouse newborns immediately stop crying and stay immobile to cooperate with maternal carrying. We examined the mouse Transport Response in three social contexts: 30-min isolation in a novel environment, 30-min maternal absence experienced with littermates in the home cage, and the control home-cage condition with the mother and littermates. The pups after postnatal day (PND) 13 attenuated their Transport Response not only in complete isolation but also by maternal absence, and activated several brain areas including the periventricular nucleus of the hypothalamus, suggesting that 30-min maternal absence was perceived as a social stress by mouse pups after PND13. This attenuation of Transport Response by maternal absence was independent with plasma corticosterone, but was diminished by prior administration of a corticotropin-releasing factor receptor 1 (CRFR1) antagonist. Among 18 brain areas examined, only neurons in the anterior cingulate cortex (ACC) co-express c-fos mRNA and CRFR1 after maternal absence. Consistently, excitotoxic ACC lesions inhibited the maternal absence-induced attenuation of Transport Response. These data indicate that the expression of mouse Transport Response is influenced not only by social isolation but also by maternal absence even in their home cage with littermates after PND13, at least partly via CRF-CRFR1 signaling in the ACC

The calming effects of maternal carrying in different mammalian species

Attachment theory postulates that mothers and their infants possess some basic physiological mechanisms that favour their dyadic interaction and bonding. Many studies have focused on the maternal physiological mechanisms that promote attachment (e.g. mothers’ automatic responses to infant faces and/or cries), and relatively less have examined infant physiology. Thus, the physiological mechanisms regulating infant bonding behaviors remain largely undefined. This review elucidates some of the neurobiological mechanisms governing social bonding and cooperation in humans by focusing on maternal carrying and its beneficial effect on mother-infant interaction in mammalian species (e.g. in humans, big cats and rodents). These studies show that infants have a specific calming response to maternal carrying. A human infant carried by his/ her walking mother exhibits a rapid heart rate decrease, and immediately stops voluntary movement and crying compared to when he/ she is held in a sitting position. Furthermore, strikingly similar responses were identified in mouse rodents, who exhibit immobility, diminished ultra-sonic vocalizations and heart rate. In general, the studies described in the current review demonstrate the calming effect of maternal carrying to be comprised of a complex set of behavioral and physiological components, each of which has a specific postnatal time window and is orchestrated in a well-matched manner with the maturation of the infants. Such reactions could have been evolutionarily adaptive in mammalian mother-infant interactions. The findings have implications for parenting practices in developmentally normal populations. In addition, we propose that infants’ physiological response may be useful in clinical assessments as we discuss possible implications on early screening for child psychopathology (e.g. Autism Spectrum Disorders, and Perinatal Brain Disorders).Published versio

Using maternal rescue of pups in a cup to investigate mother-infant interactions in mice/rodents

Efficient parental care is indispensable for survival of the mammalian offspring, and therefore both parents and offspring cooperate to achieve the best performance. For example, when parents transport altricial offspring, the offspring immediately respond by reducing its cry and movement in both human infants and rodent pups. This coordinated set of central, motor and cardiac responses is designated as the Transport Response (TR) and is shown to facilitate maternal carrying in rodents. The present study aims to investigate the core behavioural characteristics of mother-infant interaction, and to investigate the mechanisms underlying the mother-pup cooperation using pharmacological and genetic manipulations (i.e. Oprm1-/). Along with the clear developmental changes of the pups' immobility and posture during maternal carrying as previously reported, there were also adaptations in maternal strategies, particularly in positioning of foothold and oral grasp over the pup's body, with the pups' age and pup's behaviour. Tree-based models elucidated that both of these maternal variables as well as percentage of pups' struggle predict the time required for pup retrieval from a cup. When the sensory-motor control in pups was disturbed by pharmacological or genetic manipulations, these core behaviours were inefficiently performed and impede maternal retrieval. Mother-infant mutual fit is a complex construct where several intermingled mechanisms are involved. Thus mothers and infants, when interacting, should be considered together as one whole system in which any change in one side or the other, affects the output of the whole dyad. The outcome of the interaction relays on a specific dynamic pattern of infant and maternal behaviours, which mutually change and adapt to fit each other's needs. Key features to reach a successful outcome of the interaction were the maternal retrieving strategy and infants’ Transport Response behaviour.Accepted versio

Article Infant Calming Responses during Maternal Carrying in Humans and Mice

Summary Background: Mother-infant bonding is the earliest and most critical social relationship of mammalian infants. To promote this bond, infants have innate behaviors to seek maternal proximity and protest upon separation via communication with the mother vocally and through body movement. However, the physiological mechanisms regulating these infant behaviors remain largely undefined. Results: Here we show a novel set of infant cooperative responses during maternal carrying. Infants under 6 months of age carried by a walking mother immediately stopped voluntary movement and crying and exhibited a rapid heart rate decrease, compared with holding by a sitting mother. Furthermore, we identified strikingly similar responses in mouse pups as defined by immobility and diminished ultrasonic vocalizations and heart rate. Using pharmacologic and genetic interventions in mouse pups, we identified the upstream and downstream neural systems regulating the calming response. Somatosensory and proprioceptive input signaling are required for induction, and parasympathetic and cerebellar functions mediate cardiac and motor output, respectively. The loss of the calming response hindered maternal rescue of the pups, suggesting a functional significance for the identified calming response. Conclusions: Our study has demonstrated for the first time that the infant calming response to maternal carrying is a coordinated set of central, motor, and cardiac regulations and is a conserved component of mammalian mother-infant interactions. Our findings provide evidence for and have the potentia