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

Abstract

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.

Maternal physiological calming responses to infant suckling at the breast

“…We have previously demonstrated that human infants and mouse pups can be calmed immediately by parental carrying and that it reduces their cry, spontaneous movements, and their heart rate, partly mediated by the parasympathetic activation [ 10 , 26 , 42 , 43 ]. This evolutionarily conserved set of physiological and behavioral responses to carrying is termed the "Transport Response" and is widely observed across mammalian species, regarded as infant cooperative responses to parental carrying [ 4 , 9 ].…”

Physical contact in parent-infant relationship and its effect on fostering a feeling of safety

“…The upper graph indicates infant body weight growth. Transport Response occurs during the transition from oral carrying by mother to walking on their own ( Esposito et al., 2013 ; Yoshida et al, 2013 , 2018 ). …”

“…After the end of the stress hyporesponsive period at postnatal day 14, the expression of Transport Response becomes increasingly social context dependent. Transport Response was suppressed when the mother was not present in the home cage or when the pup was alone in the novel environment ( Figure 5 B) ( Yoshida et al., 2018 ). The activation of the anterior cingulate cortex that is due to corticotropin-releasing hormone from the paraventricular nucleus is thought to underlie this social context-dependent suppression of Transport Response ( Yoshida et al., 2018 ).…”

“…Transport Response was suppressed when the mother was not present in the home cage or when the pup was alone in the novel environment ( Figure 5 B) ( Yoshida et al., 2018 ). The activation of the anterior cingulate cortex that is due to corticotropin-releasing hormone from the paraventricular nucleus is thought to underlie this social context-dependent suppression of Transport Response ( Yoshida et al., 2018 ). From postnatal days 14–18, the duration of Transport Response decreases, but the hindlimbs are fully flexed during the Transport response.…”

Early‐life social stress induces permanent alterations in plasticity and perineuronal nets in the mouse anterior cingulate cortex

“…Early-life trauma has been associated with alterations in ACC connectivity, volume and thickness, and it has been hypothesized that maltreatment leads to impaired ACC role in the threat detection and response system, thus increasing vulnerability to psychopathologies (McCrory et al, 2017;McCrory & Viding, 2015;Teicher et al, 2016). ACC sensitivity to ELS has been confirmed in animal studies (Banqueri et al, 2021;Yoshida et al, 2018), which showed that ACC bears long-term morphometric and functional alterations following early adversity (Gos et al, 2008;Helmeke et al, 2001Helmeke et al, , 2008Salberg et al, 2021;Spinelli et al, 2009). The molecular mechanisms linking early stress with ACC dysfunctions and psychopathological outcomes are still under investigation.…”