Positive memory formation: Role of the love hormone "oxytocin" and childhood imprinting. Critical period is first 7 days after birth in mice

The 'following' behavior of ducks and the "upstream swimming" of salmon are imprinted in early life by sight and smell but does imprinting occur in the olfactory system of mammals as well? If so, it is unclear when and how this would be established.

A research group led by Associate Professor Hirofumi Nishizumi of the University of Fukui School of Medical Sciences elucidated the key molecular mechanism of the imprinting phenomenon by the sense of smell in early childhood. They also revealed that oxytocin, a love hormone, positively impacts odor memory. Associate Professor Nishizumi said, "We were able to clarify, for the first time ever, the mechanism by which odor imprinting occurs that affects subsequent social behavior due to the stimulation of the sense of smell in childhood. Oxytocin has also been reported to improve autism spectrum disorders. We are currently conducting joint research with the Center for Child Mental Development and hope to use our findings to optimize oxytocin administration." These findings were published in eLIFE.

Regarding the sense of smell, odor molecules are captured by the olfactory cells and the information is sent to the glomerulus and transmitted to the brain via mitral cells and tufted cells. These are two types of cells present in the nervous system. Associate Professor Nishizumi and colleagues have been studying olfactory information and behavior. In 2016, they found evidence regarding the occurrence of imprinting.

To identify the critical period of imprinting in the mouse olfactory system, they first occluded the nasal cavity of a newborn mouse and conducted a comparative experiment of the occlusion period and behavioral changes. They identified that the critical period of the sensory system is the first 7 days after birth. "For the wild-type mice, when food that was liked by the mice and other items with smells they disliked were placed in a cage, they were interested in the food they liked and did not get close to the smells they disliked. However, mice whose noses were closed during the critical period stayed longer in places with odors they disliked. In other words, smell is involved in establishing behaviors."

Further behavioral experiments revealed that on smelling vanillin, which is neither liked nor disliked by mice, wild-type mice lost interest upon smelling it several times, but mice that smelled vanillin in the first week of life could not pull themselves away from it . This tendency was maintained even at 6 weeks of age. In contrast, if the odor of 4-methylthiazole (4MT), which mice dislike, is left behind, the wild type will soon leave, while the imprinted mice will stay nearby for a longer period of time. In other words, by smelling the scent during the critical period, the subjects appeared to like it later in life.

Next, to elucidate the mechanism involved in odor imprinting, the group searched for molecules whose expression levels increased in olfactory cells, glomeruli, and trapezius/tufted cells during the first 7 days of life. From the results, Sema7A and PlxnC1 were identified. The expression level of Sema7A increases with the nerve activity of olfactory cells and is expressed by the entire nerve cell only in the first week after birth. A further detailed analysis revealed that Sema7A was elevated at the nerve endings of olfactory cells and that the expression level of PlxnC1 was increased in the glomerulus, thereby promoting synaptogenesis (the creation of new neural links), enlarging the glomerulus, and causing imprinting. Also, in the first week after birth, a large amount of oxytocin is released. Therefore, behavioral experiments were conducted on oxytocin-deficient mice.

When female mice meet male mice, they first smell them frequently but gradually stop, whereas oxytocin-deficient mice continue to smell the same mice. Oxytocin-deficient mice also exhibit autism-like behaviors. These behaviors recovered when oxytocin was placed in the cages of deficient mice within 6 days of age but not after 8 days. When 4MT and oxytocin, which were originally disliked, were added at the same time during the imprinting period of oxytocin-deficient mice, these mice liked the smell of 4MT. In other words, oxytocin has a role as a positive texture (comfortable and reassuring odor) in the brain.

Normally, mice memorize the smell of nests and the smell of the companions that they were exposed to during the critical period of their childhood as imprints. Even after they mature, the smells are identified as positive odors (pleasant, reassuring, and attachment-promoting). However, if Sema7A, PlxnC1, or oxytocin is non-functional, imprinting will not occur. As a result, they avoid the smell of peers in whom they should be very interested and display autism-like behaviors. In the future, the research group will investigate whether imprinting through the five senses occurs in humans and whether the administration of oxytocin before the critical period of the brain will lead to improvements in autism spectrum disorder therapy.