Bidirectional manipulation of mTOR signaling disrupts socially mediated vocal learning in juvenile songbirds

Abstract

Early life experiences can have long-lasting behavioral consequences because they are encoded when the brain is most malleable. The mechanistic target of rapamycin (mTOR) signaling cascade modulates experience-dependent synaptic plasticity, among other processes. mTOR has been almost exclusively examined in adult rodent learning models, but may be especially important in organizing neural circuits required for developmental acquisition of meaningful complex behaviors. It is among the most commonly implicated factors in neurodevelopmental autism spectrum disorders (ASD), characterized, in part, by distinct social and communication phenotypes. Here, we investigated mTOR in juvenile zebra finch songbirds. Much as children learn language, young male zebra finches need to interact socially with an adult tutor to learn a meaningful song. The memory of the tutor's song structure guides the juvenile's own song, which it uses to communicate for the rest of its life. We hypothesized that mTOR is required for juveniles to learn song. To this end, we first discovered that hearing song activates mTOR signaling in a brain area required for tutor song memorization in males old enough to copy song but not in younger males or females, who cannot sing. We then showed that both inhibition and constitutive activation of mTOR during tutor experiences significantly diminished tutor song copying. Finally, we found that constitutive mTOR activation lowered a behavioral measure of the juvenile's social engagement during tutor experiences, mirroring the relationship in humans. These studies therefore advance understanding about the effects of experience in the context of neurodevelopmental disorders and typical neural development.

Rapamycin blocks the neuroprotective effects of sex steroids in the adult birdsong system

“…We hypothesize that rapamycin acted by inactivating mTOR, but this needs to be tested directly. Together with the results of Ahmadiantehrani and London (), our results show that the PI3K‐Akt‐mTOR signaling pathway plays an important role in mediating plasticity in the avian forebrain. Our study demonstrates that the avian song system provides an excellent model for investigating nongenomic mechanisms by which sex steroids have neuroprotective effects in the context of naturally occurring neurodegeneration in adult brains.…”

“…In fact, rapamycin has actually been reported to be neuroprotective in different models (Cai & Yan, ; Su, Li, Jia, & Zhuo, ). Ahmadiantehrani and London () found that the number of cells immunoreactive to phosphorylated S6, an mTOR target protein, in forebrain auditory regions of juvenile male zebra finches returned to baseline levels by 15 hr following infusion of rapamycin, which further suggests that it is not toxic to cells. Rapamycin is being used in clinical anti‐aging studies in humans, without the adverse side effects that would be expected if it is neurotoxic (Kraig et al, ).…”

Mechanistic target of rapamycin (mTOR): A mediator of social development

“…The authors also discovered that social interactions were impaired (as measured by how much time the juveniles spent close to and facing their tutors, who were in adjacent cages) in finches that experienced an enhancement of mTOR via SC79 administration. This finding is consistent with other studies on constitutive increases in mTOR expression and social interactions (6).…”

“…To investigate the hypothesized role played by mTOR in the regulation of song learning from a tutor, Ahmadiantehrani and London (6) took advantage of what is known about intraspecific variation in the song-learning process in zebra finches. First, unlike many other songbird species, in zebra finches only males learn the speciestypical song, though males and females can produce calls (5).…”

“…Second, during ontogeny there is a sensitive period in which exposure to conspecific tutors is especially effective in facilitating the formation of song memories (9). Therefore, Ahmadiantehrani and London (6) hypothesize that the mTOR signaling cascade, if it is related to the socially facilitated formation of song memories, would be induced preferentially in males during ontogeny and during a time period coincident with the known sensitive period for song memory formation. It was also thought that this induction would occur preferentially in specialized areas of the auditory telencephalon, namely the caudomedial nidopallium (NCM) and the caudomedial mesopallium (CMM), known to be related to song memory formation (13).…”