Many, if not all, neural circuits are sculpted during developmental periods of heightened plasticity known as critical or sensitive periods. General mechanisms that gate plasticity during critical periods are not known, and understanding the processes that control neural plasticity may provide insights into fundamental mechanisms that govern nervous system formation and function. These studies will examine fundamental mechanisms that regulate plasticity. A promising candidate that may limit plasticity is an extracellular coating, known as a perineuronal net that appears around a special subset of neurons when critical periods close. Whether a vocal critical period can be reopened and the brain changed by removing perineuronal nets will be determined in the birdsong system. Birdsong is the best experimental model of learned vocalization (e.g., speech in humans). Because song reports the status of the underlying neural circuit as a whole, on-line, and moment-by-moment, the birdsong model may prove an invaluable tool for dynamically probing the developmental mechanisms that underlie critical periods in general, including sensory critical periods. This knowledge will further understanding of neural plasticity and its limitations. These studies will also develop a potential reagent for reopening vocal plasticity in humans, the enzyme chondroitinase that destroys perineuronal nets. The Broader Impacts associated with this work include training of undergraduates and graduate students while performing the proposed research. In addition, the PI will provide community outreach, including participation in Brain Awareness Week, the Minnesota Brain Bee and training of high school teachers through lab tours and outreach to local schools.
Critical periods are time windows in development when the effects of experience are especially potent. For example, speech is most easily acquired during a specific period in development. Several molecular and cellular factors are implicated in the closure of critical periods. It would be good to understand these factors better in order to extend or reopen critical periods in cases, such as late-diagnosed autism, when the critical period closes before speech can be learned. It is also possible that other neurological diseases represent a re-enabling of plasticity in adults. The scientists that were funded by this proposal used the songbird as a model of vocal learning. They previously showed that songbirds express a critical period factor, perineuronal nets. Other studies in other animals had shown that removal of perineuronal nets in adults with an enzyme can at least partially reopen the capacity for sensory plasticity. The scientists thus hypothesized that removal of perineuronal nets in adult songbirds would re-enable the capacity for vocal learning. However, this did not happen - only about half of the animals treated showed an effect, and the other half showed no effect whatsoever. This bimodal effect may have been due to the need to remove all of the song system nets to see a reliable effect (the study removed only the telencephic nets, but left "lower" brain area nets intact due to confounds with regard to sensory affects). Another reason for the bimodal effect may have been that the nets began to grow back as soon as they were removed and only half the birds sang enough during that window to learn a new song. This work was not published because the birdsong community is quite conservative and does not recognize the importance of perineuronal nets yet. Nevertheless, this grant funded the publication of four peer-reviewed manuscripts on closely related studies ( Meyer, C.E., Boroda, E., and Nick, T.A. (2014). Sexually dimorphic perineuronal net expression in the songbird. Basal Ganglia, 3(4):229-237. Day, N.F. and Nick, T.A. (2013) Rhythmic cortical neurons increase their oscillations and sculpt basal ganglia signaling during motor learning. Developmental Neurobiology, 73(10):754-68. Day, N.F., Terleski, K.L., Nykamp, D.Q., and Nick, T.A. (2013) Directed functional connectivity matures with motor learning in a cortical pattern generator. The Journal of Neurophysiology.109(4):913-923. Day, N.F., Kerrigan, S.J., Aoki, N., and Nick, T.A. (2011) Identification of single neurons in a forebrain network. The Journal of Neurophysiology. 106(6):3205-15.).
