This article changed my life: Embracing an early model of naturalistic neuroscience

A 1992 study published in PNAS showed that bird song increases the expression of an immediate early response gene in the forebrain of birds. The work revealed to Ribeiro the importance of studying molecular responses in naturalistic contexts.

Song presentation induces gene expression in the songbird forebrain. Mello C.V., Vicario D.S. and Clayton D.F. Proceedings of the National Academy of Sciences (1992)

This study by Claudio Mello, David Vicario, and David Clayton demonstrated that genes can respond dynamically to experiences that are relevant to animals in their environment. The researchers played recordings of songbird songs to canaries and zebra finches and found that this rapidly induced expression of the immediate early response gene ZENK in the songbirds' forebrain.

They observed that ZENK expression was especially pronounced in auditory areas of the forebrain involved in processing songs of the same species, indicating that sensory stimuli with behavioral significance can trigger genetic expression programs in specific neural circuits. This was a fundamental finding as it combined natural communication signals, neuronal activity, and molecular plasticity in the brain.

Its impact transcended auditory research. The work helped establish immediate early response genes as potent markers of neuronal activation and plasticity.

In a broader sense, the study influenced neuroscience by demonstrating how perception, behavior, and molecular mechanisms can be studied together in freely behaving animals. The study stands out not only as a classic in bird song research but also as an early model of integrative and naturalistic neuroscience.

When did you first learn about this study? What were you working on at the time? I learned about this study in early 1993 when I was completing my undergraduate studies at the University of Brasilia. At that time, I was interested in the newly discovered immediate early response genes and was fascinated by the application of this emerging field to behaviors that animals demonstrate in their natural environments.

Claudio Mello, the first author of the study, was a student at the University of Brasilia and my mentor at the time helped me contact him. Mello encouraged me to apply to the doctoral program at Rockefeller University, where he was conducting research in Fernando Nottebohm's laboratory. That's exactly what I did and in the following years, I had the privilege of being supervised by both.

Why is this study significant to you? It helped define a way of thinking about the brain that integrates behavior, neuronal circuits, and genetic expression. It demonstrated that molecular changes are not isolated cellular events but are part of the brain's response to meaningful experience. That was especially important for me because it suggests that other processes—such as memory, perception, and sleep—could be studied through the dynamic regulation of genes related to plasticity.

The study also has personal significance because it shaped my scientific trajectory during my work with Mello, inspiring experiments on immediate early response genes in both songbirds and rats.

How did this research change how you think about neuroscience? This research showed me that the brain can be studied through many levels at the same time: from natural behavior to genetic expression to systems activity. It encouraged me to see genes like ZENK not merely as molecular markers but as an entry point to the mechanisms by which experience modifies neuronal circuits.

This perspective influenced my interests in how genetic expression related to learning is regulated across sleep states, in collaboration with another previous mentor at Rockefeller University, Constantine Pavlides. It helped shape my view that sleep is an active biological state in which waking experience can be reprocessed, stabilized, and transformed at the molecular and circuit levels.

Is there an underappreciated aspect of this study that other neuroscientists should know? An underappreciated aspect of this study is how strongly it anticipated modern systems neuroscience. Long before large-scale neuronal recording and transcriptomics strategies became common, the study managed to link a natural sensory stimulus with specific molecular activation in a region of the brain.

Likewise, it demonstrated the effectiveness of using stimuli with ethological relevance—such as bird song—rather than artificial laboratory stimuli.