Researchers from the Hensch Lab—led by MCB faculty Takao Hensch, Curriculum and Pedagogy Manager Kathleen Quast (Ph.D. ‘13), and then graduate student Rebecca Reh (Ph.D. ‘15)—have identified biomarkers that herald neuronal plasticity in the cerebral cortex. Their results appeared in a recent issue of the journal PNAS (Proceedings of the National Academy of Sciences).
The team used mice to investigate the visual “critical period,” an interval early in life when sensory experiences can cause major reshaping of neural wiring. “These are both windows of opportunity to proficiently acquire new skills as well as windows of vulnerability to cognitive disorders,” Hensch explains. “Understanding the biological basis of such critical periods would allow us to correct derailed developmental trajectories, optimize learning, and potentially reopen robust brain plasticity in adulthood. Here, we discovered the very first circuit changes that occur in response to altered experience during a critical period for vision.”
Critical periods have been a topic of brain research since long-lasting changes to cellular responsiveness were first identified by David Hubel and Torsten Wiesel, who would go on to win the 1981 Nobel Prize for Physiology and Medicine in part for this work. However, clinicians and caregivers have largely had to deduce whether critical periods are open or closed based on behavioral outcomes, such as when individuals lose vision through a lazy eye.
In their experiment, Hensch, Quast, and Reh used young mice and briefly patched one eye shut just as the mice entered their critical period, creating a sensory imbalance. The scientists then recorded EEG data over the visual cortex to track each mouse’s brainwaves. “We found that a robust and transient peak in high frequency fluctuations (40 – 80 times per second), called gamma rhythms, are reliably induced then fade out after sensory imbalance only during the critical period,” Hensch says. “So, it can be a novel biomarker of brain age.”
These gamma rhythms turned up not only in young mice, but also in mouse models whose critical periods were extended into adulthood. The researchers then further identified the consequences for the neurons that initiated the gamma waves, by capturing detailed synaptic measurements. “Modeling brain dynamics at early developmental stages is especially fascinating: it offers a window through which to visualize how coordinated rhythmic dynamics of groups of neurons sculpt neuronal networks and fine-tune their functions as they transition to their adult forms,” explains Michelle McCarthy, from Nancy Kopell’s group at Boston University who collaborated on the computational aspects of the study.
“Inside the brain, the generators of gamma rhythms are sparse inhibitory neurons. This reflects the way they are wired up with each other and their ability to fire at high frequencies,” Hensch adds. “When they receive imbalanced sensory input, they prefer to fire synchronously in the gamma range. This inhibitory neuron gamma (ING) rhythm is ideally timed to rapidly weaken those very same inputs. So, we discovered which synapse is the first to be pruned 60 years after Hubel & Wiesel’s pioneering work.”
In their computational simulations, induced ING rhythms triggered the transition from a less flexible state into the critical period state. If the gamma rhythms did not appear, neither did the plasticity. Models of the system displayed the same rapid weakening of certain strong inputs subsequent to the oscillations. In their absence, other previously silent synapses gradually strengthened, leading to the later gamma rhythm fade-out.“Integrating two PhD theses worth of work, this was a truly interdisciplinary tour-de-force, combining EEG recording in freely behaving mice, a novel brain slice preparation to map specific synaptic changes, and computational modeling with colleagues at B.U. to amalgamate all of these findings,” Hensch adds.
by Takao Hensch and Diana Crow
