Erik Herzog, PhD
Department of Biology
Washington University in St. Louis
(Week of March 7, 2015)
For Whom the Bells Toll: Networked Circadian Clocks in the Brain
What is it about jet lag that makes us feel like zombies? Why does it take days to recover from a week on the night shift? Our internal clock, our circadian rhythms, keep our bodies entrained to a light/dark cycle that can be difficult to disrupt. But this cycle can be disrupted, and Dr. Herzog’s work explores how the activity of specific neurons can synchronize the body with the changing seasons and periods of light and dark. His research shows that a certain chemical messenger in the brain, and the neurons it activates, can change the rhythm of firing in multiple neurons within the network. His work demonstrates how altering the activity of part of a network can affect the whole, and adds to our understanding of how networks can adapt.
In my first seminar, titled “Maps and modules in the atomic circadian clock,” I aimed to discuss evidence that many mammalian cell types have the capacity to generate sloppy daily rhythms in gene expression. When these cells communicate with each other, their rhythms increase in amplitude and become precise from day to day. I summarized data from my lab and the field showing that the cells of a master circadian pacemaker in the brain, the suprachiasmatic nucleus (SCN), use a neuropeptide (vasoactive intestinal polypeptide, or VIP) to synchronize to each other and a neurotransmitter (GABA) to balance the synchrony among SCN cells. I related these findings to how the system normally synchronizes (entrains) to the local light-dark cycle and adapts to seasons. I presented unpublished data showing, for example, that optogenetic activation of VIP neurons produces a phenomenon we call “phase tumbling.” We find that when VIP neurons of the SCN are driven to fire in specific patterns, the rhythms of cells within the SCN assume more random phase relationships and more rapidly adjust to changes in the light-dark cycle. These results provide a way to understand the limits of normal entrainment and a potential therapy for jetlag and shift-work disorders.
In my second seminar, titled “For whom the bells toll: Networked circadian clocks in the brain,” I discussed evidence that tissues within mammals act as coupled circadian oscillators to regulate daily rhythms in physiology and behavior. I used the olfactory system as an example of a network of circadian pacemakers that drive daily rhythms in performance. I showed that mice can detect odors (e.g. vanilla) about six times better at night than during the day. Consistent with this, the olfactory epithelia and olfactory bulbs generated daily rhythms in gene expression, firing rate and neuropeptide release in vivo and in vitro. The daily rhythm in olfactory performance does not require the SCN but does depend on the canonical transcription-translation negative feedback loop functions so that loss of key clock genes, Period 1 and 2, results in mice that are constitutively super smellers, and mice lacking Bmal1 are chronically insensitive to odors. I showed unpublished data including evidence that, like the SCN, the olfactory clock system depends on the neuropeptide VIP for cell-cell synchrony and coherent daily rhythms in performance. I concluded with new data showing that glia (specifically astrocytes) are also circadian pacemakers, which provided me an opportunity to discuss chronotherapy.
Chronotherapy seeks to treat disorders with drugs at the time of day when they are most effective and with the least amount of side effects. I shared unpublished data where we treat glioblastoma medullaforme cells at the time of their daily peak in Bmal1 to maximize the effect of a standard chemotherapeutic on brain cancer outcomes.