Differences in body form and behavior between males and females are well established in numerous species, but little is known about how they are organized during development. Electric communication by the brown ghost knifefish provides a unique opportunity for elucidating the cellular mechanisms mediating one such difference. In this weakly electric fish, males produce electric organ discharges that contain higher frequencies than those of females. The difference in discharge frequencies is controlled by the pacemaker nucleus, a neural circuit in the brainstem. Using an interdisciplinary strategy, a novel mechanistic hypothesis will be tested: astrocytes (a glial cell type) regulate (buffer) extracellular potassium ions differently in males and females, and this is responsible for the difference in their electric organ discharges. Besides providing new insights into the molecular and cellular mechanisms that underlie one specific behavior that is dimorphic between males and females, this research will also advance knowledge about the role of astrocytes in potassium buffering in the nervous system, and about the regulation of neural networks by these ions. The latter two topics play an important role in the etiology of pathological conditions involving pattern-generating neural circuits (for example, high-frequency epileptic seizures are thought to result from an impairment in potassium buffering that enhances the susceptibility for such seizures). Because of the interdisciplinary nature of this research, multiple opportunities are also provided for training students in diverse disciplines, and for curriculum development at the interface between biology and other STEM disciplines. Undergraduates will be involved in carrying out this research project via directed study courses being offered at both Northeastern University and the University of Virginia; 6-month internships will also be offered for students from Northeastern University to participate in the parts of the project conducted and at the University of Virginia. The PI and co-PI will also use parts of this research in laboratory-based upper-level undergraduate courses that they teach at their respective institutions, as well as engaging in outreach activities at local high schools and a series of STEM events for the general public.
The electric organ discharge of the weakly electric fish Apteronotus leptorhynchus is a robust and well-characterized behavioral system. The frequency of these discharges is reliably different in males and females, and controlled by the neural activity of the pacemaker nucleus, an endogenous oscillator in the medulla oblongata. The neurons critically involved in the generation of these oscillations are the pacemaker and relay cells, which are enveloped by astrocytic syncytia. Significant male-female differences exist in the morphology of these astrocytes, their expression of glia-specific proteins, and the gap-junction coupling of individuals cells within the syncytium. The study will test the hypothesis that the development of the male-female difference in the frequency of the electric organ discharge is regulated through modulation by the astrocytic buffering capacity of extracellular potassium ions in the pacemaker nucleus, thereby resulting in changes in the extracellular potassium concentration and ultimately in the oscillation frequency of the neural network composed of pacemaker and relay cells. To achieve this objective, a multi- and interdisciplinary approach will be employed, including morphological and molecular analysis of the association of the astrocytic syncytium with the pacemaker and relay cells; pharmacological manipulation of glial function and examination of its behavioral effect; electrophysiological characterization of the ionic mechanisms of astrocytes that control the firing frequency of the pacemaker nucleus; and computational modeling of (i) the uptake and redistribution of potassium ions by the astrocytic syncytium, (ii) the effect of this action on the frequency of the neural oscillations of the pacemaker nucleus.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
