My lab studies the neurophysiology of oxytocin (OT) and vasopressin (VP) magnocellular neurons in the brain. These neurons reside in the supraoptic nucleus (SON), a bilateral structure that resides within the hypothalamus. These fascinating neurons are the final link in a central neuroendocrine processing chain, projecting their axons out of the brain to release OT/VP into the bloodstream for action at peripheral targets. OT facilitates the milk ejection reflex in lactating females while VP plays a critical role in mediating salt-water balance and blood volume. VP is released in response to dehydration, signaling water reabsorption by the kidneys, as well as in response to hypovolemia, signaling a vasoconstriction at endothelial cells.
Intrinsic Excitability
The primary research interest of the lab is the mechanisms underlying these neurons’ intrinsic excitability. OT and VP neurons exhibit a dynamic range of spike patterning that allows these neurons respond appropriately to homeostatic challenge. These neurons often fire phasically, and the periods of quiescence between bouts of activity allow the neurons to recover, maximizing their stimulus-secretion coupling efficiency. One of the mechanisms that shapes these bursts is the calcium-dependent potassium channels that generate afterhyperpolarization (AHP) currents, which hyperpolarize the neuron during spiking. The slow component (sAHP) is of particular interest as its explicit channel identity remains elusive. The lab studies these mechanisms using simultaneous whole cell patch clamp and live calcium imaging in an acute rat brain slice preparation.
Somatodendritic Release
A unique feature of the OT/VP magnocellular neurons is that they can release their respective peptides at soma and dendrites in addition to classic axonal release. This somatodendritic release (SDR) coordinates population activity within the supraoptic and paraventricular nuclei of hypothalamus, acting independently of axonal release. Much is unknown about the underlying mechanisms. The lab studies SDR and its potential involvement in AHP modulation.
Dendritic Vesicle Trafficking
Much effort has been dedicated to the study of OT/VP somatodendritic release, yet much less is known about the vesicle trafficking capabilities of these neurons. Using multiphoton imaging ex vivo, we can capture movement of VP-containing large dense core vesicles. We study how the movement of these vesicles changes during homeostatic challenge or disease state.
Heart Failure
The lab also has a high interest in heart failure (HF), a progressive disease marked by increased circulating VP and hyperexcitable VP neurons. Interestingly, VP neurons in HF rats exhibit abolished AHPs, indicating that this hyperexcitability is underlain in part by a lack of inhibitory intrinsic excitability mechanisms. Though this is initially a compensatory mechanism to maintain blood volume, chronic VP activation causes excessive water retention in the kidneys, leading to hyponatremia and contributing to progression of the disease. Kirchner’s lab studies how VP neurons change during HF, focusing on intrinsic excitability and SDR. Understanding the mechanisms that underlie the disease may help improve therapeutics for these patients.