State-dependent activity dynamics of hypothalamic stress effector neurons

The stress response necessitates an immediate boost in vital physiological functions from their homeostatic operation to an elevated emergency response. However, the neural mechanisms underlying this state-dependent change remain largely unknown. Using a combination of in vivo and ex vivo electrophysiology with computational modeling, we report that corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN), the effector neurons of hormonal stress response, rapidly transition between distinct activity states through recurrent inhibition. Specifically, in vivo optrode recording shows that under non-stress conditions, CRHPVN neurons often fire with rhythmic brief bursts (RB), which, somewhat counterintuitively, constrains firing rate due to long (~2 s) interburst intervals. Stressful stimuli rapidly switch RB to continuous single spiking (SS), permitting a large increase in firing rate. A spiking network model shows that recurrent inhibition can control this activity-state switch, and more broadly the gain of spiking responses to excitatory inputs. In biological CRHPVN neurons ex vivo, the injection of whole-cell currents derived from our computational model recreates the in vivo-like switch between RB and SS, providing direct evidence that physiologically relevant network inputs enable state-dependent computation in single neurons. Together, we present a novel mechanism for state-dependent activity dynamics in CRHPVN neurons

An exact mathematical description of computation with transient spatiotemporal dynamics in a complex-valued neural network

We study a complex-valued neural network (cv-NN) with linear, time-delayed interactions. We report the cv-NN displays sophisticated spatiotemporal dynamics, including partially synchronized ``chimera'' states. We then use these spatiotemporal dynamics, in combination with a nonlinear readout, for computation. The cv-NN can instantiate dynamics-based logic gates, encode short-term memories, and mediate secure message passing through a combination of interactions and time delays. The computations in this system can be fully described in an exact, closed-form mathematical expression. Finally, using direct intracellular recordings of neurons in slices from neocortex, we demonstrate that computations in the cv-NN are decodable by living biological neurons. These results demonstrate that complex-valued linear systems can perform sophisticated computations, while also being exactly solvable. Taken together, these results open future avenues for design of highly adaptable, bio-hybrid computing systems that can interface seamlessly with other neural networks

Examining the role of Chloride Homeostasis and PGE2 signaling in the Neuroendocrine stress response to inflammation

The brain senses inflammatory signals and drives the release of glucocorticoids (GCs) — potent immunosuppressants — via the activation of the hypothalamic-pituitary-adrenal (HPA) axis. This inflammation-induced HPA axis activation is largely mediated by prostaglandin E2 (PGE2), acting on two subtypes of the PGE2 receptor, EP1 and EP3. Recently, our group revealed EP3 signaling mechanisms that excite HPA axis regulatory neurons. This thesis sought to tease out the remaining EP1 signaling mechanisms. Considering that the excitability of HPA axis regulatory neurons is constrained by GABAA receptor-mediated synaptic inhibition that relies on low-level intracellular Cl-. We hypothesized that PGE2-EP1 signaling impairs GABAA receptor-mediated inhibition by increasing intracellular Cl- levels. We used two electrophysiological approaches (perforated patch and whole-cell recordings) and showed that PGE2 depolarizes the reversal potential of GABAA receptor currents (EGABA), an indicator of intracellular Cl- elevation. The effect of PGE2 was mimicked by EP1 agonist and prevented by EP1 antagonist. The depolarizing shift was slow to develop but became significant by 20 min post PGE2. Our results indicate that PGE2-EP1 coupling induces a slow depolarizing shift in EGABA for the excitation of PVN-CRH neurons during inflammation