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Thesis Format

Integrated Article

Degree

Master of Science

Program

Neuroscience

Supervisor

Inoue, Wataru

Abstract

Immune-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis elevates glucocorticoids, anti-inflammatory hormones, promoting the effective resolution of inflammation. Psychological stress can modulate this anti-inflammatory mechanism, but the mechanisms underlying this modulation remain largely unknown. The immune-induced HPA axis activation is, in large part, mediated by prostaglandin E2 (PGE2), an inflammatory mediator. In the brain, PGE2 attenuates GABAergic synaptic transmission onto corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) that act as the apex of the HPA axis. The removal of GABA-mediated inhibition (i.e. disinhibition) excites CRH neurons and, consequently, activates the HPA axis. Here, we examined the modulatory effects of psychological stress on this PGE2-mediated synaptic mechanism for HPA axis activation. To this end, we used whole-cell patch clamp electrophysiology to record GABAergic synaptic transmission onto PVN-CRH neurons as changes in the amplitude of evoked inhibitory post-synaptic current (eIPSCs). We contrasted findings in acute brain slices from mice that have been stressed by restraint (psychological stress) with those of naïve (non-stressed) mice. We first confirmed that, in slices from naïve mice, PGE2 potently depressed GABAergic synaptic transmission to PVN-CRH neurons. On the other hand, in slices from stressed mice, PGE2 had heterogeneous effects, potentiating some synapses in addition to depressing others. Using receptor subtype-specific agonists and antagonists, we showed that the EP3 subtype of the PGE2 receptor mediated the synaptic depression by inhibiting the release of GABA from the pre-synaptic terminals in naïve slices. On the other hand, the EP2 and EP4 receptors mediated the potentiation of GABA release from the pre-synaptic terminals. Acute stress did not alter these mechanisms for bidirectional synaptic plasticity. By contrast, a blockade of EP1 receptor mimicked the effects of stress, shifting the balance of depression and potentiation toward potentiation. We conclude that EP1 receptor suppresses EP2 and EP4-mediated pre-synaptic potentiation (thus making EP3-mediated depression dominant) and that psychological stress blocks this EP1-mediated mechanism. We propose that psychological stress modulates the interplay between different subtypes of EP receptors to ultimately contribute to altering the immune-induced activation of the HPA axis.

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Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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