Abstract
Glucocorticoids rapidly regulate synaptic input to neuroendocrine cells in the hypothalamic paraventricular nucleus (PVN) by inducing the retrograde release of endogenous messengers. Here we investigated the rapid effects of dexamethasone (DEX) on excitatory synaptic input to feeding-related, preautonomic PVN neurons using whole-cell patch-clamp recordings. In ∼50% of identified gastric-related preautonomic PVN neurons, DEX elicited a biphasic synaptic response characterized by an initial rapid and transient increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs), followed by a decrease in mEPSC frequency within 9 min; remaining cells displayed only a decrease in mEPSC frequency. The late-phase decrease in mEPSC frequency was mimicked by the cannabinoid receptor agonists anandamide (AEA) and WIN 55,212-2, and it was blocked by the CB1 receptor antagonist AM251. The biphasic DEX effect was mimicked by AEA. The early increase in mEPSCs was mimicked by activation of transient receptor potential vanilloid type 1 (TRPV1) receptors with capsaicin and by activation of TRPV4 receptors with 4-α-PDD. The increase was reduced, but not blocked, by selective TRPV1 antagonists and in TRPV1 knockout mice; it was blocked completely by the broad-spectrum TRPV antagonist ruthenium red and by combined application of selective TRPV1 and TRPV4 antagonists. The DEX effects were prevented entirely by intracellular infusion of the G-protein inhibitor, GDPβS. Thus, DEX biphasically modulates synaptic glutamate onto a subset of gastric-related PVN neurons, which is likely mediated by induction of a retrograde messenger. The effect includes a TRPV1/4 receptor-mediated transient increase and subsequent CB1 receptor-mediated suppression of glutamate release. Multiphasic modulation of glutamate input to PVN neurons represents a previously unappreciated complexity of control of autonomic output by glucocorticoids and endogenous cannabinoids.
Highlights
The paraventricular nucleus (PVN) of the hypothalamus plays a critical role in integrating neural and humoral signals leading to the coordination of neuroendocrine and autonomic motor outputs
Gastric-related preautonomic neurons labeled with enhanced green fluorescent protein (EGFP) were targeted for recording 72–96 h after inoculation (Figures 1A–E), a time window during which the electrophysiological properties of pseudorabies virus (PRV)-152-infected neurons were demonstrated previously to be unaffected by the virus (Smith et al, 2000; Glatzer et al, 2003, 2007)
To confirm their identity as EGFP-labeled, gastric-related neurons and their location in PVN, a subset of recorded neurons was filled with biocytin and visualized post hoc with an avidin-Texas Red or avidinrhodamine conjugate and/or an ABC-DAB reaction (Figure 1)
Summary
The paraventricular nucleus (PVN) of the hypothalamus plays a critical role in integrating neural and humoral signals leading to the coordination of neuroendocrine and autonomic motor outputs. Anatomical and physiological evidence suggests that PVN neurons are involved in controlling energy homeostasis, including regulation of feeding behavior and digestion (Sims and Lorden, 1986). Inhibition of PVN neuron activity tends to induce feeding, whereas a reduction in feeding is associated with increased PVN activity (Kow and Pfaff, 1989). This is presumably mediated in large part by neural interactions with brainstem autonomic nuclei that regulate output to the stomach. Modulation of hypothalamic-brainstem circuit activity likely plays a key role in regulating feeding behavior
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