Gαq protein signaling in the bed nucleus of the stria terminalis regulate the lipopolysaccharide-induced despair-like behavior in mice

Abstract

Major depressive disorder (MDD) is highly comorbid with anxiety disorders. It has been reported that the bed nucleus of the stria terminalis (BNST) is important for the induction of anxiety and MDD. Recently, the Gαq protein signaling within the BNST is involved in the induction of anxiety through Gαq protein signaling-mediated RNA-editing of GluR2 subunit, which produces the calcium (Ca 2+ )-impermeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. On the other hand, the role of Gαq protein signaling within the BNST on the induction of MDD has never been reported yet. Therefore, we investigated whether Gαq protein signaling-producing the Ca 2+ -impermeable AMPA receptors in the BNST is involved in the lipopolysaccharide (LPS)-induced depressive-like behavior, particularly, despair-like behavior. When mice were systemically challenged with a single dose of LPS (1.2 mg/kg, i.p.), the immobility time during tail suspension test (TST) was increased 24 h after LPS injection. However, pretreatment with bilateral intra-BNST injection of neomycin (6.5 mM, 0.125 µL/side), an inhibitor of phospholipase C that is activated by Gαq protein-coupled receptor stimulation, extended the LPS-induced increase in the immobility time of TST. Furthermore, the co-pretreatment with bilateral intra-BNST injection of neomycin with 1-naphthylacetyl spermine (3 mM, 0.125 µL/side), an antagonist of Ca 2+ -permeable AMPA receptor, to mimic one of the final forms of Gαq protein activation, abolished the aggravated effect of neomycin and significantly shortened the immobility time compared with the control mice with an intra-BNST injection of artificial cerebrospinal fluid before LPS injection. However, pretreatment with bilateral intra-BNST injection of MDL-12,330A (10 µM, 0.125 µL/side), an inhibitor of adenylyl cyclase that is activated by Gαs protein-coupled receptor stimulation, did not affect the LPS-induced increase in the immobility time of TST. These results indicate that the Gαq protein signaling-mediated RNA-editing of GluR2, which produces the Ca 2+ -impermeable AMPA receptors within the BNST, regulates the LPS-induced despair-like behavior.

High Salt Intake Induces Active Coping Behaviors by Enhancing the Resilience against Psychological Stress in Mice

“…However, their immobility time during the second 5 min period of the TST was longer than that of the first 5 min. We have previously suggested that immobility time during the second 5 min period of the TST was longer due to the induction of learned despair [41,43]. The present results indicate that despair behavior was reduced in mice with a 2% NaCl intake for 5 consecutive days, but that learned despair was not affected.…”

“…3C), indicating that the NaCl intake prevented the TMT-induced despair behavior. In our previous work, we demonstrated that the learned despair behavior could be observed in the last 5 min of 10-min TST in subsequent of the first 5 min [41,43]. Therefore, we investigated whether the NaCl intake affected the induction of learned despair behavior.…”

“…The duration of immobility was calculated as the sum of the time periods during which the mouse was motionless for at least 2 s. Immobile behavior sensitivity was set to 70%, and the mouse needed to be immobile for 1 s to initiate scoring of immobility. Mice were returned to their home cages at the completion of the TST [41,42].…”

“…To provide an index of learned despair, 10 min of the test session was divided into two periods, the initial 5 min (0-5 min) and the final 5 min (5-10 min) [41,43], in addition, the immobility time for 5 min from 1 to 6 min during TST were also analyzed for evaluating the level of the behavioral despair [44].…”

The Central Inflammatory Network: A Hypothalamic fMRI Study of Experimental Endotoxemia in Humans

“…However, anatomical studies indicate that the vast majority of BNST input to the parvocellular PVN is GABAergic [ 88 ], suggesting that the BNST provides largely inhibitory modulatory input to the HPA axis [ 89 ]. Moreover, Fukuwada et al [ 90 ] recently presented evidence for a role of the BNST in regulating endotoxin-induced despair-like behaviour in mice via Gαq protein signalling. Finally, the BNST is involved in control of inflammation-associated loss of appetite [ 91 ].…”