The subfornical organ: a novel site of action of cholecystokinin

Abstract

The subfornical organ (SFO) is an important sensory circumventricular organ implicated in the regulation of fluid homeostasis and energy balance. We investigated whether the SFO is activated by the hormone cholecystokinin (CCK). CCK₁ and CCK₂ receptors were identified in the SFO by RT-PCR. Dissociated SFO neurons that responded to CCK (40/77), were mostly depolarized (9.2 ± 0.9 mV, 30/77), but some were hyperpolarized (-7.3 ± 1.1 mV, 10/77). We next examined the responses of SFO neurons in vivo to CCK (16 μg/kg ip), in the presence and absence of CCK₁ or CCK₂ receptor antagonists (devazepide; 600 μg/kg and L-365,260; 100 μg/kg, respectively), using the functional activation markers c-Fos and phosphorylated extracellular signal-related kinase (p-ERK). The nucleus of the solitary tract (NTS) served as a control for CCK-induced activity. There was a significant increase in c-Fos expression in the NTS (259.2 ± 20.8 neurons) compared with vehicle (47.5 ± 2.5). Similarly, in the SFO, c-Fos was expressed in 40.5 ± 10.6 neurons in CCK-treated compared with 6.6 ± 2.7 in vehicle-treated rats (P < 0.01). Devazepide significantly reduced the effects of CCK in the NTS but not in SFO. L-365,260 blocked the effects of CCK in both brain regions. CCK increased the number of p-ERK neurons in NTS (27.0 ± 4.0) as well as SFO (18.0 ± 4.0), compared with vehicle (8.0 ± 2.6 and 4.3 ± 0.6, respectively; P < 0.05). Both devazepide and L-365,260 reduced CCK-induced p-ERK in NTS, but only L-365,260 reduced it in the SFO. In conclusion, the SFO represents a novel brain region at which circulating CCK may act via CCK₂ receptors to influence central autonomic control.

Distinct neural mechanisms for the control of thirst and salt appetite in the subfornical organ

“…Expressions of the CCK receptors (CCKAR and CCKBR) are detected in the SFO by reverse transcription PCR (Ahmed et al, 2014). Moreover, CCKBR-KO mice show enhanced water consumption compared to WT mice (Noble and Roques, 1999).…”

Distinct CCK-positive SFO neurons are involved in persistent or transient suppression of water intake

“…CCK-A and CCK-B receptors are both expressed in the SFO 45 . Ahmed et al reported that neuropeptide CCK caused depolarization in a large population (39.0%) or hyperpolarization in a small population (13.0%) of dissociated rat SFO neurons, and that Fos proteins in the SFO were induced by CCK through CCK-B receptors 45 . In our electrophysiological study, the activation of CCK-positive neurons in the SFO led to the activation of GABAergic neurons via CCK-B receptors (Fig.…”

Neural circuits underlying thirst and fluid homeostasis

“…Thus, SFO GLUT neurons are activated by a presystemic signal generated during eating, and this appears to be a primary cause of prandial thirst. The nature of the signal that communicates information about food ingestion to SFO GLUT neurons is unknown and may involve both neural 83-86 and endocrine 92-103 components.…”

“…16. e | Metabolic hormones secreted during feeding by the gastrointestinal tract 92-95 , pancreas 96-100 , and adipose tissue 101-103 have been proposed to regulate the electrical activity of SFO neurons ex vivo . However, it remains unclear whether such endocrine signals contribute to the natural coordination of eating and drinking by SFO GLUT neurons in vivo .…”