Circulating signals as critical regulators of autonomic state—central roles for the subfornical organ

Abstract

To maintain homeostasis autonomic control centers in the hypothalamus and medulla must respond appropriately to both external and internal stimuli. Although protected behind the blood-brain barrier, neurons in these autonomic control centers are known to be influenced by changing levels of important signaling molecules in the systemic circulation (e.g., osmolarity, glucose concentrations, and regulatory peptides). The subfornical organ belongs to a group of specialized central nervous system structures, the circumventricular organs, which are characterized by the lack of the normal blood-brain barrier, such that circulating lipophobic substances may act on neurons within this region and via well-documented efferent neural projections to hypothalamic autonomic control centers, influence autonomic function. This review focuses on the role of the subfornical organ in sensing peripheral signals and transmitting this information to autonomic control centers in the hypothalamus.

Obesity-induced hepatic steatosis is mediated by endoplasmic reticulum stress in the subfornical organ of the brain

“…However, selective overexpression of GRP78 and reductions in HFD-induced ER stress biomarkers specifically in the SFO did not influence obesity-associated elevations in arterial pressure and heart rate. These findings were surprising, considering the SFO is well recognized to play a critical role in cardiovascular control (29)(30)(31) and ER stress in the SFO is directly involved in other forms of hypertension (e.g., angiotensin-II) (24). Taken together, our findings suggest that, while brain ER stress contributes to the maintenance of hypertension and tachycardia in obesity (i.e., ICV TUDCA), this is not due to UPR activation in the SFO.…”

“…In light of our findings of ER stress-mediated cardiovascular and metabolic effects (Figure 2, A-C, H, and I), we focused our attention on the sensory circumventricular SFO. This tiny forebrain CNS nucleus located at the base of the lateral ventricle is highly vascularized and lacks a blood-brain-barrier ( Figure 3A), unlike the vast majority of brain regions, including the hypothalamus (29)(30)(31). This unique feature makes the SFO highly susceptible to ER stress during obesity due to its constant exposure to circulating metabolites, hormones, and inflammatory mediators.…”

“…Indeed, selectively reducing UPR activation in the SFO resulted in a restoration of obesity-induced hepatomegaly and heaptic steatosis. While the underlying molecular mechanisms in the SFO that modulate hepatic lipid regulation remain to be determined, the SFO contains extensive efferent connections to brainstem and hypothalamic metabolic control regions (29)(30)(31). Thus, it is possible that ER stress in the SFO alters downstream CNS networks that influence liver metabolism through hormonal (i.e., insulin/glucagon) as well as autonomic nervous system control (17)(18)(19)(20).…”

Angiotensin-II-induced reactive oxygen species along the SFO-PVN-RVLM pathway: implications in neurogenic hypertension

“…It is composed of two distinct regions: a core region and a peripheral outer zone, each region with different neuronal projections and ligand binding abilities (7). The majority of anatomical data suggest that SFO neurons have compact dendritic trees and do not receive extensive neural inputs, supporting the suggested principal role of this region in receiving afferent information from the peripheral circulation (8,9). Furthermore, SFO neurons synapse directly (monosynaptic) and indirectly (polysynaptic) to the hypothalamic areas, such as the PVN and supraoptic nucleus (10,11).…”

Connections of the lateral hypothalamic area juxtadorsomedial region in the male rat

“…The more extensive input to the LHAjd from the lateral PB suggests a more prominent influence of ascending viscerosensory information (Saper, 2002) than for the LHAjp. Similarly, the SFO retrograde labeling identifies the LHAjd as a likely recipient of humerosensory information from a circumventricular organ that has a central role in autonomic control (Smith and Ferguson, 2010) and drinking behavior (Smith et al, 1995); however, the SFO and lateral PB input to the LHAjd is relatively small in comparison with the more abundant input to the adjacent LHAs, which also has light bidirectional connections with the LHAjd (present data; Hahn and Swanson, 2010). Among their diverse functions the PB (especially the lateral PB) and the SFO have a major role in the control of water and sodium intake (Smith et al, 1995;Fitzsimons, 1998;Geerling and Loewy, 2008), and more recent work indicates that communication between the PB and the LHA is necessary for the expression of sodium appetite in rats (Dayawansa et al, 2011).…”