The Arcuate Nucleus: A Site of Fast Negative Feedback for Corticosterone Secretion in Male Rats

Abstract

Variations in circulating corticosterone (Cort) are driven by the paraventricular nucleus of the hypothalamus (PVN), mainly via the sympathetic autonomic nervous system (ANS) directly stimulating Cort release from the adrenal gland and via corticotropin-releasing hormone targeting the adenohypophysis to release adrenocorticotropic hormone (ACTH). Cort feeds back through glucocorticoid receptors (GRs). Here we show in male Wistar rats that PVN neurons projecting to the adrenal gland do not express GRs, leaving the question of how the ANS in the PVN gets information about circulating Cort levels to control the adrenal. Since the arcuate nucleus (ARC) shows a less restrictive blood–brain barrier, expresses GRs, and projects to the PVN, we investigated whether the ARC can detect and produce fast adjustments of circulating Cort. In low Cort conditions (morning), local microdialysis in the ARC with type I GR antagonist produced a fast and sustained increase of Cort. This was not observed with a type II antagonist. At the circadian peak levels of Cort (afternoon), a type II GR antagonist, but not a type I antagonist, increased Cort levels but not ACTH levels. Antagonist infusions in the PVN did not modify circulating Cort levels, demonstrating the specificity of the ARC to give Cort negative feedback. Furthermore, type I and II GR agonists in the ARC prevented the increase of Cort after stress, demonstrating the role of the ARC as sensor to modulate Cort release. Our findings show that the ARC may be essential to sense blood levels of Cort and adapt Cort secretion depending on such conditions as stress or time of day.

Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity

“…This finding appears paradoxical, as it suggests that a Jnk-mediated impairment of the negative HPA axis feedback control in Dusp8 KO mice involves CRH neurons located (with their cell bodies) in the paraventricular nucleus (PVN), but originates in the ARC. Our data are nonetheless consistent with an earlier report that assessed the GRmediated feedback inhibition of corticosterone on CRH release from PVN neurons (42). Specifically, when a GR antagonist was injected into the PVN where the CRH neurons were located, unperturbed feedback inhibition on adrenal corticosterone production was observed.…”

Suprachiasmatic Nucleus Interaction with the Arcuate Nucleus; Essential for Organizing Physiological Rhythms

“…A recent observation that glucocorticoid receptors in the ARC are essential for the circadian variation in the negative feedback of circulating corticosterone on its own release (Leon-Mercado et al, 2017) supports this observation. Locomotor activity, rhythmic in LD, was completely arrhythmic in DD.…”

Predictors of social instability stress effects on social interaction and anxiety in adolescent male rats

“…Zif268 is another immediate‐early gene used as a measure of neural activity (reviewed in Knapska & Kaczmarek, ) in the ARC of SS rats paired with an unfamiliar peer for the 16th time compared with CTL rats paired with an unfamiliar peer for the first time (Hodges & McCormick, ). The ARC is involved in the negative feedback of corticosterone release by the hypothalamic‐pituitary‐adrenal axis; the release of corticosterone in response to a stressor is decreased after corticosterone or glucocorticoid receptor agonists bind to glucocorticoids receptors in the ARC (Leon‐Mercado et al, ) and lesions to the ARC increase corticosterone secretion at baseline and in response to stressors (Larsen, Mikkelsen, Jessop, Lightman, & Chowdrey, ). Greater neural activation of the ARC in response to more time spent in social interaction in SS rats may serve to lessen the release of corticosterone in response to interacting with unfamiliar peers; in SS rats, there was a positive association between Fos‐ir cell counts in the ARC and time in social interaction.…”

“…Zif268 is another immediate-early gene used as a measure of neural activity (reviewed in Knapska & Kaczmarek, 2004) in the ARC of SS rats paired with an unfamiliar peer for the 16th time compared with CTL rats paired with an unfamiliar peer for the first time . The ARC is involved in the negative feedback of corticosterone release by the hypothalamic-pituitary-adrenal axis; the release of corticosterone in response to a stressor is decreased after corticosterone or glucocorticoid receptor agonists bind to glucocorticoids receptors in the ARC (Leon-Mercado et al, 2017) and lesions to the ARC increase corticosterone secretion at baseline and in response to stressors (Larsen, Mikkelsen, Jessop, Lightman, & Chowdrey, 1994).…”

“…To better understand the basis of the decreased social interactions evident in SS rats relative to control (CTL) rats, in the present experiment we compared neural activations in several brain regions involved in initiating and regulating either social behavior (medial amygdala, lateral septum, hippocampus, nucleus accumbens, Bredewold, Smith, Dumais, & Veenema, ; Gur, Tendler, & Wagner, ; Lukas, Toth, Veenema, & Neumann, ; Murakami, Hunter, Fontaine, Ribeiro, & Pfaff, ; Smith, Avram, Cymerblit‐Sabba, Song, & Young, ; Smith, Mogavero, Tulimieri, & Veenema, ) or the release of corticosterone (paraventricular nucleus of the hypothalamus, arcuate nucleus, Leon‐Mercado et al, ; reviewed in Spencer & Deak, ) in response to a 15 min social interaction with a novel rat on postnatal Day 46, 24 hr after the SS procedure, in CTL and SS rats. Fos is the protein product of the immediate early gene c‐fos, and Fos‐immunoreactive cell counts were used as the measure of neural activation.…”