Fever is triggered by an elevation of prostaglandin E 2 (PGE 2 ) in the brain. However, the mechanism of its elevation remains unanswered. We herein cloned the rat glutathione-dependent microsomal prostaglandin E synthase (mPGES), the terminal enzyme for PGE 2 biosynthesis, and examined its induction in the rat brain after intraperitoneal injection of pyrogen lipopolysaccharide (LPS). In Northern blot analysis, mPGES mRNA was weakly expressed in the brain under the normal conditions but was markedly induced between 2 and 4 hr after the LPS injection. In situ hybridization study revealed that LPS-induced mPGES mRNA signals were mainly associated with brain blood vessels, especially vein or venular-type ones, in the whole brain area. Immunohistochemical study demonstrated that mPGESlike immunoreactivity was expressed in the perinuclear region of brain endothelial cells, which were identified as von Willebrand factor-positive cells. Furthermore, in the perinuclear region of the endothelial cells, mPGES was colocalized with cyclooxygenase-2 (COX-2), which is the enzyme essential for the production of the mPGES substrate PGH 2 . Inhibition of cyclooxygenase-2 activity resulted in suppression of both PGE 2 level in the CSF and fever (Cao et al., 1997), suggesting that the two enzymes were functionally linked and that this link is essential for fever. These results demonstrate that brain endothelial cells play an essential role in the PGE 2 production during fever by expressing COX-2 and mPGES.

Stress necessitates an immediate engagement of multiple neural and endocrine systems. However, exposure to a single stressor causes adaptive changes that modify responses to subsequent stressors. Recent studies examining synapses onto neuroendocrine cells in the paraventricular nucleus of the hypothalamus demonstrate that stressful experiences leave indelible marks that alter the ability of these synapses to undergo plasticity. These adaptations include a unique form of metaplasticity at glutamatergic synapses, bidirectional changes in endocannabinoid signalling and bidirectional changes in strength at GABAergic synapses that rely on distinct temporal windows following stress. This rich repertoire of plasticity is likely to represent an important building block for dynamic, experience-dependent modulation of neuroendocrine stress adaptation.

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The appetite suppressing hormone leptin has emerged as an important modulator of immune function and is now considered to be a critical link between energy balance and host defense responses to pathogens. These 'adaptive' responses can, in situations of severe and sustained systemic inflammation, lead to adverse effects including brain damage that is partly mediated by neutrophil recruitment into the brain. We examined the contribution of leptin to this process in leptin-deficient (ob/ob), -resistant (db/db) and wild-type (WT) mice injected intraperitoneally with a septic dose of lipopolysaccharide (LPS). This treatment induced a dramatic increase in the number of neutrophils entering the brain of WT mice, an effect that was almost totally abolished in the mutant mice and correlated with a significant reduction in the mRNA levels of interleukin-1b, intracellular adhesion molecule-1 and neutrophil-specific chemokines. These effects were reversed with leptin replenishment in ob/ob mice leading to recovery of neutrophil recruitment into the brain. Moreover, 48 h food deprivation in WT mice, which decreased circulating leptin levels, attenuated the LPS-induced neutrophil recruitment as did a single injection of an anti-leptin antiserum 4 h before LPS treatment in WT mice. These results provide the first demonstration that leptin has a critical role in leukocyte recruitment to the brain following severe systemic inflammation with possible implications for individuals with altered leptin levels such as during obesity or starvation.

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Changes in food availability alter the output of hypothalamic nuclei that underlie energy homeostasis. Here, we asked whether food deprivation impacts the ability of GABA synapses in the dorsomedial hypothalamus (DMH), an important integrator of satiety signals, to undergo activity-dependent changes. GABA synapses in DMH slices from satiated rats exhibit endocannabinoid-mediated long-term depression (LTD(GABA)) in response to high-frequency stimulation of afferents. When CB1Rs are blocked, however, the same stimulation elicits long-term potentiation (LTP(GABA)), which manifests presynaptically and requires heterosynaptic recruitment of NMDARs and nitric oxide (NO). Interestingly, NO signaling is required for eCB-mediated LTD(GABA). Twenty-four hour food deprivation results in a CORT-mediated loss of CB1R signaling and, consequently, GABA synapses only exhibit LTP(GABA). These observations indicate that CB1R signaling promotes LTD(GABA) and gates LTP(GABA). Furthermore, the satiety state of an animal, through regulation of eCB signaling, determines the polarity of activity-dependent plasticity at GABA synapses in the DMH.

Stressful experience initiates a neuroendocrine response culminating in the release of glucocorticoid hormones into the blood. Glucocorticoids feed back to the brain causing adaptations that prevent excessive hormone responses to subsequent challenges. How these changes occur remains unknown. We report that glucocorticoid receptor activation in rodent hypothalamic neuroendocrine neurons following in vivo stress is a metaplastic signal that allows GABA synapses to undergo activity–dependent long–term depression (LTDGABA). LTDGABA is unmasked through glucocorticoid receptor inhibition of Regulator of G–protein Signaling 4 (RGS4), which amplifies signaling through postsynaptic metabotropic glutamate receptors (mGluRs). This drives somatodendritic opioid release, resulting in a persistent retrograde suppression of synaptic transmission through presynaptic μ–receptors. Together our data provide new evidence for retrograde opioid signaling at synapses in neuroendocrine circuits and represent a potential mechanism underlying GC contributions to stress adaptation.