Location-specific activation of the paraventricular nucleus of the hypothalamus by localized inflammation

Belevych, Natalya; Buchanan, Krystal; Chen, Qun; Bailey, Michael T.; Quan, Ning

doi:10.1016/j.bbi.2010.05.007

Cited by 27 publications

(16 citation statements)

References 30 publications

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“…An alternative explanation is that low-dose LPS might directly stimulate PVN, bypassing the NTS and VLM. This is similar to our previous report that indicated localized inflammation induces location-specific response only in the PVN, not in the NTS and VLM [31]. Although vagal afferents are critical for transmitting sensory signals from the peritoneal cavity, recent studies showed that spinal afferents from the peritoneal cavity can also be activated by sensory inputs [32].…”

Section: Discussionsupporting

confidence: 90%

Neural and behavioral responses to low-grade inflammation

Tarr

Chen

Wang

et al. 2012

Behavioural Brain Research

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Neural and behavioral responses after peripheral immune challenge have been observed in numerous studies. The majority of these studies have utilized relatively high doses of lipopolysaccharide (LPS) as the immune stimulant. Little attention has been given to the effects of LPS dose ranges that simulate low grade-inflammation. The current studies were designed to characterize neural and behavioral responses following low-dose LPS stimulation. Results show burrowing and open field activity was significantly impaired following a single i.p. injection of 10, but not 1, µg/kg of LPS. In addition, following repeated 1 µg/kg LPS administration for 10 days, animals showed the progressive development of motor deficits over time. To correlate behavior with CNS activity, cFos activation was determined in the paraventricular nucleus, nucleus of the solitary tract, central amygdaloid nucleus, and ventrolateral medulla. Data revealed there was a dose-dependent activation in all brain areas examined, but only the PVN showed significant activation by low-dose LPS. Additionally, animals that received 1 µg/kg of LPS for 8 days had PVN cFos activation similar to animals that received a single 10 µg/kg LPS injection. These data demonstrate neural and behavior responses can be induced by low-grade inflammation and chronic exposure to sub-threshold levels of LPS can precipitate significantly heightened neural and behavioral responses.

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Section: Discussionsupporting

confidence: 90%

Neural and behavioral responses to low-grade inflammation

Tarr

Chen

Wang

et al. 2012

Behavioural Brain Research

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“…Moreover, blockage of neural signaling in somatic nerves by local anesthesia has been shown to abolish centrally elicited responses to peripheral immune challenge (Belevych et al, 2010;Roth and De Souza, 2001). Considering the findings in previous studies (Ching et al, 2007;Elander et al, 2009), it is hence conceivable that the c-Fos expression in the by such a direct neuronal route, whereas the activation that was seen after intravenous injection of IL-1β may be dependent on signaling across the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 90%

Interleukin-1β induced activation of the hypothalamus–pituitary–adrenal axis is dependent on interleukin-1 receptors on non-hematopoietic cells

Matsuwaki

Eskilsson

Kugelberg

et al. 2014

Brain, Behavior, and Immunity

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The proinflammatory cytokine interleukin-1β (IL-1β) plays a major role in the signal transduction of immune stimuli from the periphery to the central nervous system, and has been shown to be an important mediator of the immune-induced stress hormone release. The signaling pathway by which IL-1β exerts this function involves the bloodbrain-barrier and induced central prostaglandin synthesis, but the identity of the bloodbrain-barrier cells responsible for this signal transduction has been unclear, with both endothelial cells and perivascular macrophages suggested as critical components. Here, using an irradiation and transplantation strategy, we generated mice expressing IL-1 type 1 receptors (IL-1R1) either in hematopoietic or non-hematopoietic cells and subjected these mice to peripheral immune challenge with IL-1β. Following both intraperitoneal and intravenous administration of IL-1β, mice lacking IL-1R1 in hematopoietic cells showed induced expression of the activity marker c-Fos in the paraventricular hypothalamic nucleus, and increased plasma levels of ACTH and corticosterone. In contrast, these responses were not observed in mice with IL-1R1 expression only in hematopoietic cells. Immunoreactivity for IL-1R1 was detected in brain vascular cells that displayed induced expression of the prostaglandin synthesizing enzyme cyclooxygenase-2 and that were immunoreactive for the endothelial cell marker CD31, but was not seen in cell positive for the brain macrophage marker CD206. These results imply that activation of the HPA-axis by IL-1β is dependent on IL-1R1s on nonhematopoietic cells, such as brain endothelial cells, and that IL-1R1 on perivascular macrophages are not involved. Matsuwaki et al., p. 3

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“…For example, cFOS was increased in the reward circuitry following HFD [120] and in the dorsomedial and lateral hypothalamus [121]. cFOS is similarly induced following LPS treatment in the hypothalamus [122] and this induction is location specific [123]. These studies also postulated that the location is dependent on the neuron function and suggested that cFOS was induced following neuron activation, since cFOS is the most commonly used marker of neuronal activity.…”

Section: Discussionmentioning

confidence: 93%

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

Lainez

Coss²

2019

Neuroendocrinology

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Background: The mechanisms whereby neuroinflammation negatively affects neuronal function in the hypothalamus are not clear. Our previous study determined that obesity-mediated chronic inflammation elicits sex-specific impairment in reproductive function via reduction in spine density in gonadotropin-releasing hormone (GnRH) neurons. Neuroinflammation and subsequent decrease in GnRH neuron spine density was specific for male mice, while protection in females was independent of ovarian estrogens. Methods: To examine if neuroinflammation-induced cytokines can directly regulate GnRH gene expression, herein we examined signaling pathways and mechanisms in males in vivo and in GnRH-expressing cell line, GT1–7. Results: GnRH neurons express cytokine receptors, and chronic or acute neuroinflammation represses GnRH gene expression in vivo. Leukemia inhibitory factor (LIF) in particular represses GnRH expression in GT1–7 cells, while other cytokines do not. STAT3 and MAPK pathways are activated following LIF treatment, but only MAPK pathway, specifically p38α, is sufficient to repress the GnRH gene. LIF induces cFOS that represses the GnRH gene via the -1,793 site in the enhancer region. In vivo, following high-fat diet, cFOS is induced in GnRH neurons and neurons juxtaposed to the leaky blood brain barrier of the organum vasculosum of the lamina terminalis, but not in the neurons further away. Conclusion: Our results indicate that the increase in LIF due to neuroinflammation induces cFOS and represses the GnRH gene. Therefore, in addition to synaptic changes in GnRH neurons, neuroinflammatory cytokines directly regulate gene expression and reproductive function, and the specificity for neuronal targets may stem from the proximity to the fenestrated capillaries.

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Location-specific activation of the paraventricular nucleus of the hypothalamus by localized inflammation

Cited by 27 publications

References 30 publications

Neural and behavioral responses to low-grade inflammation

Neural and behavioral responses to low-grade inflammation

Interleukin-1β induced activation of the hypothalamus–pituitary–adrenal axis is dependent on interleukin-1 receptors on non-hematopoietic cells

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

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