Neuroimaging supports the representational nature of the earliest human engravings.

The earliest human graphic productions, consisting of abstract patterns engraved on a variety of media, date to the Lower and Middle Palaeolithic. They are associated with anatomically modern and archaic hominins. The nature and significance of these engravings are still under question. To address this issue, we used functional magnetic resonance imaging to compare brain activations triggered by the perception of engraved patterns dating between 540 000 and 30 000 years before the present with those elicited by the perception of scenes, objects, symbol-like characters and written words. The perception of the engravings bilaterally activated regions along the ventral route in a pattern similar to that activated by the perception of objects, suggesting that these graphic productions are processed as organized visual representations in the brain. Moreover, the perception of the engravings led to a leftward activation of the visual word form area. These results support the hypothesis that these engravings have the visual properties of meaningful representations in present-day humans, and could have served such purpose in early modern humans and archaic hominins.

IL-10 and IL-4 regulate type-I and type-II IL-1 receptors expression on IL-1 beta-activated mouse primary astrocytes.

When activated by its ligand, the interleukin receptor type I (IL-1RI) transduces signals in cooperation with the IL-1 receptor accessory protein (IL-1RacP). In contrast, IL-1RII functions as a decoy receptor without participating in IL-1 signalling. Brain astrocytes are cellular targets of IL-1 and play a pivotal role in brain responses to inflammation. The regulation of IL-1 receptors on astrocytes by anti-inflammatory cytokines such as IL-4 and IL-10 has not been studied, despite its importance for understanding the way these cells respond to IL-1. Using RT-PCR, we first showed that the expression of IL-1RI and IL-1RII, but not IL-1RacP, mRNAs are up-regulated by IL-1 beta in a time-dependent manner. Using a radioligand binding technique, we then showed that astrocytes display an equivalent number of IL-1RI and IL-1RII. IL-1 beta decreases the number of IL-1RI binding sites, whereas it increases those of IL-1RII. IL-4 and IL-10 both up-regulate IL-1RII IL-1 beta-induced, but only IL-4 does so for IL-1RI. At the protein level, IL-4 and IL-10 dramatically reverse the ability of IL-1 beta to inhibit expression of IL-1RI but neither affects the ability of IL-1 beta to enhance the number of IL-1RII. Collectively, these results establish the existence of receptor cross-talk between pro- and anti-inflammatory cytokines on a critical type of cell that regulates inflammatory events in the brain.

Dexamethasone up-regulates type II IL-1 receptor in mouse primary activated astrocytes.

Brain astrocytes play a pivotal role in the brain response to inflammation. They express IL-1 receptors including the type I IL-1 receptor (IL-1RI) that transduces IL-1 signals in cooperation with the IL-1 receptor accessory protein (IL-1RAcP) and the type II IL-1 receptor (IL-1RII) that functions as a decoy receptor. As glucocorticoid receptors are expressed on astrocytes, we hypothesized that glucocorticoids regulate IL-1 receptors expression. IL-1beta-activated mouse primary astrocytes were treated with 10(-6) M dexamethasone, and IL-1 receptors were studied at the mRNA and protein levels. Using RT-PCR, IL-1RI and IL-1RII but not IL-1RAcP mRNAs were found to be up-regulated by dexamethasone in a time-dependent manner. Dexamethasone (Dex), but not progesterone, had no effect on IL-1RI but strongly increased IL-1RII mRNA expression. Binding studies revealed an increase in the number of IL-1RII binding sites under the effect of Dex, but no change in affinity. These findings support the concept that glucocorticoids have important regulatory effect on the response of astrocytes to IL-1.

Endogenous brain IL-1 mediates LPS-induced anorexia and hypothalamic cytokine expression.

The present study was designed to determine the role of endogenous brain interleukin (IL)-1 in the anorexic response to lipopolysaccharide (LPS). Intraperitoneal administration of LPS (5-10 microgram/mouse) induced a dramatic, but transient, decrease in food intake, associated with an enhanced expression of proinflammatory cytokine mRNA (IL-1beta, IL-6, and tumor necrosis factor-alpha) in the hypothalamus. This dose of LPS also increased plasma levels of IL-1beta. Intracerebroventricular pretreatment with IL-1 receptor antagonist (4 microgram/mouse) attenuated LPS-induced depression of food intake and totally blocked the LPS-induced enhanced expression of proinflammatory cytokine mRNA measured in the hypothalamus 1 h after treatment. In contrast, LPS-induced increases in plasma levels of IL-1beta were not altered. These findings indicate that endogenous brain IL-1 plays a pivotal role in the development of the hypothalamic cytokine response to a systemic inflammatory stimulus.

Interleukin-4 and interleukin-10 regulate IL1-beta induced mouse primary astrocyte activation: a comparative study.

The pro-inflammatory cytokine interleukin-1beta (IL-1beta) is strongly expressed during brain injury and is able to induce severe cellular brain damage via the production of soluble factors. Different processes regulate IL-1 biological activities, like the production of anti-inflammatory cytokines such as interleukin-4 (IL-4) and interleukin-10 (IL-10). In this report, we describe the sequential effects of IL-4 and IL-10 on the production of interleukin-6 (IL-6) induced by IL-1beta in mouse primary astrocytes and compare these effects to those of the synthetic glucocorticoid agonist, dexamethasone. IL-6 secretion and IL-6 mRNA expression were determined by ELISA assay and a comparative RT-PCR method, respectively. Incubation of mouse astrocytes in primary culture simultaneously with IL-1beta (10 ng/ml) + IL-10 (10 ng/ml) or IL-1beta + dexamethasone (10(-6) M) markedly reduced IL-1beta induced IL-6 secretion and IL-6 mRNA expression, respectively, whereas simultaneous addition of IL-4 (10 ng/ml) did not alter the induction of IL-6 by IL-1beta. In contrast, after 24 h of IL-1beta treatment, the level of IL-6 was decreased below constitutive levels, and this change was reversed by addition of IL-4. IL-6 production in IL-1beta pretreated cells was also increased by addition of IL-4, whereas IL-10 and dexamethasone had no effects. The delayed time dependent effect of IL-4 might be partially explained by the induction of IL-4 receptor alpha-chain mRNA expression by IL-1beta. Therefore, we conclude that IL-10 and dexamethasone have rapid immunosuppressive effects on the astrocyte response to IL-1beta stimulation, whereas IL-4, which has a delayed action, acts as an immune inducer.

Blockade of brain type II interleukin-1 receptors potentiates IL1beta-induced anorexia in mice.

Interleukin-1beta (IL1beta) peripheral activities are mediated by type I IL1 receptors (IL1RI), whereas type II IL1 receptors (IL1RII) act as 'decoy' targets. To study the functionality of IL1RII in the brain, mice were treated with an intracerebroventricular injection of a neutralising MoAb directed against IL1RII (4E2, 1 microg) followed by recombinant rat IL1beta at a dose (2 ng) that produced a moderate but significant decrease of food intake 1 h 30 min after injection. The administration of 4E2 to IL-1beta treated mice significantly potentiated IL1beta-induced decrease in food intake without altering hypothermia. The effects of IL1beta were abrogated in the positive control group treated with IL1ra (2 microg, i.c.v). These results suggest that brain IL1RII down-regulate the effects of IL1beta on its cell targets in the brain.

Brain type I but not type II IL-1 receptors mediate the effects of IL-1 beta on behavior in mice.

In the immune system, interleukin (IL)-1 beta effects are mediated by the type I IL-1 receptors (IL-1RI), whereas the type II IL-1 receptors (IL-1RII) act as inhibitory receptors. IL-1RI and IL-1RII are also present in the brain. To study their functionality in the brain, mice were centrally treated with neutralizing monoclonal antibody (MAb) directed against IL-1RI (35F5, 1 microgram) or against IL-1RII (4E2, 2 micrograms) and were centrally injected with recombinant rat IL-1 beta at a dose (2 ng) that decreased social exploration. Only 35F5 was effective in abrogating the behavioral effect of IL-1 beta. Moreover, 4E2 (1 microgram i.c.v.) did not potentiate the behavioral response to a subthreshold dose of IL-1 beta (1 ng i.c.v.). To examine the ability of brain IL-1RI to mediate the effects of endogenous IL-1 beta, mice were centrally treated with 35F5 (4 micrograms) and peripherally injected with IL-1 beta (1 microgram). Like IL-1 receptor antagonist (4 micrograms i.c.v.), 35F5 abrogated the effects of IL-1 beta. These results suggest that brain IL-1RI mediates the behavioral effects of IL-1 beta in mice.

Effect of intracerebroventricular administration of vasopressin on stress-induced hyperthermia in rats.

Vasopressin has been reported to be an endogenous antipyretic peptide. The present study assessed whether this peptide has similar effects on stress-induced hyperthermia. Infusion of 3 ng of vasopressin into the lateral ventricle prior to a 40-min restraint stress reduced significantly the hyperthermic response of rats to this stress, compared to saline-injected controls. Half of the vasopressin-injected animals showed an immediate hypothermic response, with a significant reduction in body temperature of 0.34 degree C or more within 10 min; however, the effect of vasopressin on stress-induced hyperthermia remained significant after exclusion of these animals from the analysis. Administration of a V1 receptor antagonist prior to the stress did not affect the hyperthermic response, which may suggest that the hyperthermic response had reached maximal (ceiling) levels. Administration of vasopressin, or of the V1 receptor antagonist immediately after the stress, did not affect defervescence, suggesting that vasopressinergic systems are not implicated in the defervescence process. Thus, the results show that ICV administration of vasopressin reduces stress-induced hyperthermia. The mechanisms underlying the effects remain to be elucidated.

Endogenous glucocorticoids down regulate central effects of interleukin-1 beta on body temperature and behaviour in mice.

Adrenalectomy sensitizes laboratory animals to the pyrogenic and behavioural effects of proinflammatory cytokines. To determine whether these effects are mediated by central sites of action of glucocorticoids, interleukin-1 beta was injected intracerebroventricularly (i.c.v.) in adrenalectomized mice with or without corticosterone supplementation and in mice pretreated i.c.v. with the glucocorticoid type II receptor antagonist RU38486. Adrenalectomized mice were more sensitive to the depressing effects of i.c.v. IL-1 beta on body temperature and social exploration than sham-operated mice. Corticosterone supplementation reversed the increased sensitivity to the low (300 pg/mouse) but not to the high dose (900 pg/mouse) of IL-1 beta. Central administration of RU38486 (0.5-1 microgram/mouse) mimicked the effects of adrenalectomy on behaviour but not on body temperature. These results suggest that endogenous glucocorticoids released in response to IL-1 beta act in the brain to modulate the sensitivity of the cellular targets of this cytokine.