Tetsuro Hori

Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents

Leptin is well known to be involved in the control of feeding, reproduction and neuroendocrine functions through its action on the hypothalamus. However, leptin receptors are found in brain regions other than the hypothalamus (including the hippocampus and cerebral cortex) suggesting extrahypothalamic functions. We investigated hippocampal long-term potentiation (LTP) and long-term depression (LTD), and the spatial-memory function in two leptin receptor-deficient rodents (Zucker rats and db/db mice). In brain slices, the CA1 hippocampal region of both strains showed impairments of LTP and LTD; leptin (10(-12) M) did not improve these impairments in either strain. These strains also showed lower basal levels of Ca(2+)/calmodulin-dependent protein kinase II activity in the CA1 region than the respective controls, and the levels did not respond to tetanic stimulation. These strains also showed impaired spatial memory in the Morris water-maze test (i.e. longer swim-path lengths during training sessions and less frequent crossings of the platforms original location in the probe test. From these results we suggest that the leptin receptor-deficient animals show impaired LTP in CA1 and poor spatial memory due, at least in part, to a deficiency in leptin receptors in the hippocampus.

Mechanisms and mediators of psychological stress-induced rise in core temperature.

Objective Despite numerous case reports on “psychogenic fever,” it remains uncertain how psychological stress raises core temperature and whether the rise in core temperature is a real fever or a hyperthermia. This article reviews studies on the psychological stress–induced rise in core temperature (PSRCT) in animals with the aim to facilitate studies on the mechanisms of so-called psychogenic fever in humans. Methods To address this question, we reviewed the mechanisms and mediators of the PSRCT and classic conditioning of the fever response in animals. Results The PSRCT is not due to the increased locomotor activity during stress, and the magnitude of the PSRCT is the same in warm and cold environments, indicating that it is a centrally regulated rise in temperature due to an elevated thermoregulatory “set point.” The PSRCT caused by conventional psychological stress models, such as open-field stress, is attenuated by cyclooxygenase inhibitors, which block prostaglandin synthesis. On the other hand, the PSRCT elicited by an “anticipatory anxiety stress” is not inhibited by cyclooxygenase inhibitors but by benzodiazepines and serotonin Type 1A receptor agonists. The febrile response can be conditioned to neutral stimuli after paired presentation with unconditioned stimuli such as injection of lipopolysaccharide, a typical pyrogen. Conclusions Most findings indicate that the PSRCT is a fever, a rise in the thermoregulatory set point. The PSRCT may occur through prostaglandin E2–dependent mechanisms and prostaglandin E2–independent, 5-HT–mediated mechanisms. The febrile response can be conditioned. Thus, these mechanisms might be involved in psychogenic fever in humans.

Exposure to bisphenol A during the fetal and suckling periods disrupts sexual differentiation of the locus coeruleus and of behavior in the rat

This study tested the effect of exposure to bisphenol A (BPA) early in life on the sexual differentiation in the brain and behavior in Wistar rats. We administered BPA only to mother rats during pregnancy and lactation at a dosage of approximately 1.5 mg/kg per day far less than the no-observed-adverse-effect level (NOAEL; 50 mg/kg per day). Control female offspring showed a higher activity, a lower avoidance memory, and larger locus coeruleus than the male controls, while the BPA-exposed group did not show any sexual dimorphism. BPA did not affect the reproductive organs or sex hormones. Our results suggest that the current methods to determine the NOAEL of artificial industrial chemicals may not be sufficient to detect a disruption of the sexual differentiation in the brain.

Intracerebroventricular injection of interleukin-1β induces hyperalgesia in rats

To determine whether interleukin-1 beta (IL-1 beta) in the brain may modulate nociception, recombinant human IL-1 beta (rhIL-1 beta) (1 pg/kg to 1 microgram/kg) was microinjected into the lateral cerebral ventricle of rats and the latency before initiating the licking of their hindpaws after being placed on a hot plate (50.0 +/- 0.1 degrees C) was measured. A significant reduction of the paw-lick latency was observed after injections of nonpyrogenic doses (10 pg/kg to 1 ng/kg) of rhIL-1 beta, showing a maximal response at a dose of 100 pg/kg which began to appear 5 min after injection, reached a peak within 30 min and then gradually subsided. An increase in the amount of rhIL-1 beta to > 1 ng/kg (up to 1 microgram/kg) had no effect on the nociceptive threshold. The rhIL-1 beta-induced hyperalgesia was completely abolished by pretreatment with an IL-1 receptor antagonist (IL-1ra) or Na salicylate. Similar pretreatment with alpha-melanocyte-stimulating hormone (alpha-MSH) also inhibited the rhIL-1 beta-induced hyperalgesia. However, pretreatment with alpha-helical corticotropin-releasing factor (CRF)9-41 failed to affect it. The results suggest that IL-1 beta in the brain produces hyperalgesia by its receptor-mediated and prostaglandin-dependent action which is sensitive to alpha-MSH. The hyperalgesic action of central IL-1 does not appear to depend on the CRF system.

The effects of interleukin 1β on the activity of adrenal, splenic and renal sympathetic nerves in the rat

The effects of intravenous (i.v.) administration of recombinant human interleukin-1 beta (rhIL-1 beta) on the activity of adrenal, splenic and renal sympathetic nerves were observed in urethane-anesthetized rats. An i.v. injection of IL-1 beta in doses of 10 pg-20 ng per animal (300-400 g, b.w.) resulted in a dose-dependent increase in the activity of the adrenal and splenic nerves, which lasted for more than 2-6 h. On the other hand, the activity of renal nerves showed a transient increase which was followed by a long-lasting suppression after injection of rhIL-1 beta (100 pg, i.v.). An i.v. injection of cyclooxygenase inhibitors (6 mg ibuprofen or 20 mg sodium salicylate) suppressed almost completely the rhIL-1 beta (100 pg)-induced activity in adrenal and splenic nerves. Although rhIL-1 beta (100 pg, i.v.) produced a fall in arterial blood pressure, baroreceptor denervation did not affect the excitatory responses of the adrenal and splenic nerves to rhIL-1 beta. The results suggest the regional differentiation of activity in the visceral sympathetic nerves in response to rhIL-1 beta. The rhIL-1 beta-induced activation of splenic sympathetic nerves implicates their involvement in the modulation of immunity by brain.

Effects of interleukin-1 and arachiodonate on the preoptic and anterior hypothalamic neurons

Effects of microelectrophoretic application of ultrapure human interleukin-1 (IL-1), an endogenous pyrogen, on the activity of 80 neurons in the preoptic and anterior hypothalamus (PO/AH) were investigated in the urethane anesthetized rat. IL-1 predominantly decreased the activity of warm-sensitive neurons (15 of 19) and increased the activity of cold-sensitive neurons (10 of 12), but had no effect on 37 of 49 thermally insensitive neurons. The neuronal responses to IL-1 were blocked or attenuated by concurrent application of mepacrine (a phospholipase inhibitor) or sodium salicylate (a cyclooxygenase inhibitor). Local application of sodium arachidonate decreased the activity in 17 of 28 warm-units and excited 12 of 16 cold-units, and the effects of arachidonate were blocked by sodium salicylate. The results are compatible with the view that one or more cyclooxygenase metabolites of arachidonic acid are involved in the IL-1 induced fever.

Interleukin-6 inhibits long-term potentiation in rat hippocampal slices

The effects of recombinant human interleukin-6 (rhIL-6) on long-term potentiation (LTP) induced in the Schaffer collateral/commissural-CA1 pathway were examined using rat hippocampal slices. Field excitatory postsynaptic potential was recorded in the stratum radiatum of the CA1 region. Ten-min applications of rhIL-6 (50-2000 U/ml), started 5 min before the tetanus, significantly inhibited the induction of LTP, and in high doses of rhIL-6 also inhibited short-term potentiation (over 200 U/ml) and post-tetanic potentiation (over 500 U/ml). The effects of rhIL-6 (500 U/ml) were completely abolished by the preincubation of the slices with monoclonal anti-IL-6 receptor antibody (16 microg/ml) for 2 h. Heat-inactivated rhIL-6 had no effect on the synaptic potentiation. RhIL-6 affected neither the previously established LTP nor the basal synaptic transmission. These findings indicated that rhIL-6 modulated synaptic potentiation through the IL-6 receptor-mediated process in the hippocampus, probably by affecting post- and presynaptic sites in the CA1 region. The possible mechanisms of the IL-6-induced suppression of the synaptic potentiation were discussed.

The Autonomic Nervous System as a Communication Channel between the Brain and the Immune System

Much evidence from various fields has revealed multiple channels of communication between the brain and the immune system. Among the routes of signal transmission, this review focuses on the roles and mechanisms of neural communication between the two systems. As for the centrifugal neural pathway by which the brain modulates immunity, there are various requirements for the noradrenergic sympathetic innervation of the primary and secondary lymphoid organs. In addition to the presence of beta- and alpha-adrenergic receptors on different types of immunocompetent cells, histological studies have demonstrated direct contact between tyrosine-hydroxylase-positive nerve terminals and lymphocytes in the spleen and thymus. The exposure of lymphocytes and macrophages to adrenergic agonists in vitro modulates their functions. A surgical or chemical sympathectomy is known to alter the immune responses in rodents. Recent data from the rat show that stress-induced immunosuppression is only slightly affected, if at all, by hypophysectomy or adrenalectomy, whereas it is largely dependent on sympathetic innervation. The splenic sympathetic nerve alters the firing rate by an ablation or stimulation of the hypothalamus, the administration of cytokines or neuropeptides, and an exposure to stress. Furthermore, such procedures provoke the increase in the release of noradrenaline in the rat spleen as assessed by in vivo microdialysis. The altered activities of the splenic sympathetic nerves mentioned above have been found to be causally related to the alteration in immunological responses including natural killer cytotoxicity. The splenic sympathetic nerve may thus constitute a communication channel that mediates central modulation of peripheral cellular immunity. Although the roles and mechanisms of parasympathetic control of lymphoid organs still remain obscure, recent data suggest that the thymic vagal efferent nerve may be involved in central modulation of immunity. Finally, electrophysiological studies have shown that hepatic vagal afferents may be one of the pathways through which blood-borne cytokines signal the brain.

In vivo measurement of hypothalamic serotonin release by intracerebral microdialysis: Significant enhancement by immobilization stress in rats

Intracerebral microdialysis was used to measure extracellular serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the hypothalamus of unanesthetized rats. Increase in the concentration of K+ in the perfusing Ringer solution (70 mM) produced a sharp increase in serotonin release, which was significantly attenuated by omitting Ca2+ from the perfusion medium. Intraperitoneal injection of 5-hydroxytryptophan, a precursor of serotonin, or local perfusion of pargyline, a monoamine oxidase inhibitor, elevated the hypothalamic serotonin. Releasers or uptake inhibitors of serotonin, such as fenfluramine, cocaine, mazindol, or imipramine, when added to the perfusion medium, significantly increased serotonin level, whereas 5-HIAA was unaffected by these substances. Immobilization-stress caused an immediate increase in both the extracellular serotonin and 5-HIAA in the hypothalamus, suggesting that the hypothalamic serotonergic system is activated during immobilization stress. The present study indicates that the brain microdialysis is useful for analysis of local changes in serotonin concentration which directly reflect neuronal transmission.

Intracerebroventricular injection of interleukin-6 induces thermal hyperalgesia in rats.

We assessed the effect of interleukin-6 (IL-6) in the brain on nociception by using the hot-plate test in rats. Recombinant human IL-6 (rhIL-6, 30 pg-300 ng) was microinjected into the lateral cerebroventricle (LCV) and the paw-withdrawal latency was then measured for 60 min after injection. RhIL-6 at 300 pg reduced the paw-withdrawal latency at 15 min after injection. Further increase of rhIL-6 doses to 3, 30 and 300 ng resulted in the decreased paw-withdrawal latency at 15 and 30 min. Although the peak responses observed at 3-300 ng did not differ significantly, the time taken for recovery tended to be longer with increasing doses. The rhIL-6 (30 ng)-induced reduction of the paw-withdrawal latency was completely blocked by the co-injection of either Na salicylate (30 ng, LCV) or alpha-melanocyte stimulating hormone (30 ng, LCV), an anti-cytokine substance. However, it was not affected by the co-injection of IL-1 receptor antagonist (30 ng, LCV) which had been previously shown to be able to block IL-1 beta-induced hyperalgesia. These findings indicate that IL-6 in the brain induces hyperalgesia by its prostanoids-dependent action in rats. The hyperalgesic action of central IL-6 thus does not appear to depend on the action of IL-1.