Neuroscience
-
Manipulations that increase the expression of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) in the hippocampus (e.g. peripheral administration of lipopolysaccharide, i.c.v. glycoprotein 120, social isolation) as well as the intrahippocampal injection of IL-1beta following a learning experience, dramatically impair the memory of that experience if the formation of the memory requires the hippocampus. Here we employed social isolation to further study this phenomenon, as well as its relation to brain-derived neurotrophic factor (BDNF). ⋯ Moreover, an intrahippocampal injection of the IL-1 receptor antagonist prior to the isolation period prevented both the BDNF downregulation and the memory impairments produced by the isolation. These data suggest that hippocampal-dependent memory impairments induced by elevated levels of brain IL-1beta may occur via an IL-1beta-induced downregulation in hippocampal BDNF.
-
The viral transneuronal labeling method was used to demonstrate that orexin-containing neurons of the lateral hypothalamic area (LHA) are linked via multisynaptic connections to different sympathetic outflow systems. Two different types of transneuronal tracing experiments were performed: single- and double-virus studies. In the first series of experiments, Bartha pseudorabies virus (PRV), a retrograde transneuronal tracer, was injected into single sympathetic targets, viz., stellate ganglion, adrenal gland, celiac ganglion, and kidney. ⋯ The reverse placement of viral injections was made in another set of rats. In both paradigms, some orexin LHA neurons were transneuronally labeled with both viruses, indicating that they are capable of modulating multiple sympathetic outflow systems. These findings raise the possibility that orexin LHA neurons regulate general sympathetic functions, such as those that occur during arousal or the fight-or-flight response.
-
Chronic opiate applications produce long-term impacts on many functions of the brain and induce tolerance, dependence, and addiction. It has been demonstrated that opioid drugs are capable to induce apoptosis of neuronal cells, but the mechanism is not clear. c-Jun N-terminal kinase 3 (JNK3), specifically expressed in brain, has been proved to mediate neuronal apoptosis and is involved in opiate-induced cell apoptosis in vitro. The present study investigated the effect of opioid administration on expression of JNK3, an important mediator involved in apoptosis of neurons, in rat brain. ⋯ The increased JNK3 mRNA in these brain areas returned to the control levels in 28 days following cessation of chronic morphine treatment. Taken together, these results demonstrated for the first time that the expression of JNK3 gene is regulated by opioids and that chronic opioid administration and withdrawal could induce sustained elevation of JNK3 mRNA in many important brain areas. The changes in JNK3 gene expression in brain induced by chronic opioid treatment may play a role in opioid-induced apoptosis and neurotoxicity.
-
Changes in kappa-opioid receptor levels have been implicated in the development of physical dependence upon and withdrawal from the mixed agonist-antagonist opioid, butorphanol. Immunoblotting analysis was performed to determine the levels of kappa- and mu-opioid receptors in brain regions of rats in withdrawal from dependence upon butorphanol or morphine. Physical dependence was induced by a 72 h i.c.v. infusion with either butorphanol or morphine (26 nmol/microl/h). ⋯ These findings contrasted with those from morphine-withdrawal rats, in which the only changes noted were increases in the thalamus and paraventricular thalamus. Changes in the levels of the mu-opioid receptor protein were observed in 11 of 21 brain regions examined in morphine-withdrawal rats, but only in three of 21 in butorphanol-withdrawal rats. These results implicate a substantive and largely unique role for kappa-opioid receptors in mediation of the development of physical dependence upon, and the expression of withdrawal from, butorphanol, as opposed to the prototypical opioid analgesic, morphine.
-
Glial cell line-derived neurotrophic factor (GDNF) signals through multisubunit receptor complex consisting of RET tyrosine kinase and a glycosylphosphatidylinositol-anchored coreceptor called GDNF family receptor alpha1 (GFRalpha1). In the current study, we cloned a human SEP1 gene as a GDNF-inducible gene using human neuroblastoma cells that express RET and GFRalpha1. The induction of the SEP1 gene showed two peaks at 0.5-2 h and 24-48 h after GDNF stimulation by Northern blotting and quantitative real-time reverse transcriptase polymerase chain reaction. ⋯ In addition, we found a high level of SEP1 expression in neurons of the dorsal root and superior cervical ganglia and motor neurons of the spinal cord of mice in which RET is also expressed. SEP1 was co-immunoprecipitated with alpha- and beta-tubulins from the lysate of mouse brain. These results thus suggested that SEP1 is a GDNF-inducible and microtubule-associated protein that may play a role in the nervous system.