The autonomic nervous system.

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The autonomic nervous system.

Mode of access: Internet.

The involuntary nervous system,

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The diseases of the nervous system,

Mode of access: Internet.

The threat of predictable and unpredictable pain: Differential effects on central nervous system processing?

Central nervous system performance is disrupted by pain and by the threat of pain. It is not known whether disruption caused by the threat of pain is dependent on the likelihood of pain occurring. We hypothesised that when a painful stimulus is possible but unpredictable central nervous system performance is reduced, but when the pain is predictable and unavoidable it is not. Sixteen healthy subjects performed a reaction time task during predictable and unpredictable conditions (100% and 50% probability of pain, respectively). Group data showed increased reaction time with the threat of pain by 50 ms (95% Cl 16 to 83 ms) for the predictable condition and 46 ms (95% CI 12 to 80 ms) for the unpredictable condition (p < 0.01 for both), but there was no difference between predictable and unpredictable conditions (p = 0.41). However, individual data showed that there was a differential effect in 75% of subjects (p < 0.05 for all) and that there was a greater effect of predictable pain for some subjects and a greater effect of unpredictable pain for others. Reaction time was related to reported anxiety (r = 0.49, p = 0.02 for both conditions). The predictability of a painful stimulus may have a differential effect on central nervous system performance within individuals, but anxiety about the impending pain appears to be important in determining this effect.

EphA4 regulates central nervous system vascular formation

Molecules involved in axon guidance have recently also been shown to play a role in blood vessel guidance. To examine whether axon guidance molecules, such as the EphA4 receptor tyrosine kinase, might also play a role in development of the central nervous system (CNS) vasculature and repair following CNS injury, we examined wild-type and EphA4 null mutant (-/-) mice. EphA4-/- mice exhibited an abnormal CNS vascular structure in both the cerebral cortex and the spinal cord, with disorganized branching and a 30% smaller diameter. During development, EphA4 was expressed on endothelial cells. This pattern of expression was not maintained in the adult. After spinal cord injury in wild-type mice, expression of EphA4 was markedly up-regulated on activated astrocytes, many of which were tightly associated with blood vessels. In EphA4-/- spinal cord following injury, astrocytes were not as tightly associated with blood vessels as the wild-type astrocytes. In uninjured EphA4-/- mice, the blood-brain barrier (BBB) appeared normal, but it showed prolonged leakage following spinal cord injury. These results support a role for EphA4 in CNS vascular formation and guidance during development and an additional role in BBB repair.

Non-coding RNAs in the nervous system

Increasing evidence suggests that the development and function of the nervous system is heavily dependent on RNA editing and the intricate spatiotemporal expression of a wide repertoire of non-coding RNAs, including micro RNAs, small nucleolar RNAs and longer non-coding RNAs. Non-coding RNAs may provide the key to understanding the multi-tiered links between neural development, nervous system function, and neurological diseases.

In vivo and in vitro aspects of imidazoline-2(1/2)sites within the central nervous system

The in vivo and in vitro characteristics of the I2 binding site were probed using the technique of drug discrimination and receptor autoradiography. Data presented in this thesis indicates the I2 ligand 2-BFI generates a cue in drug discrimination. Further studies indicated agmatine, a proposed endogenous imidazoline ligand, and a number of imidazoline and imidazole analogues of 2-BFI substitute significantly for 2-BFI. In addition to specific I2 ligands the administration of NRl's (noradrenaline reuptake inhibitors), the sympathomimetic d-amphetamine, the α1-adrenoceptor agonist methoxamine, but not the β1 agonist dobutamine or the β2 agonist salbutamol, gave rise to significant levels of substitution for the 2-BFI cue. The administration of the α1-adrenoceptor antagonist WB4101, prior to 2- BFI itself significantly reduced levels of 2-BFI appropriate responding. Administration of the reversible MAO-A inhibitors moclobemide and Ro41-1049, but not the reversible MAO-B inhibitors lazabemide and Ro16-6491, gave rise to potent dose dependent levels of substitution for the 2-BFI cue. Further studies indicated the administration of a number of β-carbolines and the structurally related indole alkaloid ibogaine also gave rise to dose dependent significant levels of substitution. Due to the relationship of indole alkaloids to serotonin the 5-HT releaser fenfluramine and a number of SSRI's (selective serotonin reuptake inhibitor) were also administered and these compounds gave rise to significant partial (20-80% responses to the 2-BFI lever) levels of substitution. The autoradiographical studies reported here indicate [3H]2-BFI labels I2 sites within the rat arcuate nucleus, area postrema, pineal gland, interpeduncular nucleus and subfornical organ. Subsequent experiments confirmed that the drug discrimination dosing schedule significantly increases levels of [3H]2-BFI 12 binding within two of these nuclei. However, levels of [3H]2-BFI specific binding were significantly reduced within four of these nuclei after chronic treatment with the irreversible MAO inhibitors deprenyl and tranylcypromine but not pargyline, which only reduced levels significantly in two. Further autoradiographical studies indicated that the distribution of [3H]2-BFI within the C57/B mouse compares favourably to that within the rat. Comparison of these levels of binding to those from transgenic mice who over-express MAO-B indicates two possibly distinct populations of [3H]2-BFI 12 sites exist in mouse brain. The data presented here indicates the 2-BFI cue is associated with the selective activation of α1-adrenoceptors and possibly 5-HT receptors. 2-BFI trained rats recognise reversible MAO-A but not MAO-B inhibitors. However, data within this thesis indicates the autoradiographical distribution of I2 sites bears a closer resemblance to that of MAO-B not MAO-A and further studies using transgenic mice that over-express MAO-B suggests a non-MAO-B I2 site exists in mouse brain.

Specific lipidome signatures in central nervous system from methionine-restricted mice

Membrane lipid composition is an important correlate of the rate of aging of animals. Dietary methionine restriction (MetR) increases lifespan in rodents. The underlying mechanisms have not been elucidated but could include changes in tissue lipidomes. In this work, we demonstrate that 80% MetR in mice induces marked changes in the brain, spinal cord, and liver lipidomes. Further, at least 50% of the lipids changed are common in the brain and spinal cord but not in the liver, suggesting a nervous system-specific lipidomic profile of MetR. The differentially expressed lipids includes (a) specific phospholipid species, which could reflect adaptive membrane responses, (b) sphingolipids, which could lead to changes in ceramide signaling pathways, and (c) the physiologically redox-relevant ubiquinone 9, indicating adaptations in phase II antioxidant response metabolism. In addition, specific oxidation products derived from cholesterol, phosphatidylcholine, and phosphatidylethanolamine were significantly decreased in the brain, spinal cord, and liver from MetR mice. These results demonstrate the importance of adaptive responses of membrane lipids leading to increased stress resistance as a major mechanistic contributor to the lowered rate of aging in MetR mice. © 2013 American Chemical Society.