Neurosteroids: a new brain function?

The biosynthesis of neurosteroids proceeds through cholesterol side-chain cleavage, and gives rise to pregnenolone (P) and dehydroepiandrosterone (D). These steroids accumulate in the rat brain independently of the supply by peripheral endocrine glands. This led to the discovery of a steroid biosynthesis pathway in rat brain oligodendrocytes based on enzyme immunocytochemistry and conversion of radioactive precursors to C-21 steroids. Several biological functions have been proposed for P and D. They may serve as precursors of other steroids (such as progesterone and testosterone and their metabolites). They are implicated in the control of some behavioural activities. They have excitatory effects on neurons, and they modulate the function of GABAA-receptors. These observations may apply to all mammalian species including the human, and the physiological significance of neurosteroid synthesis needs further investigation. The relationship between steroids and cerebral function may be reconsidered in the light of a new fact: the existence of a biosynthetic pathway of these compounds from cholesterol, assured in the brain by the oligodendrocytes, glial cells which synthesize myelin.     

Fragmentation of clones: how does it influence dispersal and competitive ability?

We applied individual-based simulations to study the effect of physiological integration among ramets in clonal species that live in patchy habitats. Three strategies were compared: (1) Splitter, in which the genet was fragmented into independent ramets; (2) Transient Integrator, where only groups of ramets were connected; and (3) Permanent Integrator, in which fragmentation did not occur, and the whole genet was integrated. We studied the dynamics of spatial spreading and population growth in these strategies separately and in competition. Various habitat types were modeled by changing the density of favorable habitat patches. We found that the spatial pattern of good patches significantly influenced the growth of the populations. When the resource patches were scarce, a large proportion of the carrying capacity of the habitat was not utilized by any of the strategies. It was the Splitter that proved to be the most severely dispersal-limited. But at the same time, it could compete for the good patches most efficiently. The balance between these two contradictory effects was largely determined by the proportion of favorable to unfavorable areas. When this proportion was low or intermediate (up to ca. 50% good), integration was more advantageous. At higher proportions, fragmentation became beneficial. Fragmentation into groups of ramets (Transient Integration) was not sufficient, only radical splitting could ensure a significant selective advantage. Transient Integrators got fragmented according to the spatial pattern of ramet mortality. It was interesting that the enrichment of the area in good sites did not lead to larger fragment sizes. It merely raised the number of fragments. Nevertheless, these small fragments were more similar to integrated genets (in the Permanent Integrator) than to solitary ramets (in the Splitter) in terms of dispersal and competitive ability. This suggests that even a slightly integrated clonal species can be ecologically considered as an integrator.     

Cerebellar function: coordination, learning or timing?

Theories of cerebellar function have largely involved three ideas: movement coordination, motor learning or timing. New evidence indicates these distinctions are not particularly meaningful, as the cerebellum influences movement execution by feedforward use of sensory information via temporally specific learning.     

The current excitement in bioinformatics-analysis of whole-genome expression data: how does it relate to protein structure and function?

Whole-genome expression profiles provide a rich new data-trove for bioinformatics. Initial analyses of the profiles have included clustering and cross-referencing to 'external' information on protein structure and function. Expression profile clusters do relate to protein function, but the correlation is not perfect, with the discrepancies partially resulting from the difficulty in consistently defining function. Other attributes of proteins can also be related to expression-in particular, structure and localization-and sometimes show a clearer relationship than function.     

4.5S RNA: does form predict function?

4.5S RNA is a stable RNA of Escherichia coli, and functional homologs of the molecule apparently exist in all prokaryotes: eubacteria, archebacteria, and mycoplasma. Genetic and physiological measurements of the function of 4.5S RNA in E. coli indicate a role for this RNA in protein synthesis. A conserved domain of 4.5S RNA displays structural similarity with the eukaryotic 7S RNA that functions in protein secretion. Although complementation by eukaryotic 7S RNAs remains to be demonstrated, a number of archaebacterial 7S RNAs are able to replace 4.5S RNA for growth of E. coli, and 4.5S RNA is able to mediate a number of 7S RNA functions in vitro. Surprisingly, no effects on protein secretion in E. coli have been directly attributed to 4.5S RNA. These observations raise the question of whether molecules of similar structure necessarily perform the same function.     

Human CD8+CD25 +CD127 low regulatory T cells: microRNA signature and impact on TGF-β and IL-10 expression

Regulatory T cells (Tregs) are central for maintaining immune balance and their dysfunction drives the expansion of critical immunologic disorders. During the past decade, microRNAs (miRNAs) have emerged as potent regulators of gene expression among which immune-related genes and their immunomodulatory properties have been associated with different immune-based diseases. The miRNA signature of human peripheral blood (PB) CD8⁺CD25 ⁺CD127 ^low Tregs has not been described yet. We thus identified, using TaqMan low-density array (TLDA) technique followed by individual quantitative real-time polymerase chain reaction (qRT-PCR) confirmation, 14 miRNAs, among which 12 were downregulated whereas two were upregulated in CD8 ⁺CD25 ⁺CD127 ^low Tregs in comparison to CD8 ⁺CD25 ⁻ T cells. In the next step, microRNA Data Integration Portal (mirDIP) was used to identify potential miRNA target sites in the 3′-untranslated region (3′-UTR) of key Treg cell-immunomodulatory genes with a special focus on interleukin 10 (IL-10) and transforming growth factor β (TGF-β). Having identified potential miR target sites in the 3′-UTR of IL-10 (miR-27b-3p and miR-340-5p) and TGF-β (miR-330-3p), we showed through transfection and transduction assays that the overexpression of two underexpressed miRNAs, miR-27b-3p and miR-340-5p, downregulated IL-10 expression upon targeting its 3′-UTR. Similarly, overexpression of miR-330-3p negatively regulated TGF-β expression. These results highlighted an important impact of the CD8 ⁺ Treg mirnome on the expression of genes with significant implication on immunosuppression. These observations could help in better understanding the mechanism(s) orchestrating Treg immunosuppressive function toward unraveling new targets for treating autoimmune pathologies and cancer.     

HSP70 expression: does it a novel fatigue signalling factor from immune system to the brain?

Integrative physiology studies have shown that immune system and central nervous system interplay very closely towards behavioural modulation. Since the 70-kDa heat shock proteins (HSP70s), whose heavy expression during exercise is well documented in the skeletal muscle and other tissues, is also extremely well conserved in nature during all evolutionary periods of species, it is conceivable that HSP70s might participate of physiologic responses such as fatigue induced by some types of physical exercise. In this way, increased circulating levels of extracellular HSP70 (eHSP70) could be envisaged as an immunomodulatory mechanism induced by exercise, besides other chemical messengers (e.g. cytokines) released during an exercise effort, that are able to binding a number of receptors in neural cells. Studies from this laboratory led us to believe that increased levels of eHSP70 in the plasma during exercise and the huge release of eHSP70 from lymphocytes during high-load exercise bouts may participate in the fatigue sensation, also acting as a danger signal from the immune system.     

Pituitary hormones in the brain: what is their function?

Data concerning the presence in the central nervous system of the anterior and intermediate lobe hormones ACTH, beta-lipotropin, alpha-melanocyte stimulating hormone, beta-endorphin, prolactin, growth hormone, gonadotrophic hormone, and thyrotropin stimulating hormone are reviewed. Available evidence for the ACTH-lipotropin family of peptides indicates that synthesis can occur in brain as well as in pituitary. Although behavioral effects have been described for some of these peptides and their fragments (ACTH, alpha-MSH, beta-endorphin, prolactin), the physiological relevance and the mechanisms of such effects, the nature of the biosynthetic pathways involved, and the factors regulating the brain concentrations of these peptides remain to be explored.     

Hypochlorite-oxidized low-density lipoprotein upregulates CD36 and PPARγ mRNA expression and modulates SR-BI gene expression in murine macrophages

Huntington's disease (HD) is associated with expansion of polyglutamine tract in a protein named huntingtin (htt) that is expressed in virtually all body tissues. Thus mutated htt (HD-htt) might affect all organs, although clinical manifestations of HD are associated with selective loss of corticostriatal neurons of the brain. In this work we studied how HD-htt affects mitochondria in human peripheral blood cells. We compared various functions of mitochondria isolated from cultured lymphoblastoid cells derived from three HD patients with juvenile onset of the disease (HD-LBM) and three age-matched control (C-LBM) individuals. Respiratory parameters in different metabolic states, with succinate and glutamate plus malate were the same for all control and HD cell lines. State 4 membrane potential in HD-LBM was slightly lower than in C-LBM. The calcium retention capacity (CRC) of mitochondria was estimated using simultaneously several methods to register permeability transition (PT). We found that LBM do not undergo swelling upon Ca2+-induced PT, and do not increase CRC in the presence of ADP + oligomycin. Although each cell line had different CRC values, qualitatively PT was different in C-LBM and HD-LBM. With C-LBM cyclosporin A (CsA) increased CRC significantly, while with HD-LBM CsA was ineffective. In C-LBM depolarization of mitochondria and a large pore opening (PT) always occurred simultaneously. In HD-LBM depolarization occurred at 20-50% lower Ca2+ loads than PT. We suggest that HD-htt promotes low H+ conductance of the mitochondria by interacting with proteins at the contacts sites without directly promoting PT or hampering mitochondrial oxidative phosphorylation.     

Neuropeptide-specific peptidases: does brain contain a specific TRH-degrading enzyme?

The particulate fraction of brain homogenates contains an enzyme that cleaves the pyroglutamyl-histidyl bond of thyrotropin-releasing hormone (TRH) but is clearly distinct from the more widely distributed pyroglutamyl peptidase (EC 3.4.19.3). This particulate enzyme is highly localized to brain where it is found on synaptosomal membranes. It exhibits an unusual degree of substrate specificity. For example, it does not cleave the pyroglutamyl-histidyl bond of luteinizing hormone-releasing hormone (LHRH) or the pyroglutamyl histidyl bond of the chromogenic substrate pyroglutamyl-histidyl-2-naphthylamide. Evidence is reviewed supporting the possibility that this enzyme, first detected in serum and originally referred to as "thyroliberinase", may be the first neuropeptide-specific peptidase to be characterized.     

How does the brain control its own activity? A new function for the basal ganglia

It has long been a problem in neuroscience to known how the brain controls its own activity, how it is able to control the level of CNS excitability and how it is able to select and act on some information as opposed to some other information. In this paper I propose a new theory in which the basal ganglia play a role in selecting information ("selective attention") and in controlling the general level of excitability of the CNS ("state control"), the two processes being to some extent interdependent. The basal ganglia achieve these functions by actions on the thalamic-frontal cortical axis and on the brainstem mesencephalic reticular formation.     

How does gene expression clustering work?

Clustering is often one of the first steps in gene expression analysis. How do clustering algorithms work, which ones should we use and what can we expect from them?     

Accumulation of aluminum in rat brain: does it lead to behavioral and electrophysiological changes?

The present study was undertaken to examine possible aluminum (Al) accumulation in the brain of rats and to investigate whether subchronic exposure to the metal leads to behavioral and neurophysiological changes in both treated and control groups. Each of the groups consisted of 10 animals. Aluminum chloride (AlCl₃) at a low (50 mg/kg/d) or high (200 mg/kg/d) dose was applied to male Wistar rats by gavage for 8 wk. Al-free water by gavage was given to the control group throughout the experiment. Behavioral effects were evaluated by open-field (OF) motor activity and by acoustic startle response (ASR). Electrophysiological examination was done by recording spontaneous activity and sensory-evoked potentials from the visual, somatosensory, as well as auditory cortex. The Al content of each whole brain was determined by electrothermal atomic absorption spectrophotometry. Subchronic Al exposure slightly caused some changes in the evoked potentials and electrocorticograms and in the OF and ASR performance, but these results were not statistically significant. The brain Al levels of the control and the low and high dose of Al-exposed groups were measured as 0.717±0.208 μg/g (wet weight), 0.963±0.491 μg/g (wet weight) and 1.816±1.157 μg/g (wet weight), respectively.