Neuroscience
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Co-cultures of 3T3-L1 adipocytes with neurons from the rat dorsal root ganglia (DRG) showed enhanced neuritogenesis and synaptogenesis. Microarray analysis for upregulated genes in adipocyte/DRG co-cultures currently points to apolipoproteins D and E (ApoD, ApoE) as influential proteins. We therefore tested adipocyte-secreted cholesterol and the carrier proteins ApoD and ApoE3. ⋯ The application of ApoD, ApoE3, and cholesterol to DRG cell cultures corresponded with increased expression of the chemokine stromal cell-derived factor 1 and its receptor CXC chemokine receptor 4 (CXCR4). Surprisingly, the inhibition of CXCR4 by the antagonistic drug AMD3100 decreased the apolipoprotein/cholesterol dependent neurotrophic effects. We thus assume that apolipoprotein-induced neuritogenesis in DRG cells interferes with CXCR4 signaling, and that adipocyte-derived apolipoproteins might be helpful in nerve repair.
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Recent evidence shows that the primary motor cortex continues to send motor commands when amputees execute phantom movements. These commands are retargeted toward the remaining stump muscles as a result of motor system reorganization. As amputation-induced reorganization in the primary motor cortex has been associated with phantom limb pain we hypothesized that the motor control of the phantom limb would differ between amputees with and without phantom limb pain. ⋯ Also, the amount of EMG modulation recorded in a stump muscle during a phantom hand movement was positively correlated with the intensity of phantom limb pain. Since phantom hand movement-related EMG patterns in above-elbow stump muscles can be considered as a marker of motor system reorganization, this result indirectly supports the hypothesis that amputation-induced plasticity is associated with phantom limb pain severity. The discordance between the (amputated) hand motor command and the feedback from above-elbow muscles might partially explain why subjects exhibiting large EMG modulation during phantom hand movement have more phantom limb pain.
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Defeat is a social stressor involving subordination by a threatening conspecific. Type 2 corticotropin-releasing factor receptors (CRF(2)) are abundant in brain regions implicated in defeat responses and are putative stress-related molecules. The present study sought to determine whether neuroactivation and CRF(2) expression co-occurred at brain region or cellular levels following acute defeat. ⋯ Defeated rats had fivefold, sevenfold, and 10-fold more Fos-positive cells than controls in the arcuate, ventromedial nucleus of the hypothalamus, and medial amygdala post-defeat. Significant colocalization of CRF(2) mRNA and Fos-positive cells was observed in the posterior medial amygdala but not in the arcuate nucleus or ventromedial hypothalamus. The results indicate CRF(2) receptor-positive neurons in the posterior medial amygdala are involved in the neural response to social defeat.
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Parathyroid hormone receptor 2 (PTH2R) and its ligand, tuberoinfundibular peptide of 39 residues (TIP39) constitute a neuromodulator system implicated in endocrine and nociceptive regulation. We now describe the presence and distribution of the PTH2R and TIP39 in the brain of primates using a range of tissues and ages from macaque and human brain. In situ hybridization histochemistry of TIP39 mRNA, studied in young macaque brain, due to its possible decline beyond late postnatal ages, was present only in the thalamic subparafascicular area and the pontine medial paralemniscal nucleus. ⋯ The distribution of PTH2R-immunoreactive fibers in human, determined by immunocytochemistry, was similar to that in rodents, including dense fiber networks in the medial preoptic area, hypothalamic paraventricular, periventricular and infundibular (arcuate) nuclei, lateral hypothalamic area, median eminence, thalamic paraventricular nucleus, periaqueductal gray, lateral parabrachial nucleus, nucleus of the solitary tract, sensory trigeminal nuclei, medullary dorsal reticular nucleus, and dorsal horn of the spinal cord. Co-localization suggested that PTH2R fibers are glutamatergic, and that TIP39 may directly influence hypophysiotropic somatostatin containing and indirectly influence corticotropin releasing-hormone containing neurons. The results demonstrate that TIP39 and the PTH2R are expressed in the brain of primates in locations that suggest involvement in regulation of fear, anxiety, reproductive behaviors, release of pituitary hormones, and nociception.
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We have previously reported that repeated central administration of sub-anxiogenic doses of the corticotropin releasing factor 1 (CRF(1)) agonist Cortagine, termed "priming," elicits a phenotype of increased anxiety-like behaviors in the elevated plus maze (EPM) and open-field test, and enhanced retention of contextual conditioned fear in C57BL/6J mice. Observed behavioral changes were functionally coupled to CRF(1)-mediated elevated central cholecystokinin (CCK) tone in discrete brain regions. However, the changes in gene expression that mediated "priming"-induced behavioral and concurrent molecular changes in specific brain regions remained unknown. ⋯ In particular, several genes of the protein kinase A (PKA) and protein kinase C (PKC) signaling cascades, known to be involved in synaptic plasticity, such as neurogranin, calmodulin 3, and the PKA regulatory subunit 1 b were found to be upregulated in the PFC and hippocampus of CRF(1) agonist "primed" mice. Moreover, we show pharmacologically that one of the newly implicated memory regulatory elements, diazepam-binding inhibitor (DBI) is functionally involved in hippocampus-dependent enhancement of contextual fear, a cardinal phenotypic feature of the "primed" mice. Finally, an interaction network mapping of the altered genes and their known interacting partners identified additional molecular candidates responsible for CRF(1)-mediated hypersensitive fear circuitry.