Neuroscience
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Comparative Study
Increased c-Fos expression in the centromedial nucleus of the thalamus in metabotropic glutamate 8 receptor knockout mice following the elevated plus maze test.
Ligands for metabotropic glutamate 8 (mGlu8) receptors, such as (S)-2-amino-4-phosphonobutanoic acid and (S)-3,4-dicarboxyphenylglycine suppress CNS excitability via presynaptic regulation of glutamate release and are anticonvulsant in mice. These observations suggest that mGlu8 receptors play a role in the regulation of neuronal excitability. To further characterize the role of mGlu8 receptors in vivo, the mGlu8 receptor knockout mouse was generated. ⋯ Basal c-Fos expression in the absence of EPM exposure did not differ between wild-type and mGlu8 receptor knockout mice in any brain region we examined. As the centromedial nucleus of the thalamus is important in regulating sensory information to higher brain regions, these results support the hypothesis that mGlu8 receptors are involved in the response to certain novel, aversive environments. In particular, the deletion of the mGlu8 receptor reduced the threshold of neuronal activation in stress-related brain regions such as the centromedial nucleus of the thalamus.
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Bombesin receptor subtype 3 (BRS-3) is an orphan G-protein coupled receptor that shares between 47 and 51% homology with other known bombesin receptors. The natural ligand for BRS-3 is currently unknown and little is known about the mechanisms regulating BRS-3 gene expression. Unlike other mammalian bombesin receptors that have been shown to be predominantly expressed in the CNS and gastrointestinal tract, expression of the BRS-3 receptor in the rat brain has previously not been observed. ⋯ Particularly strong immunosignals were observed in the cerebral cortex, hippocampal formation, hypothalamus and thalamus. Other regions of the brain such as the basal ganglia, midbrain and reticular formation were also immunopositive for BRS-3. In conclusion, our neuroanatomical data provide evidence that BRS-3 is as widely expressed in the rat brain as other bombesin-like peptide receptors and suggest that this receptor may also have important roles in the CNS, mediating the functions of a so far unidentified ligand.
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Comparative Study
Differential regulation of corticosteroid receptors by monoamine neurotransmitters and antidepressant drugs in primary hippocampal culture.
Hyperactivity of the hypothalamic-pituitary-adrenal axis is a characteristic feature of depressive illness. The centrally located corticosteroid receptors, the glucocorticoid and mineralocorticoid receptors, are thought to be important modulators of this axis and changes in the levels of these receptors, particularly in the hippocampus, may underlie the hyperactivity observed. Various antidepressant drugs increase hippocampal mineralocorticoid and glucocorticoid receptor levels in vivo. ⋯ However, glucocorticoid receptor induction by fluoxetine or amitriptyline was not blocked by WAY 100635 or propanolol. These results show that 5HT, NA and antidepressants act directly but via distinct mechanisms on hippocampal neurones to regulate mineralocorticoid and glucocorticoid receptor expression. Thusly, manipulation of neurotransmitter or antidepressant levels in the brain may aid in reversing hypothalamic-pituitary-adrenal axis hyperactivity by restoring hippocampal corticosteroid receptor balance.
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The suprachiasmatic nucleus (SCN), the dominant circadian pacemaker in mammalian brain, sends axonal projections to the hypothalamic paraventricular nucleus (PVN), a composite of magno- and parvocellular neurons. This neural network likely offers SCN output neurons a means to entrain diurnal rhythmicity in various autonomic and neuroendocrine functions. Earlier investigations using patch-clamp recordings in slice preparations have suggested differential innervation by SCN efferents to magnocellular versus parvocellular PVN cells. ⋯ At 1 microM where baclofen had no significant postsynaptic effect, evidence of activation of presynaptic GABA(B) receptors included reduction in SCN-evoked IPSCs and EPSCs with no change in their kinetics, and paired-pulse depression that was sensitive to both baclofen and saclofen. Baclofen also induced significant reductions in frequency but not amplitudes of miniature IPSCs and EPSCs. These observations suggest that levels of synaptically released GABA from the terminals of SCN output neurons can influence the relative contribution of pre- versus postsynaptic GABA(B) receptors in modulating both excitatory and inhibitory SCN innervation to parvocellular PVN neurons.
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Comparative Study
Closed-head minimal traumatic brain injury produces long-term cognitive deficits in mice.
Victims of minimal traumatic brain injury (mTBI) do not show clear morphological brain defects, but frequently suffer lasting cognitive deficits, emotional difficulties and behavioral disturbances. In the present study we adopted a non-invasive closed-head weight-drop mouse model to produce mTBI. We examined the effects of 20, 25, or 30 g weight drop 7, 30, 60 and 90 days following injury on mice's ability to perform the Morris water maze. ⋯ These results indicate that the severity of injury may correlate with the degree of integration of the learning task. These cognitive deficits occurred without any other clear neurological damage, no evident brain edema, no notable damage to the blood-brain barrier and no early anatomical changes to the brain (observed by magnetic resonance imaging imaging). These results demonstrate that persistent deficits of cognitive learning abilities in mice, similar to those observed in human post-concussive syndrome, can follow mTBI without any anatomical damage to the brain and its surrounding tissue.