Neuroscience
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Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease (AD). Insulin is a neuroprotective growth factor, and an impairment of insulin signalling has been found in AD brains. Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone, normalises insulin signalling and also acts as a neuroprotective growth factor. ⋯ Chronic oxidative stress in the brain was reduced in 12- and 19-month-old mice as shown in the reduction of 8-oxoguanine levels in the cortex of D-Ala(2)GIP-injected APP/PS1 mice. The results demonstrate that D-Ala(2)GIP has neuroprotective properties on key markers found in Alzheimer's disease. This finding shows that novel GIP analogues have the potential to be developed as novel therapeutics for Alzheimer's disease.
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The 5- and 12/15-lipoxygenase (LOX) isozymes have been implicated to contribute to disease development in CNS disorders such as Alzheimer's disease. These LOX isozymes are distinct in function, with differential effects on neuroinflammation, and the impact of the distinct isozymes in the pathogenesis of Parkinson's disease has not as yet been evaluated. To determine whether the isozymes contribute differently to nigrostriatal vulnerability, the effects of 5- and 12/15-LOX deficiency on dopaminergic tone under naïve and toxicant-challenged conditions were tested. ⋯ In contrast, null 5-LOX littermates demonstrated no significant striatal DA depletion or astrogliosis (as noted by Western blot analyses for glial acidic fibrillary protein (GFAP) immunoreactivity). In naïve null 12/15-LOX mice, no significant change in striatal DA values was observed compared to WT, and following MPTP treatment, the transgenics revealed striatal DA reduction similar to the challenged WT mice. Taken together, these data provide the first evidence that: (i) LOX isozymes are involved in the maintenance of normal dopaminergic function in the striatum and (ii) the 5- and 12/15-LOX isozymes contribute differentially to striatal vulnerability in response to neurotoxicant challenge.
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Like other marsupials, the opossum Monodelphis domestica is born very immature and crawls, unaided by the mother, from the urogenital opening to a nipple where it attaches and pursues its development. If the alternate, rhythmic movements of the forelimbs which allow this locomotion are generated by the developing spinal motor networks, sensory information is nonetheless needed to guide the newborn to a nipple. Behavioral, anatomical and physiological studies suggest that the auditory and the visual systems are insufficiently developed in newborn opossums to influence spinal motor centers, while the vestibular, trigeminal, and olfactory systems are likelier candidates. ⋯ Numerous nerve fibers were observed in the snout dermis, especially in the maxillary region, but also elsewhere in the head skin. Some 5G cells project to the upper spinal cord, but more project to the caudal medulla where they could contact secondary trigeminal neurons or reticular cells projecting to the spinal cord. These results support a significant influence of the trigeminal and the vestibular systems, but not of olfaction, on forelimb movement of neonatal opossums.
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Hyperpolarization-activated currents (I(h)) affect multiple neuronal functions including membrane potential, intrinsic firing properties, synaptic integration and frequency-dependent resonance behavior. Consistently, I(h) plays a key role for oscillations at the cellular and network level, including theta and gamma oscillations in rodent hippocampal circuits. Little is known, however, about the contribution of I(h) to a prominent memory-related pattern of network activity called sharp-wave-ripple complexes (SPW-R). ⋯ Likewise, coupling between field oscillations and units was unchanged, showing unaltered recruitment of neurons into oscillating assemblies. Control experiments exclude a contribution of T-type calcium channels to the observed effects. Together, we report a specific contribution of hyperpolarization-activated cation currents to the generation of sharp waves in the hippocampus.
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The neuropeptide arginine vasopressin (AVP) exerts a modulatory role on hippocampal excitability through vasopressin V(1A) and V(1B) receptors. However, the origin and mode of termination of the AVP innervation of the hippocampus remain unknown. We have used light and electron microscopy to trace the origin, distribution and synaptic relationships of AVP-immuno-positive fibres and nerve terminals in the rat hippocampus. ⋯ Fluoro-Gold injection into the hippocampus revealed retrogradely labelled AVP-positive somata in hypothalamic supraoptic and paraventricular nuclei. Hypothalamo-hippocampal AVP-positive axons entered the hippocampus mostly through a ventral route, also innervating the amygdala and to a lesser extent through the dorsal fimbria fornix, in continuation of the septal AVP innervation. Thus, it appears the AVP-containing neurons of the magnocellular hypothalamic nuclei serve as important sources for hippocampal AVP innervation, although the AVP-expressing neurons located in amygdala and bed nucleus of the stria terminalis reported previously may also contribute.