Treatment Efficacy of NGF Nanoparticles Combining Neural Stem Cell Transplantation on Alzheimer's Disease Model Rats.

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia. It causes progressive brain disorder involving loss of normal memory and thinking skills. The transplantation of neural stem cells (NSCs) has been reported to improve learning and memory function of AD rats, and protects basal forebrain cholinergic neurons. Nerve growth factor - poly (ethylene glycol) - poly (lactic-co-glycolic acid)-nanoparticles (NGF-PEG-PLGA-NPs) can facilitate the differentiation of NSCs in vitro. This study thus investigated the treatment efficacy of NGF-PEG-PLGA-NPs combining NSC transplantation in AD model rats. MATERIAL AND METHODS: AD rats were prepared by injection of 192IgG-saporin into their lateral ventricles. Embryonic rat NSCs were separated, induced by NGF-PEG-PLGA-NPs in vitro, and were transplanted. The Morris water-maze test was used to evaluate learning and memory function, followed by immunohistochemical staining for basal forebrain cholinergic neurons, hippocampal synaptophysin, and acetylcholine esterase (AchE) fibers. RESULTS: Rats in the combined treatment group had significantly improved spatial learning ability compared to AD model animals (p<0.05). The number of basal forebrain cholinergic neurons, hippocampal synaptophysin, and AchE-positive fibers were all significantly larger than in the NSC-transplantation group, with no difference from control animals. CONCLUSIONS: NGF-PEG-PLGA-NPs plus NSC transplantation can significantly improve learning and memory functions of AD rats, replenish basal forebrain cholinergic neurons, and help form hippocampal synapses and AchE-positive fibers. These findings may offer practical support for and insight into treatment of Alzheimer's disease.

Cholinergic neurons of the basal forebrain mediate biochemical and electrophysiological mechanisms underlying sleep homeostasis.

The tight coordination of biochemical and electrophysiological mechanisms underlies the homeostatic sleep pressure (HSP) produced by sleep deprivation (SD). We have reported that during SD the levels of inducible nitric oxide synthase (iNOS), extracellular nitric oxide (NO), adenosine [AD]ex , lactate [Lac]ex and pyruvate [Pyr]ex increase in the basal forebrain (BF). However, it is not clear whether all of them contribute to HSP leading to increased electroencephalogram (EEG) delta activity during non-rapid eye movement (NREM) recovery sleep (RS) following SD. Previously, we showed that NREM delta increase evident during RS depends on the presence of BF cholinergic (ChBF) neurons. Here, we investigated the role of ChBF cells in coordination of biochemical and EEG changes seen during SD and RS in the rat. Increases in low-theta power (5-7 Hz), but not high-theta (7-9 Hz), during SD correlated with the increase in NREM delta power during RS, and with the changes in nitrate/nitrite [NOx ]ex and [AD]ex . Lesions of ChBF cells using IgG 192-saporin prevented increases in [NOx ]ex , [AD]ex and low-theta activity, during SD, but did not prevent increases in [Lac]ex and [Pyr]ex . Infusion of NO donor DETA NONOate into the saporin-treated BF failed to increase NREM RS and delta power, suggesting ChBF cells are important for mediating NO homeostatic effects. Finally, SD-induced iNOS was mostly expressed in ChBF cells, and the intensity of iNOS induction correlated with the increase in low-theta activity. Together, our data indicate ChBF cells are important in regulating the biochemical and EEG mechanisms that contribute to HSP.

Excessive disgust caused by brain lesions or temporary inactivations: mapping hotspots of the nucleus accumbens and ventral pallidum.

Disgust is a prototypical type of negative affect. In animal models of excessive disgust, only a few brain sites are known in which localized dysfunction (lesions or neural inactivations) can induce intense 'disgust reactions' (e.g. gapes) to a normally pleasant sensation such as sweetness. Here, we aimed to map forebrain candidates more precisely, to identify where either local neuronal damage (excitotoxin lesions) or local pharmacological inactivation (muscimol/baclofen microinjections) caused rats to show excessive sensory disgust reactions to sucrose. Our study compared subregions of the nucleus accumbens shell, ventral pallidum, lateral hypothalamus, and adjacent extended amygdala. The results indicated that the posterior half of the ventral pallidum was the only forebrain site where intense sensory disgust gapes in response to sucrose were induced by both lesions and temporary inactivations (this site was previously identified as a hedonic hotspot for enhancements of sweetness 'liking'). By comparison, for the nucleus accumbens, temporary GABA inactivations in the caudal half of the medial shell also generated sensory disgust, but lesions never did at any site. Furthermore, even inactivations failed to induce disgust in the rostral half of the accumbens shell (which also contains a hedonic hotspot). In other structures, neither lesions nor inactivations induced disgust as long as the posterior ventral pallidum remained spared. We conclude that the posterior ventral pallidum is an especially crucial hotspot for producing excessive sensory disgust by local pharmacological/lesion dysfunction. By comparison, the nucleus accumbens appears to segregate sites for pharmacological disgust induction and hedonic enhancement into separate posterior and rostral halves of the medial shell.