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    ABSTRACT: The neuroendocrine response to episodes of acute stress is crucial for survival whereas the prolonged response to chronic stress can be detrimental. Learning and memory are particularly susceptible to stress with cognitive deficits being well characterized consequences of chronic stress. Although there is good evidence that acute stress can enhance cognitive performance, the mechanism(s) for this are unclear. We find that hippocampal slices, either prepared from rats following 30 min restraint stress or directly exposed to glucocorticoids, exhibit an N-methyl-d-aspartic acid receptor-independent form of long-term potentiation. We demonstrate that the mechanism involves an NMDA receptor and PKA-dependent insertion of Ca(2+)-permeable AMPA receptors into synapses. These then trigger the additional NMDA receptor-independent form of LTP during high frequency stimulation.
    Full-text · Article · Nov 2013 · Brain
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    ABSTRACT: The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the regulation of sympathetic nerve activity (SNA), which is significantly elevated in chronic heart failure (CHF). Fractalkine (FKN) and its cognate receptor, CX3CR1, are constitutively expressed in the central nervous system but its role and physiological significance are not well known. The aims of the present this study were to determine whether FKN plays a cardiovascular role within the PVN and to investigate how the actions of FKN this might be altered in CHF. Here we show that both FKN and CX3CR1 are expressed on neurons in the PVN of rats suggesting that it may play a physiological function in this brain nucleus. Unilateral microinjection of FKN, directly into the PVN of anaesthetised rats, elicited a significant dose-related decrease in blood pressure (1.0nmol, -5±3 mmHg; 2.5nmol, 13±2; 5.0nmol, 22±3 mmHg; 7.5nmol -32±3 mmHg) and a concomitant increase in heart rate (1.0nmol, 6±3 bpm; 2.5nmol, 11±3; 5nmol, 18±4 bpm; 7.5nmol 27±5 bpm) compared to control saline microinjections. In order to see if FKN signaling is altered in CHF rats we first performed qRT-PCR and western blot analysis and followed these experiments with functional studies in HF and sham-control rats. We found a significant increase in CX3CR1 mRNA and protein expression, as determined by quantitative RT-PCR and Western blot analysis respectively, in PVN of rats with CHF compared to sham control rats. We also found that the blood pressure effects of FKN (2.5 nmol in 50 nl) were significantly attenuated in rats with CHF (ΔMAP -6±3 mmHg) compared to sham-operated control (ΔMAP -16±6 mmHg) rats. These data suggest that FKN and its receptor, CX3CR1 modulates cardiovascular function at the level of the PVN and that its actions within this nucleus are altered in heart failure.
    Full-text · Article · Sep 2013 · Experimental physiology
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    ABSTRACT: Basal forebrain cholinergic neurons (bfCNs) which provide innervation to the hippocampus and cortex, are required for memory and learning, and are primarily affected in Alzheimer's Disease (AD), resulting in related cognitive decline. Therefore generation of a source of bfCNs from human pluripotent stem cells (hPSCs) is crucial for in vitro disease modeling and development of novel AD therapies. In addition, for the advancement of regenerative approaches there is a requirement for an accurate developmental model to study the neurogenesis and survival of this population. Here we demonstrate the efficient production of bfCNs, using a novel embryoid body (EB) based non-adherent differentiation (NAdD) protocol. We establish a specific basal forebrain neural stem cell (NSC) phenotype via expression of the basal forebrain transcription factors NKX2.1 and LHX8, as well as the general forebrain marker FOXG1. We present evidence that this lineage is achieved via recapitulation of embryonic events, with induction of intrinsic hedgehog signaling, through the use of a 3D non-adherent differentiation system. This is the first example of hPSC-derived basal forebrain-like NSCs, which are scalable via self-renewal in prolonged culture. Furthermore upon terminal differentiation these basal forebrain-like NSCs generate high numbers of cholinergic neurons expressing the specific markers ChAT, VACht and ISL1. These hPSC-derived bfCNs possess characteristics that are crucial in a model to study AD related cholinergic neuronal loss in the basal forebrain. Examples are expression of the therapeutic target p75(NTR), the release of acetylcholine, and demonstration of a mature, and functional electrophysiological profile. In conclusion, this work provides a renewable source of human functional bfCNs applicable for studying AD specifically in the cholinergic system, and also provides a model of the key embryonic events in human bfCN development.
    No preview · Article · Aug 2013 · Stem Cell Research
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