Neuroscience
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Neurodegenerative diseases are difficult to study due to unavailability of human neurons. Cell culture systems and primary rodent cultures have shown to be indispensable to clarify disease mechanisms and provide insights into gene functions. Nevertheless, it is hard to translate new findings into new medicines. ⋯ Addition of C6 glioma conditioned medium improved the bursting frequency of cells without further maturation or evidence for glutamatergic responses. Furthermore, cells were suitable for lentiviral transduction within the tested time frame. Altogether, iCell® neurons might be useful to model neurodegenerative diseases in which young GABAergic subtypes are affected.
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Properties of excitatory synaptic responses in fast-spiking interneurons (FSIs) and pyramidal neurons (PNs) are different; however, the mechanisms and determinants of this diversity have not been fully investigated. In the present study, voltage-clamp recording of miniature excitatory post-synaptic currents (mEPSCs) was performed of layer 2-3 FSIs and PNs in the medial prefrontal cortex of rats aged 19-22days. The average mEPSCs in the FSIs exhibited amplitudes that were two times larger than those of the PNs and with much faster rise and decay. ⋯ In the FSIs, the distributions were well approximated only by a sum of two such functions, suggesting the presence of at least two subpopulations of events with different modal amplitudes. According to our estimates, two-thirds of the mEPSCs in FSIs belong to the high-amplitude subpopulation, and the modal amplitude in this subpopulation is approximately two times larger than that in the low-amplitude subpopulation. Using different statistical models, varying binning size, and data subsets, we confirmed the robustness and consistency of these findings.
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While spinal cord astrocytes play a key role in the generation of cancer pain, there have been no studies that have examined the relationship of tumor-induced astrocyte activation and aromatase expression during the development of cancer pain. Here, we examined tumor-induced mechanical hyperalgesia and cold allodynia, and changes in Glial fibrillary acid protein (GFAP) and aromatase expression in murine models of painful and non-painful bone cancer. We demonstrate that implantation of fibrosarcoma cells, but not melanoma cells, produces robust mechanical hyperalgesia and cold allodynia in tumor-bearing mice compared to saline-injected controls. ⋯ Finally, administration of an aromatase inhibitor reduced tumor-induced hyperalgesia in fibrosarcoma-bearing animals. We conclude that a painful fibrosarcoma tumor induces a significant increase in spinal astrocyte activation and aromatase expression and that the up-regulation of aromatase plays a role in the development of bone tumor-induced hyperalgesia. Since spinal aromatase is also upregulated, but to a lesser extent, in non-painful melanoma bone tumors, it may also be neuroprotective and responsive to the changing tumor environment.
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Treatment of apnea of prematurity with methylxanthines like caffeine, aminophylline or theophylline can evoke hippocampal seizures. However, it is unknown at which interstitial brain concentrations methylxanthines promote such neonatal seizures or interfere with physiological 'early network oscillations' (ENOs) that are considered as pivotal for maturation of hippocampal neural networks. We studied theophylline and caffeine effects on ENOs in CA3 neurons (CA3-ENOs) and CA3 electrical stimulation-evoked monosynaptic CA1 field potentials (CA1-FPs) in sliced and intact hippocampi, respectively, from 8 to 10-days-old rats. ⋯ GABAA receptor blockade induced seizure-like discharges and occluded theophylline-evoked seizure-like discharges in the slices, but not in the intact hippocampi. In summary, submillimolar methylxanthine concentrations do not acutely affect spontaneous CA3-ENOs or electrically evoked synaptic activities and low millimolar doses are needed to evoke seizure-like discharges in isolated developing hippocampal neural networks. We conclude that mechanisms of methylxanthine-related seizure-like discharges do not involve SERCA inhibition-related neuronal Ca(2+) dysregulation, PDE4 blockade or adenosine and glycine receptor inhibition, whereas GABA(A) receptor blockade may contribute partially.
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Stimuli paired with rewards acquire reinforcing properties to promote reward-seeking behavior. Previous work supports the role of ventral tegmental area (VTA) nicotinic acetylcholine receptors (nAChRs) in mediating conditioned reinforcement elicited by drug-associated cues. However, it is not known whether these cholinergic mechanisms are specific to drug-associated cues or whether VTA cholinergic mechanisms also underlie the ability of cues paired with natural rewards to act as conditioned reinforcers. ⋯ AP-5 robustly attenuated conditioned reinforcement and blocked discrimination between CR and NCR noseports at the 1-μg dose. MEC infusion decreased responding for both CR and NCR while 66.7-μg SCOP disrupted the subject's ability to discriminate between CR and NCR. Together, our data suggest that VTA NMDARs and mAChRs, but not nAChRs, play a role in the ability of natural reward-associated cues to act as conditioned reinforcers.