Neuroscience
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Dopamine/cAMP signaling has been reported to mediate behavioral responses related to drug addiction. It also modulates the plasticity and firing properties of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), although the effects of cAMP signaling on the resting membrane potential (RMP) of MSNs has not been specifically defined. In this study, activation of dopamine D1-like receptors (D1Rs) by SKF-38393 elicited membrane depolarization and inward currents in MSNs from the NAc core of 14-17 day-old mice. ⋯ Collectively, these data suggest that stimulation of postsynaptic D1Rs in MSNs of the NAc core causes membrane depolarization by inhibiting Kir currents. This effect is mediated by AC/cAMP signaling but it is independent on PKA, PKC, Epac and CNG channel activation, suggesting that it may stem from cAMP's direct interaction with Kir channels. D1R/cAMP-mediated excitatory effects may influence the generation of output signals from MSNs by facilitating their transition from the quiescent down-state to the functionally active up-state.
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While it is well established that exercise can improve cognitive performance, it is unclear how long these benefits endure after exercise has ended. Accordingly, the effects of voluntary exercise on cognitive function and brain-derived neurotrophic factor (BDNF) protein levels, a major player in the mechanisms governing the dynamics of memory formation and storage, were assessed immediately after a 3-week running period, or after a 1-week or 2-week delay following the exercise period. All exercised mice showed improved performance on the radial arm water maze relative to sedentary animals. ⋯ Assessment of the time course of hippocampal BDNF availability following exercise revealed significant elevations of BDNF immediately after the exercise period (186% of sedentary levels) and at 1 and 2 weeks after exercise ended, with levels returning to baseline by 3-4 weeks. BDNF protein levels showed a positive correlation with cognitive improvement in radial water maze training and with memory performance on day 4, supporting the idea that BDNF availability contributes to the time-dependent cognitive benefits of exercise revealed in this study. Overall, this novel approach assessing the temporal endurance of cognitive and biochemical effects of exercise unveils new concepts in the exercise-learning field, and reveals that beneficial effects of exercise on brain plasticity continue to evolve even after exercise has ended.
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The sigma-1 receptor regulates various ion channel activity and possesses protein chaperone function. Using an antibody against the full sequence of the sigma-1 receptor we detected immunostaining in wild type but not in knockout mice. The receptor was found primarily in motoneurons localized to the brainstem and spinal cord. ⋯ Ultrastructural analysis of the neurons indicates that the immunostained receptor is located close but separate from the plasma membrane, possibly in subsurface cisternae formed from the endoplasmic reticulum (ER), which are a prominent feature of cholinergic postsynaptic densities. Behavioral testing on a rotorod revealed that Sigma-1 receptor knockout mice remained on the rotorod for significantly less time (a shorter latency period) compared to the wild type mice. Together these data indicate that the sigma-1 receptor may play a role in the regulation of motor behavior.
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Meta Analysis Comparative Study
A cross-laboratory comparison of expression profiling data from normal human postmortem brain.
Expression profiling of post-mortem human brain tissue has been widely used to study molecular changes associated with neuropsychiatric diseases as well as normal processes such as aging. Changes in expression associated with factors such as age, gender or postmortem interval are often more pronounced than changes associated with disease. Therefore in addition to being of interest in their own right, careful consideration of these effects are important in the interpretation of disease studies. ⋯ Importantly, meta-analysis identifies genes which are not significant in any individual study. Finally, we show that many schizophrenia candidate genes appear in the meta-signatures, reinforcing the idea that studies must be carefully controlled for interactions between these factors and disease. In addition to the inherent value of the meta-signatures, our results provide critical information for future studies of disease effects in the human brain.
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Addictive drugs including opioids activate signal transduction pathways that regulate gene expression in the brain. However, changes in CNS gene expression following morphine exposure are poorly understood. We determined changes in gene expression following short- and long-term morphine treatment in the hypothalamus and pituitary using genome-wide DNA microarray analysis and confirmed those alterations in gene expression by real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. ⋯ Subsequent RT-PCR analysis confirmed similar regulation in expression of these genes in the hypothalamus and pituitary. Finally, we found functional correlation between morphine-induced alterations in food intake and regulation of genes involved in this process. Changes in genes related to food intake may uncover new pathways related to some of the physiological effects of opioids.