Neuroscience
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AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a cellular and whole organism energy sensor to regulate ATP-consuming (anabolic) and ATP-generating (catabolic) pathways. The heterotrimeric AMPK complex consists of a catalytic α-subunit, regulatory β-subunit, and an AMP/ATP-binding γ-subunit. Several alternate isoforms exist for each subunit (α1, α2, β1, β2, γ1, γ2 and γ3). ⋯ The presence of a single functional AMPK catalytic complex was sufficient to mediate these inhibitory effects of energetic stress. Activation of AMPK mediates these effects by suppressing both the mTOR and Akt signaling pathways. These findings demonstrate that the energy-sensing AMPK pathway regulates neuronal structure in distinct regions of developing neurons at multiple stages of development.
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Epilepsy is a debilitating disease affecting 1-2% of the world's population. Despite this high prevalence, 30% of patients suffering from epilepsy are not successfully managed by current medication suggesting a critical need for new anti-epileptic drugs (AEDs). In an effort to discover new therapeutics for the management of epilepsy, we began our study by screening drugs that, like some currently used AEDs, inhibit histone deacetylases (HDACs) using a well-established larval zebrafish model. ⋯ As VK3 affects mitochondrial function, we tested the effects of our compounds on mitochondrial respiration and ATP production in a mouse hippocampal cell line. We demonstrate that these compounds affect ATP metabolism and increase total cellular ATP. Our data indicate the potential utility of these and other VK analogs for the prevention of seizures and suggest the potential mechanism for this protection may lie in the ability of these compounds to affect energy production.
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Stress affects brain activity and promotes long-term changes in multiple neural systems. Exposure to stressors causes substantial effects on the perception and response to pain. In several animal models, chronic stress produces lasting hyperalgesia. ⋯ CFA injection into the hindpaw after the FS shows significantly enhanced thermal hyperalgesia and induced a decrease in the expression of c-Fos in the AIC and the posterior IC (PIC). Quantitative image analysis showed that the numbers of c-Fos-immunoreactive neurons in the left AIC and PIC were significantly lower in the FS+CFA group (L AIC, 95.9±6.8; L PIC, 181.9±23.1) than those in the naive group (L AIC, 151.1±19.3, p<0.05; L PIC, 274.2±37.3, p<0.05). These findings suggest a neuroplastic change in the IC after FS, which may be involved in the enhancement of CFA-induced thermal hyperalgesia through dysfunction of the descending pain modulatory system.
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Hemokinin-1 (HK-1) is a peptide encoded by the preprotachykinin gene, TAC-4, and shares the hydrophobic carboxyl-terminal (C-terminal) region common to mammalian tachykinin peptides, such as substance P (SP). It is generally believed that C-terminal fragments of SP elicit an excitatory effect, while pretreatment with amino-terminal (N-terminal) fragments of SP inhibits the function of SP; however, there is no available information on HK-1. Therefore, to clarify the characteristics of C-terminal and N-terminal fragments of HK-1, HK-1 was divided into HK-1 (1-5) as the N-terminal fragment and HK-1 (6-11) as the C-terminal fragment based on the similarity of amino acids between HK-1 and SP. ⋯ Furthermore, intrathecal administration of HK-1 (1-5) and SP (1-5) markedly attenuated the induction of flinching and enhancement of c-Fos expression in the spinal cord following the intradermal administration of formalin, a noxious stimulant, while pretreatment with HK-1 (1-5), but not SP (1-5), markedly attenuated the induction of scratching behavior by subcutaneous administration of pruritic agents, such as serotonin or histamine. Taken together, these findings indicate that HK-1 (1-5) suppresses pruritic and nociceptive processing, while SP (1-5) suppresses nociceptive processing. Therefore, it is suggested that HK-1 (1-5) may be a useful tool for revealing pruritic processing and HK-1 may play a crucial role in pruritic processing.
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Serotonin/substance P synthesizing cells in the raphé nuclei of the brain are candidates for designation as central chemoreceptors that are stimulated by CO2/pH. We have previously demonstrated that these neurons are CO2-stimulated in situ. Evidence also suggests that CO2-inhibited raphé neurons recorded in vitro and in situ synthesize GABA. ⋯ Non-5-HT cells fire faster and are more robustly stimulated by CO2 than are 5-HT cells. Thus, we have characterized a previously unrecognized type of CO2-stimulated medullary raphé neuron that is not serotonergic, but may receive input from neighboring serotonin/substance P synthesizing chemosensitive neurons. The potential network properties of the three types of chemosensitive raphé neurons (the present non-5-HT cells, serotonergic cells, and CO2-inhibited cells) remain to be elucidated.