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    • It has been suggested that consciousness is associated

    2018-10-26

    It has been suggested that consciousness is associated with “continuous” gamma band activity rather than an interrupted pattern of activity [78,79]. The original description of the RAS specifically suggested that it participates in “tonic or continuous” arousal, and that lesions of the RAS eliminated “tonic” arousal [80,81]. RAS structures like the PPN, in which every cell manifests gamma band activity, and in which a subgroup of cells are electrically coupled, then becomes a “gamma-making machine”. We hypothesized that it is the activation of the RAS during waking and REM sleep that induces coherent activity (through electrically coupled cells) and high frequency oscillations (through P/Q-type calcium channel and subthreshold oscillations). This leads to the generation of the background of gamma activity necessary to support a state capable of reliably assessing the world around us on a continuous basis. That is, these mechanisms may underlie the process of preconscious awareness [82,83].
    Two states, two pathways Injections of glutamate into the PPN of the rat were found to increase both waking and REM sleep, but injections of NMDA increased only waking, while injections of kainic MAPK Inhibitor Library (KA) increased only REM sleep [84–87]. Thus, the two states of waking and REM sleep appear to be independently activated by NMDA vs KA receptors. Moreover, the intracellular pathways mediating the two states are different. For example, the CaMKII activation inhibitor, KN-93, microinjected into the PPN of freely moving rats (in vivo) resulted in decreased waking but not REM sleep [88]. We showed that beta/gamma band oscillations in PPN neurons recorded in vitro were blocked by superfusion of KN-93 [89], suggesting that some cells manifest their oscillations via the CaMKII pathway. Moreover, the effects of the stimulant modafinil, which are mediated by increased electrical coupling, are modulated by the CaMKII pathway since KN-93 inhibits the action of modafinil [41,42,45,90]. These findings suggest that waking in vivo may be modulated by the CaMKII pathway, while REM sleep may be modulated by the cAMP pathway in the PPN [18,83,90]. In addition, it appears that the cAMP-dependent pathway phosphorylates N-type calcium channels [90], while CaMKII regulates P/Q-type calcium channels [91]. Therefore, the presence of P/Q-type calcium channels is related to CaMKII and waking, while the presence of N-type calcium channels is more related to cAMP and REM sleep [89]. We have preliminary findings showing that in some PPN cells (50%), the N-type calcium channel blocker ω-conotoxin-GVIA (ω-CgTx) reduced gamma oscillation amplitude, while subsequent addition of the P/Q-type blocker ω-agatoxin-IVA (ω-Aga) blocked the remaining oscillations. Other PPN cells (20%) manifested gamma oscillations that were not significantly affected by the addition of ω-CgTx, however, ω-Aga blocked the remaining oscillations. In the rest of the cells (30%), ω-Aga had no effect on gamma oscillations, while ω-CgTx blocked them. Similar results were found during recordings of voltage-dependent calcium currents. These results confirm the presence of cells in the PPN that manifest gamma band oscillations through only N-type, only P/Q-type, and both N- and P/Q-type calcium channels. This new cell type classification suggests that some PPN neurons fire only during REM sleep (“REM-on”, N-type only), only during waking (“Wake-on”, P/Q-type only), or during both waking and REM sleep (“Wake/REM-on”, N-type+P/Q-type) [92].
    Neuronal calcium sensor protein 1 (NCS-1) in schizophrenia and bipolar disorder Human postmortem studies reported increased expression of neuronal calcium sensor protein (NCS-1) in the brains of some bipolar disorder and schizophrenic patients compared to normal controls and major depression patients [93,94]. The distribution of levels of NCS-1 suggest that some patients have a 50% increase in expression, while others fall within the normal range. That is, gamma band activity is reduced or disrupted [95–97] in precisely the same disorders that show brain NCS-1 over expression. However, some studies suggest that other patients show increased gamma band activity [98]. We tested the hypothesis that NCS-1 modulates calcium channels in PPN neurons that generate gamma band oscillations, and that excessive levels of NCS-1, as would be expected with over expression, reduce or block gamma band oscillations in these cells [99].