Neuroscience
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Human amyloid β1-42 (hAβ1-42) peptides are known to self-aggregate into oligomers that contribute to the degeneration of neurons and development of Alzheimer's disease (AD) pathology. Unlike humans, rodents do not develop AD, possibly due to differences in three amino acids (R5G, Y10F and H13R) within the hydrophilic N-terminal domain of Aβ1-42. This is partly supported by evidence that hAβ1-42 is more prone to fibrillization and has a higher cellular toxicity than rodent Aβ1-42 (rAβ1-42). ⋯ Interestingly, the mutants are still able to aggregate into oligomers, which are predominantly larger than those comprised of hAβ1-42. Our cell viability experiments further showed a rank order of oligomer toxicity of hAβ1-42 > rAβ1-42 ≫ mutant Aβ1-42, suggesting that toxicity can be influenced by N-terminal Aβ1-42 mutations via reduction of fibril formation and/or alteration of oligomer size. These results, taken together, confirm that N-terminal mutations can affect Aβ fibril and oligomer formation with reduced toxicity despite lying outside the core amyloid region of Aβ peptide.
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Slow-wave activity (SWA) in the electroencephalogram during slow-wave sleep (SWS) varies as a function of sleep-wake history. A putative sleep-active population of neuronal nitric oxide synthase (nNOS)-containing interneurons in the cerebral cortex, defined as such by the expression of Fos in animals euthanized after protracted deep sleep, may be a local regulator of SWA. We investigated whether electrophysiological responses to activation of these cells are consistent with their role of a local regulator of SWA. ⋯ Optogenetic stimulation of the cerebral cortex of animals expressing Channelrhodopsin2 in nNOS interneurons triggered an acute positive deflection of the local field potential that was followed by protracted oscillatory events only during quiet wake and slow wave sleep. The response during wake was maximal when the electroencephalogram (EEG) was in a negative polarization state and abolished when the EEG was in a positive polarization state. Since the polarization state of the EEG is a manifestation of slow-wave oscillations in the activity of underlying pyramidal neurons between the depolarized (LFP negative) and hyperpolarized (LFP positive) states, these data indicate that sleep-active cortical neurons expressing nNOS function in sleep slow-wave physiology.
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In the primary visual cortex (V1), neuronal responses to stimuli within the receptive field (RF) are modulated by stimuli in the RF surround. A common effect of surround modulation is surround suppression, which is dependent on the feature difference between stimuli within and surround the RF and is suggested to be involved in the perceptual phenomenon of figure-ground segregation. In this study, we examined the relationship between feature-specific surround suppression of V1 neurons and figure detection behavior based on figure-ground feature difference. ⋯ Consistent with the behavioral performance, the sensitivity of V1 neurons to RF-surround phase difference could be influenced by stimulus contrast. Furthermore, inhibiting V1 by optogenetically activating either parvalbumin (PV)- or somatostatin (SOM)-expressing inhibitory neurons both decreased the behavioral performance of figure detection. Thus, the phase-specific surround suppression in V1 represents a neural correlate of figure detection behavior based on figure-ground phase discontinuity.
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Chemokines are known to have a role in the nervous system, influencing a range of processes including the development of chronic pain. To date there are very few studies describing the functions of the chemokine lymphotactin (XCL1) or its receptor (XCR1) in the nervous system. We investigated the role of the XCL1-XCR1 axis in nociceptive processing, using a combination of immunohistochemical, pharmacological and electrophysiological techniques. ⋯ Incubation of brainstem slices with XCL1 induced activation of c-Fos, ERK and p38 in the superficial layers of Vc, and enhanced levels of intrinsic excitability. These effects were blocked by the XCR1 antagonist viral CC chemokine macrophage inhibitory protein-II (vMIP-II). This study has identified for the first time a role for XCL1-XCR1 in nociceptive processing, demonstrating upregulation of XCR1 at nerve injury sites and identifying XCL1 as a modulator of central excitability and signaling via XCR1 in Vc, a key area for modulation of orofacial pain, thus indicating XCR1 as a potential target for novel analgesics.
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Brain CYP2D is responsible for the synthesis of endogenous neurotransmitters such as dopamine and serotonin. This study is to investigate the effects of cerebral CYP2D on mouse behavior and the mechanism whereby growth hormone regulates brain CYP2D. The inhibition of cerebellar CYP2D significantly affected the spatial learning and exploratory behavior of mice. ⋯ Pulsatile GH decreased the binding of PPARα to the CYP2D6 promoter by 40% and promoted the binding of PPARγ to the CYP2D6 promoter by approximately 60%. The male GH secretory pattern altered PPAR expression and the binding of PPARs to the CYP2D promoter, leading to the elevation of brain CYP2D in a tissue-specific manner. Growth hormone may alter the learning and memory functions in patients receiving GH replacement therapy via brain CYP2D.