In order to assess the contribution of a central clock in the hypothalamic suprachiasmatic nucleus (SCN) to circadian behavior and the organization of peripheral clocks, we generated forebrain/SCN-specific Bmal1 knockout mice by using floxed Bmal1 and pan-neuronal Cre lines. The forebrain knockout mice showed >90% deletion of BMAL1 in the SCN and exhibited an immediate and complete loss of circadian behavior in constant conditions. Circadian rhythms in peripheral tissues persisted, but became desynchronized and damped in constant darkness. The loss of synchrony was rescued by light/dark cycles, and partially by restricted feeding (only in the liver and kidney but not in the other tissues) in a distinct manner. These results suggest that the forebrain/SCN is essential for internal temporal order of robust circadian programs in peripheral clocks and that individual peripheral clocks are affected differently by light and feeding in the absence of a functional oscillator in the forebrain.
Animal experimentation: All animal care and use procedures were in accordance with guidelines of the Northwestern University (Protocol 2006-0035) and UT Southwestern Institutional Animal Care and Use Committees (Protocols 2009-0054 and 2012-0090).
- Louis Ptáček, University of California, San Francisco, United States
© 2014, Izumo et al.
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Infantile neuroaxonal dystrophy (INAD) is caused by recessive variants in PLA2G6 and is a lethal pediatric neurodegenerative disorder. Loss of the Drosophila homolog of PLA2G6, leads to ceramide accumulation, lysosome expansion, and mitochondrial defects. Here, we report that retromer function, ceramide metabolism, the endolysosomal pathway, and mitochondrial morphology are affected in INAD patient-derived neurons. We show that in INAD mouse models, the same features are affected in Purkinje cells, arguing that the neuropathological mechanisms are evolutionary conserved and that these features can be used as biomarkers. We tested 20 drugs that target these pathways and found that Ambroxol, Desipramine, Azoramide, and Genistein alleviate neurodegenerative phenotypes in INAD flies and INAD patient-derived neural progenitor cells. We also develop an AAV-based gene therapy approach that delays neurodegeneration and prolongs lifespan in an INAD mouse model.
Even during sustained attention, enhanced processing of attended stimuli waxes and wanes rhythmically, with periods of enhanced and relatively diminished visual processing (and subsequent target detection) alternating at 4 or 8 Hz in a sustained visual attention task. These alternating attentional states occur alongside alternating dynamical states, in which lateral intraparietal cortex (LIP), the frontal eye field (FEF), and the mediodorsal pulvinar (mdPul) exhibit different activity and functional connectivity at α, β and γ frequencies-rhythms associated with visual processing, working memory, and motor suppression. To assess whether and how these multiple interacting rhythms contribute to periodicity in attention, we propose a detailed computational model of FEF and LIP. When driven by θ-rhythmic inputs simulating experimentally-observed mdPul activity, this model reproduced the rhythmic dynamics and behavioral consequences of observed attentional states, revealing that the frequencies and mechanisms of the observed rhythms allow for peak sensitivity in visual target detection while maintaining functional flexibility.