SUMMARY Learning involves a transformation of brain-wide operation dynamics. However, our understanding of learning-related changes in macroscopic dynamics is limited. Here we monitored cortex-wide activity of the mouse brain using wide-field calcium imaging while the mouse learned a motor task over weeks. Over learning, the sequential activity across cortical modules became temporally more compressed and its trial-by-trial variability decreased. Moreover, a new flow of activity emerged during learning, originating from premotor cortex (M2), and M2 became predictive of the activity of many other modules. Inactivation experiments showed that M2 is critical for the post-learning dynamics in the cortex-wide activity. Furthermore, two-photon calcium imaging revealed that M2 ensemble activity also showed earlier activity onset and reduced variability with learning, which was accompanied by changes in the activity-movement relationship. These results reveal newly emergent properties of macroscopic cortical dynamics during motor learning and highlight the importance of M2 in controlling learned movements.
The last decades have witnessed substantial progress in optical technologies revolutionizing our ability to record and manipulate neural activity in genetically modified animal models. Meanwhile, human studies mostly rely on electrophysiological recordings of cortical potentials, which cannot be inferred from optical recordings, leading to a gap between our understanding of dynamics of microscale populations and brain-scale neural activity. By enabling concurrent integration of electrical and optical modalities, transparent graphene microelectrodes can close this gap. However, the high impedance of graphene constitutes a big challenge toward the widespread use of this technology. Here, it is experimentally demonstrated that this high impedance of graphene microelectrodes is fundamentally limited by quantum capacitance. This quantum capacitance limit is overcome by creating a parallel conduction path using platinum nanoparticles. A 100 times reduction in graphene electrode impedance is achieved, while maintaining the high optical transparency crucial for deep two-photon microscopy. Using a transgenic mouse model, simultaneous electrical recording of cortical activity with high fidelity is demonstrated while imaging calcium signals at various cortical depths right beneath the transparent microelectrodes. Multimodal analysis of Ca 2+ spikes and cortical surface potentials offers unique opportunities to bridge our understanding of cellular dynamics and brain-scale neural activity.
BackgroundProfound synapse loss is one of the major pathological hallmarks associated with Alzheimer’s disease, which might underlie memory impairment. Our previous work demonstrates that magnesium ion is a critical factor in controlling synapse density/plasticity. Here, we tested whether elevation of brain magnesium, using a recently developed compound (magnesium-L-threonate, MgT), can ameliorate the AD-like pathologies and cognitive deficits in the APPswe/PS1dE9 mice, a transgenic mouse model of Alzheimer’s disease.ResultsMgT treatment reduced Aβ-plaque, prevented synapse loss and memory decline in the transgenic mice. Strikingly, MgT treatment was effective even when the treatment was given to the mice at the end-stage of their Alzheimer’s disease-like pathological progression. To explore how elevation of brain magnesium ameliorates the AD-like pathologies in the brain of transgenic mice, we studied molecules critical for APP metabolism and signaling pathways implicated in synaptic plasticity/density. In the transgenic mice, the NMDAR signaling pathway was downregulated, while the BACE1 expression were upregulated. MgT treatment prevented the impairment of these signaling pathways, stabilized BACE1 expression and reduced sAPPβ and β-CTF in the transgenic mice. At the molecular level, elevation of extracellular magnesium prevented the high Aβ-induced reductions in synaptic NMDARs by preventing calcineurin overactivation in hippocampal slices.ConclusionsOur results suggest that elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of Alzheimer’s disease, and hence it might have therapeutic potential for treating Alzheimer’s disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-014-0065-y) contains supplementary material, which is available to authorized users.
Profound synapse loss is one of the major pathological hallmarks associated with Alzheimer's disease (AD) and might underlie memory impairment. Our previous work demonstrated that the magnesium ion is a critical factor in controlling synapse density/plasticity. Here, we investigated whether elevation of brain magnesium by the use of a recently developed compound, magnesium-L-threonate (MgT), can ameliorate the AD-like pathologies and cognitive deficits in the APPswe/PS1dE9 mice, a transgenic (Tg) mouse model of AD. MgT treatment reduced A plaque and prevented synapse loss and memory decline in the Tg mice. Strikingly, MgT treatment was effective even when given to the mice at the end stage of their AD-like pathological progression. To explore how elevation of brain magnesium ameliorates the AD-like pathologies in the brains of Tg mice, we studied molecules critical for APP metabolism and signaling pathways implicated in synaptic plasticity/density. In the Tg mice, the NMDAR/CREB/BDNF signaling was downregulated, whereas calpain/ calcineurin/Cdk5 neurodegenerative signaling and -secretase (BACE1) expression were upregulated. MgT treatment prevented the impairment of these signaling pathways, stabilized BACE1 expression, and reduced soluble APP and -C-terminal fragments in the Tg mice. At the molecular level, elevation of extracellular magnesium prevented the high-A-induced reductions in synaptic NMDARs by preventing calcineurin overactivation in hippocampal slices. Correlation studies suggested that the protection of NMDAR signaling might underlie the stabilization of BACE1 expression. Our results suggest that elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of AD and may have therapeutic potential for treating AD in humans.
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