Regular cycling between representations of alternatives in the hippocampus, bioRxiv, 2019-01-29
Cognitive faculties such as imagination, planning, and decision-making require the ability to represent alternative scenarios. In animals, split-second decision-making implies that the brain can represent alternatives at a commensurate speed. Yet despite this insight, it has remained unknown whether there exists neural activity that can consistently represent alternatives in <1 s. Here we report that neural activity in the hippocampus, a brain structure vital to cognition, can regularly cycle between representations of alternative locations (bifurcating paths in a maze) at 8 Hz. This cycling dynamic was paced by the internally generated 8 Hz theta rhythm, often occurred in the absence of overt deliberative behavior, and unexpectedly also governed an additional hippocampal representation defined by alternatives (heading direction). These findings implicate a fast, regular, and generalized neural mechanism underlying the representation of competing possibilities.
biorxiv neuroscience 100-200-users 2019High-pass filtering artifacts in multivariate classification of neural time series data, bioRxiv, 2019-01-27
The application of time-resolved multivariate pattern classification analyses (MVPA) to EEG and MEG data has become increasingly popular. Traditionally, such time series data are high-pass filtered before analyses, in order to remove slow drifts. Here we show that high-pass filtering should be applied with extreme caution in MVPA, as it may easily create artifacts that result in displacement of decoding accuracy, leading to statistically significant above-chance classification during time periods in which the source is clearly not in brain activity. In both real and simulated EEG data, we show that spurious decoding may emerge with filter cut-off settings from as modest as 0.1 Hz. We provide an alternative method of removing slow drift noise, referred to as robust detrending (de Cheveigne & Arzounian, 2018), which, when applied in concert with masking of cortical events does not result in the temporal displacement of information. We show that temporal generalization may benefit from robust detrending, without any of the unwanted side effects introduced by filtering. However, we conclude that for sufficiently clean data sets, no filtering or detrending at all may work sufficiently well. Implications for other types of data are discussed, followed by a number of recommendations.
biorxiv neuroscience 100-200-users 2019C99 selectively accumulates in vulnerable neurons in Alzheimer’s disease, bioRxiv, 2019-01-23
ABSTRACTIntroductionThe levels and distribution of amyloid deposits in the brain does not correlate well with Alzheimer’s disease (AD) progression. Therefore, it is likely that Amyloid-precursor-protein proteolytic fragments other than beta-amyloid contribute to the onset of AD.MethodsWe developed a sensitive assay adapted to the detection of C99, the direct precursor of beta-amyloid. Three postmortem groups were studied control with normal and stable cognition; subjects with moderate AD, and individuals with severe AD. The amount of C99 and beta-amyloid was quantified and correlated with the severity of AD.ResultsC99 accumulates in vulnerable neurons, and its levels correlate with the degree of cognitive impairment in patients suffering from AD. In contrast, beta-amyloid levels are increased in both vulnerable and resistant brain areas.DiscussionThese results raise the possibility that C99, rather than beta-amyloid plaques, is responsible for the death of nerve cells in Alzheimer’s disease.
biorxiv neuroscience 100-200-users 2019C99, not beta-amyloid, is associated with selective death of vulnerable neurons in Alzheimer's disease. Supplementary, bioRxiv, 2019-01-23
Amyloid Precursor Protein (APP) and its cleavage product beta-amyloid are widely believed to be key players in the development of Alzheimer's disease (AD). However, the distribution of amyloid deposits in the brain does not correlate well with disease progression. Therefore, it seemed possible that APP metabolites other than beta-amyloid might make a strong contribution to AD pathology. We developed a sensitive assay adapted to the detection of C99, an intermediate in the conversion of APP to beta-amyloid. Brain tissue sections were obtained from patients suffering from sporadic AD and non-demented controls. Our results demonstrate that C99 levels, but not Abeta levels, correlate with the degree of vulnerability to neurodegeneration and cognitive impairment in patients suffering from AD.
biorxiv neuroscience 100-200-users 2019Multimodal cell type correspondence by intersectional mFISH in intact tissues, bioRxiv, 2019-01-21
AbstractDefining a complete set of cell types within the cortex requires reconciling disparate results achieved through diverging methodologies. To address this correspondence problem, multiple methodologies must be applied to the same cells across multiple single-cell experiments. Here we present a new approach applying spatial transcriptomics using multiplexed fluorescence in situ hybridization, (mFISH) to brain tissue previously interrogated through two photon optogenetic mapping of synaptic connectivity. This approach can resolve the anatomical, transcriptomic, connectomic, electrophysiological, and morphological characteristics of single cells within the mouse cortex.
biorxiv neuroscience 0-100-users 2019Prospective, brain-wide labeling of neuronal subclasses with enhancer-driven AAVs, bioRxiv, 2019-01-21
Labeling and perturbation of specific cell types in multicellular systems has transformed our ability to understand them. The rapid pace of cell type identification by new single-cell analysis methods has not been met with efficient access to these newly discovered types. To enable access to specific neural populations in the mouse cortex, we have collected single cell chromatin accessibility data from select cell types. We clustered the single cell data and mapped them to single cell transcriptomics to identify highly specific enhancers for cell subclasses. These enhancers, when cloned into AAVs and delivered to the brain by retro orbital injections, transgene expression in specific cell subclasses throughout the mouse brain. This approach will enable functional investigation of cell types in the mouse cortex and beyond.
biorxiv neuroscience 200-500-users 2019