Neural ensembles in navigation: From single cells to population codes

The conserved MAP3K12/Dual Leucine Zipper Kinase (DLK) plays versatile roles in neuronal development, axon injury and stress responses, and neurodegeneration, depending on cell-type and cellular contexts. Emerging evidence implicates abnormal DLK signaling in several neurodegenerative diseases. However, our understanding of the DLK-dependent gene network in the central nervous system remains limited. Here, we investigated the roles of DLK in hippocampal glutamatergic neurons using conditional knockout and induced overexpression mice. We found that dorsal CA1 and dentate gyrus neurons are vulnerable to elevated expression of DLK, while CA3 neurons appear largely unaffected. We identified the DLK-dependent translatome that includes conserved molecular signatures and displays cell-type specificity. Increasing DLK signaling is associated with disruptions to microtubules, potentially involving STMN4. Additionally, primary cultured hippocampal neurons expressing different levels of DLK show altered neurite outgrowth, axon specification, and synapse formation. The identification of translational targets of DLK in hippocampal glutamatergic neurons has relevance to our understanding of neurodegenerative diseases. 

Translatome analysis reveals cellular network in DLK-dependent hippocampal glutamatergic neuron degeneration

From local APP expression to network dysfunction.

Deficits in spatial navigation are among the early symptoms in Alzheimer’s disease patients, consistent with the hippocampal formation as the site for spatial computations and disease onset. Although the correspondence between the early symptoms and brain regions that are affected early in the disease has been recognized, it is not clear whether progressive cognitive decline is solely caused by a spreading pathology or whether a focal pathology can by itself cause aberrant neuronal activity in a larger network. These possibilities cannot be distinguished in standard disease models which broadly express APP across brain regions. We therefore generated a mouse model in which the expression of mutant human APP was limited to hippocampal CA3 cells (CA3-APP mice). We first asked whether the limited pathology in CA3 can result in memory deficits and found impaired performance of CA3-APP mice in a hippocampus-dependent memory task. By then recording in the CA1 region, we asked to what extent neuronal activity patterns emerged in a brain region which received projections from APP-expressing CA3 cells, but did itself not show any primary pathology. While the spatial firing patterns of CA1 cells were preserved, we observed a reduced theta oscillation frequency in the local field potential and in a subpopulation of principal cells in CA1. Furthermore, CA1 interneurons showed decreased theta oscillation frequencies, and this effect was even more pronounced in CA3 interneurons, which also do not directly express APP. Pathology that is highly localized and limited to presynaptic cells is thus sufficient to cause aberrant firing patterns in postsynaptic neuronal networks, which indicates that disease progression is not only from a spreading molecular pathology but also mediated by progressive physiological dysfunction.

/pdf/localized-app-pathology-in-the-hippocampus-is-sufficient-to-3da64dko.pdf

Localized APP pathology in the hippocampus is sufficient to result in progressive disorganization of the timing of neuronal firing patterns


 Various studies have been carried out for soils at normal room temperature but the studies on frozen soils are meagre. For every construction, soil investigation is the most important and the primary step for a site. For constructions at normal room temperature, there are plenty of experimentation and research data on soil is available. But lack of research data for colder regions, where the ambient temperature is below zero degree Celsius for most of the time. It is therefore the need to study soil under iced condition to get a better idea about the behaviour of frozen soils. There are few research on construction and mechanical behaviour of frozen soil but no study on the very basic parameters of like void ratio, bulk density, porosity, and the degree of freezing and how these parameters change as the soil temperature changes from normal room temperature to negative values. The main emphasis is on the study and experimentation on frozen soil and to formulate different relationships between individual soil parameters at various temperatures. The methodology used is to model the soil surface (open grounds in colder regions) by taking sand as the soil after sieving. The model samples are taken into beakers with different bulk densities to replicate real site condition in the freezer. Then by calculating factors like density, porosity, void ratio, etc at negative temperature (-5, -10, -15, -20 degree Celsius) and forming relationship with same parameters with that on room temperature. The experimental data obtained is used in “Eureqa software” that will utilize the input so provided and will find mathematical relation that exist in the soil parameters.

/pdf/experimental-studies-on-frozen-soil-2uefpu1l4n.pdf

Experimental Studies on Frozen Soil

• MRI, DRE, and endoscopic measurements of rectal tumor height strongly correlate. • Correlations are strong in the middle rectum, but weak or non-existent otherwise. • DRE demonstrated the lowest average measurements. • Low and high rectal tumors may be most difficult to characterize. • More research is needed to establish a gold standard for assessing tumor height. Outcomes in rectal cancer are dependent on tumor height. Modalities for assessing tumor height include MRI, endoscopy, and digital rectal exam (DRE). We seek to identify correlations between these modalities. Retrospective analysis of 120 rectal cancer patients at a single institution. Correlation coefficients and distance of the tumor to anal verge between MRI, endoscopy, and DRE were compared by region. The distances of tumor (cm) from anal verge were: MRI: 6.2 ± 3.0, endoscopy: 5.9 ± 2.9, DRE: 5.4 ± 2.4 ( p = 0.238). Endoscopy and DRE strongly correlated with MRI (spearman coefficient 0.899 and 0.842, respectively). Endoscopy and DRE also strongly correlated (spearman coefficient 0.876). Correlation coefficients were highest in the middle rectum, weak in the low rectum, and non-correlated in the upper rectum. MRI, endoscopy, and DRE strongly correlated overall. DRE demonstrated the lowest average distance. Correlations differed by region, suggesting high or low rectal tumors are difficult to characterize. 

How do they measure up: Assessing the height of rectal cancer with digital rectal exam, endoscopy, and MRI

Progressive cognitive decline in Alzheimer’s disease could either be caused by a spreading molecular pathology or by an initially focal pathology that causes aberrant neuronal activity in a larger network. To distinguish between these possibilities, we generated a mouse model with expression of mutant human amyloid precursor protein (APP) in only hippocampal CA3 cells. We found that performance in a hippocampus-dependent memory task was impaired in young adult and aged mutant mice. In both age groups, we then recorded from the CA1 region, which receives inputs from APP-expressing CA3 cells. We observed that theta oscillation frequency in CA1 was reduced along with disrupted relative timing of principal cells. Highly localized pathology limited to the presynaptic CA3 cells is thus sufficient to cause aberrant firing patterns in postsynaptic neuronal networks, which indicates that disease progression is not only from spreading pathology but also mediated by progressively advancing physiological dysfunction. 

Localized APP expression results in progressive network dysfunction by disorganizing spike timing

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Localized APP pathology in the hippocampus is sufficient to result in progressive disorganization of the timing of neuronal firing patterns

Experimental Studies on Frozen Soil

How do they measure up: Assessing the height of rectal cancer with digital rectal exam, endoscopy, and MRI

Localized APP expression results in progressive network dysfunction by disorganizing spike timing