Presenilin-Dependent Receptor Processing Is Required for Axon Guidance

SummaryThe Alzheimer's disease-linked gene presenilin is required for intramembrane proteolysis of amyloid-β precursor protein, contributing to the pathogenesis of neurodegeneration that is characterized by loss of neuronal connections, but the role of Presenilin in establishing neuronal connections is less clear. Through a forward genetic screen in mice for recessive genes affecting motor neurons, we identified the Columbus allele, which disrupts motor axon projections from the spinal cord. We mapped this mutation to the Presenilin-1 gene. Motor neurons and commissural interneurons in Columbus mutants lacking Presenilin-1 acquire an inappropriate attraction to Netrin produced by the floor plate because of an accumulation of DCC receptor fragments within the membrane that are insensitive to Slit/Robo silencing. Our findings reveal that Presenilin-dependent DCC receptor processing coordinates the interplay between Netrin/DCC and Slit/Robo signaling. Thus, Presenilin is a key neural circuit builder that gates the spatiotemporal pattern of guidance signaling, thereby ensuring neural projections occur with high fidelity

Locus of Control and Negative Cognitive Styles in Adolescence as Risk Factors for Depression Onset in Young Adulthood:Findings From a Prospective Birth Cohort Study

Whilst previous observational studies have linked negative thought processes such as an external locus of control and holding negative cognitive styles with depression, the directionality of these associations and the potential role that these factors play in the transition to adulthood and parenthood has not yet been investigated. This study examined the association between locus of control and negative cognitive styles in adolescence and probable depression in young adulthood and whether parenthood moderated these associations. Using a UK prospective population-based birth cohort study: the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined the association between external locus of control and negative cognitive styles in adolescence with odds of depression in 4,301 young adults using logistic regression models unadjusted and adjusted for potential confounding factors. Interaction terms were employed to examine whether parenthood (i.e., having become a parent or not) moderated these associations. Over 20% of young adults in our sample were at or above the clinical threshold indicating probable depression. For each standard deviation (SD) increase in external locus of control in adolescence, there was a 19% (95% CI: 8–32%) higher odds of having probable depression in young adulthood, after adjusting for various confounding factors including baseline mood and different demographic and life events variables. Similarly, for each SD increase in negative cognitive styles in adolescence, there was a 29% (95% CI: 16–44%) higher odds of having probable depression in the adjusted model. We found little evidence that parenthood status moderated the relationship between external locus of control or negative cognitive styles in adolescence and probable depression following adjustment for confounding factors. Effect estimates were comparable when performed in the complete case dataset. These findings suggest that having an external locus of control and holding negative cognitive styles in mid- to late adolescence is associated with an increased likelihood of probable depression in young adulthood

Cholinergic Input Is Required during Embryonic Development to Mediate Proper Assembly of Spinal Locomotor Circuits

SummaryRhythmic limb movements are controlled by pattern-generating neurons within the ventral spinal cord, but little is known about how these locomotor circuits are assembled during development. At early stages of embryogenesis, motor neurons are spontaneously active, releasing acetylcholine that triggers the depolarization of adjacent cells in the spinal cord. To investigate whether acetylcholine-driven activity is required for assembly of the central pattern-generating (CPG) circuit, we studied mice lacking the choline acetyltransferase (ChAT) enzyme. Our studies show that a rhythmically active spinal circuit forms in ChAT mutants, but the duration of each cycle period is elongated, and right-left and flexor-extensor coordination are abnormal. In contrast, blocking acetylcholine receptors after the locomotor network is wired does not affect right-left or flexor-extensor coordination. These findings suggest that the cholinergic neurotransmitter pathway is involved in configuring the CPG during a transient period of development

The Avon Longitudinal Study of Parents and Children (ALSPAC):an update on the enrolled sample of index children in 2019

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective population-based study. Initial recruitment of pregnant women took place in 1990-1992 and the health and development of the index children from these pregnancies and their family members have been followed ever since. The eligible sampling frame was constructed retrospectively using linked recruitment and health service records. Additional offspring that were eligible to enrol in the study have been welcomed through major recruitment drives at the ages of 7 and 18 years; and through opportunistic contacts since the age of 7. This data note provides a status update on the recruitment of the index children since the age of 7 years with a focus on enrolment since the age of 18, which has not been previously described. A total of 913 additional G1 (the cohort of index children) participants have been enrolled in the study since the age of 7 years with 195 of these joining since the age of 18. This additional enrolment provides a baseline sample of 14,901 G1 participants who were alive at 1 year of age

Olfactory receptor accessory proteins play crucial roles in receptor function and gene choice

Each of the olfactory sensory neurons (OSNs) chooses to express a single G protein-coupled olfactory receptor (OR) from a pool of hundreds. Here, we show the receptor transporting protein (RTP) family members play a dual role in both normal OR trafficking and determining OR gene choice probabilities. Rtp1 and Rtp2 double knockout mice (RTP1,2DKO) show OR trafficking defects and decreased OSN activation. Surprisingly, we discovered a small subset of the ORs are expressed in larger numbers of OSNs despite the presence of fewer total OSNs in RTP1,2DKO. Unlike typical ORs, some overrepresented ORs show robust cell surface expression in heterologous cells without the co-expression of RTPs. We present a model in which developing OSNs exhibit unstable OR expression until they choose to express an OR that exits the ER or undergo cell death. Our study sheds light on the new link between OR protein trafficking and OR transcriptional regulation.R01 DC012095 - NIDCD NIH HHS; R01 DC014423 - NIDCD NIH HH

DLK induces developmental neuronal degeneration via selective regulation of proapoptotic JNK activity

DLK is part of a specialized JNK signaling complex in axons that promotes apoptosis via c-Jun but axon degeneration via distinct JNK substrates