Can Molecular Gradients Wire the Brain?

Abstract

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder, a major subset of which is characterized by the accumulation of abnormal forms of the protein tau, leading to impairments in motor functions as well as language and behavioral alterations. Tau58-2/B mice express human tau with the P301S mutation found in familial forms of FTLD in neurons. By assessing three age cohorts of Tau58-2/B mice in a comprehensive behavioral test battery, we found that the tauopathy animals showed age-dependent signs of impulsivity, decreased social exploration and executive dysfunction. The deficit in executive function was first limited to decreased spatial working memory, but with aging this was extended to impaired instrumental short-term memory. Tau pathology was prominent in brain regions underlying these behaviors. Thus, Tau-58-2/B mice recapitulate neurological deficits of the behavioral variant of frontotemporal dementia (bvFTD), presenting them as a suitable model to test therapeutic interventions for the amelioration of this variant.2 Keywords: Behavior; executive function; frontotemporal dementia; frontotemporal lobar degeneration; social exploration; tau Highlights• Tau58-2/B mice present with a tau pathology in cortical areas implicated in bvFTD.• Tau58-2/B mice exhibit motor and sensory gating anomalies at an early age.• With aging the mice show decreased sociability but no altered exploration.• The mice further display increased risk-taking behaviors and executive deficits.• First limited to spatial working memory, it later extends to instrumental memory.

Chemotactic responses of growing neurites to precisely controlled gradients of nerve growth factor

“…growing up or down molecular concentration gradients. While it is still believed that this is a key strategy for guiding axons in vivo , this idea has also recently begun to generate controversy 3–5 . However, it is certainly true that neurites in vitro show chemotactic responses to many of the molecules present in the developing nervous system 6–8 .…”

Mixed analytical-stochastic simulation method for the recovery of a Brownian gradient source from probability fluxes to small windows

“…Estimating the fluctuations in the number of receptor-ligand molecules reaching a cell can be found in [4,10,3]. These models are generally based on homogenization of the boundary condition, rendering it impossible to recover any directional information since they assign the same flux to the entire boundary.…”

“…In the context of cell biology, how a cell can sample its environment and decide its final destination remains open, but it starts with the detection of an external gradient concentration that the cell must use to transform cell positional information into its genetic specialization and differentiation [30,12]. During axonal growth and guidance, the growth cone (which is the tip of a neuronal cell) uses external concentration gradients [10,25] to decide whether to continue moving or to stop, to turn right or left. Bacteria and spermatozoa can orient themselves in various chemotactical or mechanical gradients [2,11].…”

Noise and sensitivity in cell signalling

“…Purcell result (similar to the second term of equation 2.22) [72,73]. To summarise, the latency of turning responses suggests averaging times on the order of 100 s. For typical concentrations and diffusion coefficients, and a growth cone radius of 10 µm, this yields an error in concentration estimates of less than 1%, and a similar level of accuracy for gradient sensing by comparisons between each side of a growth cone [72,73].…”

“…To summarise, the latency of turning responses suggests averaging times on the order of 100 s. For typical concentrations and diffusion coefficients, and a growth cone radius of 10 µm, this yields an error in concentration estimates of less than 1%, and a similar level of accuracy for gradient sensing by comparisons between each side of a growth cone [72,73]. Including the effects of receptor saturation in these calculations leads to an eventual decay in precision at high concentrations, implying a maximum distance for navigation up a gradient [73].…”