The gene's eye view, the Gouldian knot, Fisherian swords and the causes of selection

The biological units-of-selection debate has centred on questions of which units experience selection and adaptation. Here, I use a causal framework and the Price equation to develop the gene's eye perspective. Genes are causally special in being both replicators and interactors. Gene effects are tied together in a complex Gouldian knot of interactions, but Fisher deployed three swords to try to cut the knot. The first, Fisher's average excess, is non-causal, so not fully satisfactory in that respect. The Price equation highlights Fisher's other two swords, choosing to model only selection, and only the part that is transmissible across generations. The models developed here show that many causes of organismal fitness do not cause Gouldian complications. Only two kinds of elements must be added to the focal gene for a causal explanation of its selective change: co-replicators that are associated with the focal gene and co-interactors that interact non-additively with the focal gene. Identical equations for co-replication and co-interaction describe interactions between gene copies at a single locus or at separate loci, and also for genes situated within the same individual or in different individuals. These results resolve some of the objections to the gene's eye view. This article is part of the theme issue ‘Fifty years of the Price equation’.

Enhanced β-secretase processing of amyloid precursor protein in the skeletal muscle of ALS animal models

ABSTRACTAmyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder primarily characterized by motor neuron degeneration and muscle paralysis. Several studies indicate that pathological changes in the skeletal muscle contribute to disease progression. We report a significant increase of β-secretase processing of amyloid precursor protein (APP) in the skeletal muscle but not the spinal cord or cerebral cortex of hSOD1 (G93A) transgenic ALS mouse models. Enhanced β-secretase processing of APP was manifested by up-regulated expression of βCTF, the 22-kd CTF of APP, and β-secretase processing enzyme, BACE1. Morphological analysis demonstrated that enhanced β-secretase processing of APP mainly occurred in the atrophic myofibers of ALS mice. We also observed a similar change in APP processing in an hSOD1 (G93A) transgenic ALS pig model, suggesting that enhanced β-secretase processing of APP in skeletal muscle may be a common pathological feature of ALS. These findings reveal a selective change in APP processing in skeletal muscle of ALS animal models, and highlight the involvement of aberrant APP processing in ALS pathogenesis.

Reward modulates the effect of visual cortical microstimulation on perceptual decisions

Effective perceptual decisions rely upon combining sensory information with knowledge of the rewards available for different choices. However, it is not known where reward signals interact with the multiple stages of the perceptual decision-making pathway and by what mechanisms this may occur. We combined electrical microstimulation of functionally specific groups of neurons in visual area V5/MT with performance-contingent reward manipulation, while monkeys performed a visual discrimination task. Microstimulation was less effective in shifting perceptual choices towards the stimulus preferences of the stimulated neurons when available reward was larger. Psychophysical control experiments showed this result was not explained by a selective change in response strategy on microstimulated trials. A bounded accumulation decision model, applied to analyse behavioural performance, revealed that the interaction of expected reward with microstimulation can be explained if expected reward modulates a sensory representation stage of perceptual decision-making, in addition to the better-known effects at the integration stage.

Novelty is not enough: laser-evoked potentials are determined by stimulus saliency, not absolute novelty

Event-related potentials (ERPs) elicited by transient nociceptive stimuli in humans are largely sensitive to bottom-up novelty induced, for example, by changes in stimulus attributes (e.g., modality or spatial location) within a stream of repeated stimuli. Here we aimed 1) to test the contribution of a selective change of the intensity of a repeated stimulus in determining the magnitude of nociceptive ERPs, and 2) to dissect the effect of this change of intensity in terms of “novelty” and “saliency” (an increase of stimulus intensity is more salient than a decrease of stimulus intensity). Nociceptive ERPs were elicited by trains of three consecutive laser stimuli (S1-S2-S3) delivered to the hand dorsum at a constant 1-s interstimulus interval. Three, equally spaced intensities were used: low (L), medium (M), and high (H). While the intensities of S1 and S2 were always identical (L, M, or H), the intensity of S3 was either identical (e.g., HHH) or different (e.g., MMH) from the intensity of S1 and S2. Introducing a selective change in stimulus intensity elicited significantly larger N1 and N2 waves of the S3-ERP but only when the change consisted in an increase in stimulus intensity. This observation indicates that nociceptive ERPs do not simply reflect processes involved in the detection of novelty but, instead, are mainly determined by stimulus saliency.