Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis.

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.

Assessment of anhedonia in psychological trauma: development of the Hedonic Deficit and Interference Scale.

Symptoms of anhedonia, or deficits in the ability to experience positive affect, are increasingly recognized as an outcome of traumatic stress. Herein we demonstrate a phenomenon of "negative affective interference", specifically, negative affective responses to positive events, in association with childhood trauma history. Young adults (n=99) completed a Hedonic Deficit & Interference Scale (HDIS), a self-report measure developed for this study, as well as a modified version of the Fawcette-Clarke Pleasure Capacity Scale that assessed not only positive but also negative affective responses to positive events. The two assessment approaches demonstrated convergent validity and predicted concurrent individual differences in trait positive and negative affect, and extraversion and neuroticism. Histories of childhood emotional and sexual abuse were differentially associated with negative affective responses to positive events. Future research and clinical directions are discussed.