Serotonin as a biomarker of toxin-induced Parkinsonism.

BACKGROUND: Loss of dopaminergic neurons underlies the motor symptoms of Parkinson's disease (PD). However stereotypical PD symptoms only manifest after approximately 80% of dopamine neurons have died making dopamine-related motor phenotypes unreliable markers of the earlier stages of the disease. There are other non-motor symptoms, such as depression, that may present decades before motor symptoms. METHODS: Because serotonin is implicated in depression, here we use niche, fast electrochemistry paired with mathematical modelling and machine learning to, for the first time, robustly evaluate serotonin neurochemistry in vivo in real time in a toxicological model of Parkinsonism, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). RESULTS: Mice treated with acute MPTP had lower concentrations of in vivo, evoked and ambient serotonin in the hippocampus, consistent with the clinical comorbidity of depression with PD. These mice did not chemically respond to SSRI, as strongly as control animals did, following the clinical literature showing that antidepressant success during PD is highly variable. Following L-DOPA administration, using a novel machine learning analysis tool, we observed a dynamic shift from evoked serotonin release in the hippocampus to dopamine release. We hypothesize that this finding shows, in real time, that serotonergic neurons uptake L-DOPA and produce dopamine at the expense of serotonin, supporting the significant clinical correlation between L-DOPA and depression. Finally, we found that this post L-DOPA dopamine release was less regulated, staying in the synapse for longer. This finding is perhaps due to lack of autoreceptor control and may provide a ground from which to study L-DOPA induced dyskinesia. CONCLUSIONS: These results validate key prior hypotheses about the roles of serotonin during PD and open an avenue to study to potentially improve therapeutics for levodopa-induced dyskinesia and depression.

The role of developmental plasticity in evolutionary innovation.

Explaining the origins of novel traits is central to evolutionary biology. Longstanding theory suggests that developmental plasticity, the ability of an individual to modify its development in response to environmental conditions, might facilitate the evolution of novel traits. Yet whether and how such developmental flexibility promotes innovations that persist over evolutionary time remains unclear. Here, we examine three distinct ways by which developmental plasticity can promote evolutionary innovation. First, we show how the process of genetic accommodation provides a feasible and possibly common avenue by which environmentally induced phenotypes can become subject to heritable modification. Second, we posit that the developmental underpinnings of plasticity increase the degrees of freedom by which environmental and genetic factors influence ontogeny, thereby diversifying targets for evolutionary processes to act on and increasing opportunities for the construction of novel, functional and potentially adaptive phenotypes. Finally, we examine the developmental genetic architectures of environment-dependent trait expression, and highlight their specific implications for the evolutionary origin of novel traits. We critically review the empirical evidence supporting each of these processes, and propose future experiments and tests that would further illuminate the interplay between environmental factors, condition-dependent development, and the initiation and elaboration of novel phenotypes.