Altered dopaminergic function in a mouse model of Huntington's disease

In this work, we introduce multiplicative drift analysis as a suitable way to analyze the runtime of randomized search heuristics such as evolutionary algorithms. We give a multiplicative version of the classical drift theorem. This allows easier analyses in those settings where the optimization progress is roughly proportional to the current distance to the optimum. To display the strength of this tool, we regard the classical problem how the (1+1) Evolutionary Algorithm optimizes an arbitrary linear pseudo-Boolean function. Here, we first give a relatively simple proof for the fact that any linear function is optimized in expected time $O(n \log n)$, where $n$ is the length of the bit string. Afterwards, we show that in fact any such function is optimized in expected time at most {(1+o(1)) 1.39 \euler n\ln (n)}, again using multiplicative drift analysis. We also prove a corresponding lower bound of ${(1-o(1))e n\ln(n)}$ which actually holds for all functions with a unique global optimum. We further demonstrate how our drift theorem immediately gives natural proofs (with better constants) for the best known runtime bounds for the (1+1) Evolutionary Algorithm on combinatorial problems like finding minimum spanning trees, shortest paths, or Euler tours.Comment: Contains results from our GECCO 2010 and CEC 2010 conference pape

Changes in Dopamine Signalling Do Not Underlie Aberrant Hippocampal Plasticity in a Mouse Model of Huntington’s Disease

Altered dopamine receptor labelling has been demonstrated in presymptomatic and symptomatic Huntington's disease (HD) gene carriers, indicating that alterations in dopaminergic signalling are an early event in HD. We have previously described early alterations in synaptic transmission and plasticity in both the cortex and hippocampus of the R6/1 mouse model of Huntington's disease. Deficits in cortical synaptic plasticity were associated with altered dopaminergic signalling and could be reversed by D1- or D2-like dopamine receptor activation. In light of these findings we here investigated whether defects in dopamine signalling could also contribute to the marked alteration in hippocampal synaptic function. To this end we performed dopamine receptor labelling and pharmacology in the R6/1 hippocampus and report a marked, age-dependent elevation of hippocampal D1 and D2 receptor labelling in R6/1 hippocampal subfields. Yet, pharmacological inhibition or activation of D1- or D2-like receptors did not modify the aberrant synaptic plasticity observed in R6/1 mice. These findings demonstrate that global perturbations to dopamine receptor expression do occur in HD transgenic mice, similarly in HD gene carriers and patients. However, the direction of change and the lack of effect of dopaminergic pharmacological agents on synaptic function demonstrate that the perturbations are heterogeneous and region-specific, a finding that may explain the mixed results of dopamine therapy in HD