Huntington's disease (HD) symptoms are driven to a large extent by dysfunction of the basal ganglia circuitry. HD patients exhibit reduced striatal phoshodiesterase 10 (PDE10) levels. Using HD mouse models that exhibit reduced PDE10, we demonstrate the benefit of pharmacologic PDE10 inhibition to acutely correct basal ganglia circuitry deficits. PDE10 inhibition restored corticostriatal input and boosted cortically driven indirect pathway activity. Cyclic nucleotide signaling is impaired in HD models, and PDE10 loss may represent a homeostatic adaptation to maintain signaling. Elevation of both cAMP and cGMP by PDE10 inhibition was required for rescue. Phosphoproteomic profiling of striatum in response to PDE10 inhibition highlighted plausible neural substrates responsible for the improvement. Early chronic PDE10 inhibition in Q175 mice showed improvements beyond those seen with acute administration after symptom onset, including partial reversal of striatal deregulated transcripts and the prevention of the emergence of HD neurophysiological deficits. VIDEO ABSTRACT.

A major question concerning the learning and memory deficits characteristic of epilepsy is the relative importance of the initial insult that leads to recurrent, unprovoked seizures versus the seizures themselves. A related issue is whether seizure-induced cognitive decline is permanent or reversible when convulsions cease. To address these problems, adult rats were extensively trained in the “spatial accuracy task”, a dry-land analog of the Morris water maze. This task allows the rat’s estimate of the location of a hidden goal zone to be repeatedly measured within each behavioral session. One aim was to measure, in well-trained animals, the time course of any cognitive impairment caused by a daily flurothyl-induced generalized seizure over 11 days. A second aim was to look for possible recovery during 9 subsequent days with no seizures. We saw a cumulative degradation in spatial performance during the seizure days and reversal of the deficit after seizures were stopped such that performance returned to baseline. Interestingly, the rate of learning to an asymptote, the rate of performance decline during one-per-day seizures and the rate of relearning during the recovery period were all similar. Given that the hippocampus plays an important role in spatial memory and that it is the brain structure most vulnerable to abnormal excitation the implication is that the hippocampus remains essential for precise spatial navigation even after prolonged training in locating a fixed goal zone. Clinically, this finding questions the assumption that patients who experience seizures should return to a baseline cognitive level within hours.

Compared with other diffusion metrics, mean kurtosis may serve as an optimal parameter for evaluating and predicting the meningioma grade. Moreover, diffusion metrics may potentially reflect cellular proliferation.

HighlightsPatient-specific 42-ICNs template was created from 156 PD patients’ rs-fMRI data.6 FC markers significantly contributed to depression discrimination in PD.Classifiers achieved the mean accuracy of 82.4% for depression diagnosis in PD.