A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism.

Induction of neuroprotective heat-shock proteins via pharmacological Hsp90 inhibitors is currently being investigated as a potential treatment for neurodegenerative diseases. Two major hurdles for therapeutic use of Hsp90 inhibitors are systemic toxicity and limited central nervous system permeability. We demonstrate here that chronic treatment with a proprietary Hsp90 inhibitor compound (OS47720) not only elicits a heat-shock-like response but also offers synaptic protection in symptomatic Tg2576 mice, a model of Alzheimer's disease, without noticeable systemic toxicity. Despite a short half-life of OS47720 in mouse brain, a single intraperitoneal injection induces rapid and long-lasting (>3 days) nuclear activation of the heat-shock factor, HSF1. Mechanistic study indicates that the remedial effects of OS47720 depend upon HSF1 activation and the subsequent HSF1-mediated transcriptional events on synaptic genes. Taken together, this work reveals a novel role of HSF1 in synaptic function and memory, which likely occurs through modulation of the synaptic transcriptome.

Whisker barrel cortex delta oscillations and gamma power in the awake mouse are linked to respiration.

Current evidence suggests that delta oscillations (0.5-4 Hz) in the brain are generated by intrinsic network mechanisms involving cortical and thalamic circuits. Here we report that delta band oscillation in spike and local field potential (LFP) activity in the whisker barrel cortex of awake mice is phase locked to respiration. Furthermore, LFP oscillations in the gamma frequency band (30-80 Hz) are amplitude modulated in phase with the respiratory rhythm. Removal of the olfactory bulb eliminates respiration-locked delta oscillations and delta-gamma phase-amplitude coupling. Our findings thus suggest respiration-locked olfactory bulb activity as a main driving force behind delta oscillations and gamma power modulation in the whisker barrel cortex in the awake state.

On-beam synchrony in the cerebellum as the mechanism for the timing and coordination of movement.

In trained reaching rats, we recorded simple spikes of pairs of Purkinje cells that, with respect to each other, were either aligned on a beam of shared parallel fibers or instead were located off beam. Rates of simple spike firing in both on-beam and off-beam Purkinje cell pairs commonly showed great variety in depth of modulation during reaching behavior. But with respect to timing, on-beam Purkinje cell pairs had simple spikes that were tightly time-locked to each other (either delayed or simultaneous) and to movement, despite the variability in rate. By contrast, off-beam Purkinje cell pairs had simple spikes that were not time-locked to each other, neither delayed nor simultaneous. We discuss the implications of these observations for the cerebellar role in timing and coordinating movement.

Research training in psychiatric residency programs: a survey.

Although it seems reasonable to assume that the absence of research training may account for the fact that few psychiatrists involve themselves in research, there is at present little, if any, objective data regarding the extent of research training in psychiatric residency programs. Accordingly, an 11-item questionnaire designed to assess training opportunities and staff and resident interest in research was sent to 400 training facilities in general and child psychiatry. An 82% return rate was obtained. In general, findings suggest that while in many training centers research is viewed as unimportant and frequently given the lowest priority, most facilities appear to have ample personnel to provide adequate research training. While opportunities for research training may be "available" in most training programs for those students sufficiently motivated to seek them out, the low priority assigned to this aspect of training may deflect most residents from becoming involved in research. This is likely to leave the resident poorly equipped to engage in research activities after the completion of training. The implications of the findings for residency training are discussed.