Age-related changes in neuronal receptive fields of primary auditory cortex in frequency, amplitude, and temporal domains.

Aging populations often experience difficulties hearing. This phenomenon, known as age-related hearing loss, is associated with decreases in hearing sensitivity and pathophysiological changes in the central auditory system, including the primary auditory cortex (AI). To better understand changes in the central auditory system, this study is designed to compare the receptive fields of AI neurons of young and old C57 mice in frequency, amplitude, and temporal domains by using random-delivery (various interval) of multi-frequency gamma-shaped tone pips and a novel data processing approach known as the intensity-stacked spectrotemporal receptive field (iSTRF). We show that the fundamental changes in the response properties of AI neurons in old mice were in line with the literature. Compared to young mice, AI neurons in old mice tuned to lower frequency and higher amplitude of tones with broader frequency tuning, shorter dB (dynamic) range, longer response duration, as well as a higher firing rate. We further compared the entire iSTRF and core iSTRF (above 50% maximal firing rate) between young and old mice; the core iSTRF represented the AI neuronal responses to sound that fall into the central frequency and amplitude ranges from the auditory periphery. It is remarkable that the difference was significant in the entire iSTRF while little difference was observed in the core iSTRFs between young and old mice. However, the lower best frequency and higher best amplitude were obvious in both iSTRFs that were mostly determined by the deficits in the inner ears of old mice. In the frequency domain, the tuning quality factor of entire iSTRFs was significantly greater in old mice, while that of core iSTRFs was not compared to young mice. In the amplitude domain, significantly shorter dB range in old mice were observed in the entire iSTRF, but not in the core iSTRF. In the temporal domain, the response duration of old AI neurons was significantly longer in entire iSTRFs, but not in core iSTRFs, when compared to young AI neurons. Furthermore, the average firing rate of old AI neurons was significantly higher in entire iSTRF, but not in core iSTRF. It is also interesting that the ratio of the firing rate to background firing rate (signal-noise ratio) were similar between young and old AI neurons. Our data suggests that age-related hearing loss has relatively less impact on auditory information processing when sounds fall into the optimal frequency and amplitude ranges of given AI neurons.

Blast-induced axonal degeneration in the rat cerebellum in the absence of head movement.

Blast exposure can injure brain by multiple mechanisms, and injury attributable to direct effects of the blast wave itself have been difficult to distinguish from that caused by rapid head displacement and other secondary processes. To resolve this issue, we used a rat model of blast exposure in which head movement was either strictly prevented or permitted in the lateral plane. Blast was found to produce axonal injury even with strict prevention of head movement. This axonal injury was restricted to the cerebellum, with the exception of injury in visual tracts secondary to ocular trauma. The cerebellar axonal injury was increased in rats in which blast-induced head movement was permitted, but the pattern of injury was unchanged. These findings support the contentions that blast per se, independent of head movement, is sufficient to induce axonal injury, and that axons in cerebellar white matter are particularly vulnerable to direct blast-induced injury.

Effects of Veliparib on Microglial Activation and Functional Outcomes after Traumatic Brain Injury in the Rat and Pig.

The inflammation response induced by brain trauma can impair recovery. This response requires several hours to develop fully and thus provides a clinically relevant therapeutic window of opportunity. Poly(ADP-ribose) polymerase inhibitors suppress inflammatory responses, including brain microglial activation. We evaluated delayed treatment with veliparib, a poly(ADP-ribose) polymerase inhibitor, currently in clinical trials as a cancer therapeutic, in rats and pigs subjected to controlled cortical impact (CCI). In rats, CCI induced a robust inflammatory response at the lesion margins, scattered cell death in the dentate gyrus, and a delayed, progressive loss of corpus callosum axons. Pre-determined measures of cognitive and motor function showed evidence of attentional deficits that resolved after three weeks and motor deficits that recovered only partially over eight weeks. Veliparib was administered beginning 2 or 24 h after CCI and continued for up to 12 days. Veliparib suppressed CCI-induced microglial activation at doses of 3 mg/kg or higher and reduced reactive astrocytosis and cell death in the dentate gyrus, but had no significant effect on delayed axonal loss or functional recovery. In pigs, CCI similarly induced a perilesional microglial activation that was attenuated by veliparib. CCI in the pig did not, however, induce detectable persisting cognitive or motor impairment. Our results showed veliparib suppression of CCI-induced microglial activation with a delay-to-treatment interval of at least 24 h in both rats and pigs, but with no associated functional improvement. The lack of improvement in long-term recovery underscores the complexities in translating anti-inflammatory effects to clinically relevant outcomes.

Human Cytomegalovirus interleukin-10 promotes proliferation and migration of MCF-7 breast cancer cells.

Breast cancer is the most common malignancy affecting women worldwide. While a small fraction of breast cancers have a hereditary component, environmental and behavioral factors also impact the development of cancer. Human cytomegalovirus (HCMV) is a member of the Herpesviridae family that is widespread in the general population and has been linked to several forms of cancer. While HCMV DNA has been found in some breast cancer tissue specimens, we wanted to investigate whether a secreted viral cytokine might have an effect on cancerous or even pre-cancerous cells. HCMV encodes an ortholog of the human cellular cytokine interleukin-10 (IL-10). The HCMV UL111A gene product is cmvIL-10, which has 27% sequence identity to IL-10 and binds the cellular IL-10 receptor (IL-10R) to induce downstream cell signaling. We found that MCF-7 human breast cancer cells express IL-10R and that exposure to cmvIL-10 results in enhanced proliferation and increased chemotaxis of MCF-7 cells. PCR arrays revealed that treatment with cmvIL-10 alters expression of cell adhesion molecules and increases MMP gene expression. In particular, MMP-10 gene expression was found to be significantly up-regulated and this correlated with an increase in cell-associated MMP-10 protein produced by MCF-7 cells exposed to cmvIL-10. These results suggest that the presence of cmvIL-10 in the tumor microenvironment could contribute to the development of more invasive tumors.