Short-term exposure to HIV Tat induces glial activation and changes in perineuronal nets.

Despite widespread use of combination antiretroviral therapy (cART), there remains a subset of individuals who display cognitive impairment broadly known as HIV-associated neurocognitive disorder (HAND). Interestingly, HIV-infected cells continuously release the HIV-1 protein Tat even in the presence of cART. Persistent exposure to Tat is proposed to increase both neuroinflammation and neurotoxicity. In vitro evidence shows that matrix metalloproteinases (MMPs) are among the neuroinflammatory molecules induced by Tat, which are known to disrupt specialized neuronal extracellular matrix structures called perineuronal nets (PNNs). PNNs predominantly surround parvalbumin interneurons and help to buffer these cells from oxidant stress and to independently increase their excitability. In order to better understand the link between short-term exposure to Tat, neuroinflammation, and PNNs, we explored the direct effects of Tat on glial cells and neurons. Herein, we report that in mixed glial cultures, Tat directly increases the expression of proinflammatory molecules, including MMP-9. Moreover, direct injection of Tat protein into mouse hippocampus increases the expression of astrocyte and microglia markers as well as MMP-9. The number of PNNs is decreased following Tat exposure, followed later by decreased numbers of hippocampal parvalbumin-expressing neurons. In older mice, Tat induced significant increases in the gene expression of proinflammatory molecules including markers of gliosis, MMPs and complement system proteins. Taken together, these data support a direct effect of Tat on glial-derived MMP expression subsequently affecting PNNs and neuronal health, with older mice more susceptible to Tat-induced inflammation.

Sleep, inflammation, and hemodynamics in rodent models of traumatic brain injury.

Traumatic brain injury (TBI) can induce dysregulation of sleep. Sleep disturbances include hypersomnia and hyposomnia, sleep fragmentation, difficulty falling asleep, and altered electroencephalograms. TBI results in inflammation and altered hemodynamics, such as changes in blood brain barrier permeability and cerebral blood flow. Both inflammation and altered hemodynamics, which are known sleep regulators, contribute to sleep impairments post-TBI. TBIs are heterogenous in cause and biomechanics, which leads to different molecular and symptomatic outcomes. Animal models of TBI have been developed to model the heterogeneity of TBIs observed in the clinic. This review discusses the intricate relationship between sleep, inflammation, and hemodynamics in pre-clinical rodent models of TBI.