GABAergic regulation of the perifornical–lateral hypothalamic neurons during non-rapid eye movement sleep in rats

The perifornical–lateral hypothalamic area (PF–LHA) has been implicated in the regulation of behavioral arousal. The PF–LHA predominantly contains neurons that are active during behavioral and cortical activation and quiescent during non-rapid eye movement (nonREM) sleep, that is, are nonREM-off neurons. Some in vitro and in vivo studies indicate that PF–LHA neurons, including hypocretin-expressing neurons, are under GABAergic control. However, a role of GABA in suppressing the discharge of PF–LHA neurons during spontaneous nonREM sleep has not been confirmed. We recorded the sleep–wake discharge profiles of PF–LHA neurons and simultaneously assessed the contributions of local GABA_A receptor activation and blockade on their wake- and nonREM sleep-related discharge activities by delivering GABA_A receptor agonist, muscimol (500 nm, 5 μM, and 10 μM) and its antagonist, bicuculline (5 μM, 10 μM, and 20 μM), adjacent to the recorded neurons via reverse microdialysis. Muscimol dose-dependently decreased the discharge of PF–LHA neurons including nonREM-off neurons. Muscimol-induced suppression of discharge during nonREM sleep was significantly weaker than the suppression produced during waking. In the presence of bicuculline, PF–LHA neurons, including nonREM-off neurons, exhibited elevated discharge, which was dose-dependent and was significantly higher during nonREM sleep, compared to waking. These results suggest that GABA_A receptor mediated increased GABAergic tone contributes to the suppression of PF–LHA neurons, including nonREM-off neurons, during spontaneous nonREM sleep.     

Functional imaging of changes in cerebellar activity related to learning during a novel eye–hand tracking task

Coordination between the eyes and the hand is likely to be based on a process of motor learning, so that the interactions between the two systems can be accurately controlled. By using an unusual tracking task we measured the change in brain activation levels, as recorded with 3T functional magnetic resonance imaging (fMRI), between naïve human subjects and the same subjects after a period of extended training. Initially the performance of the two groups was similar. One subject group was then trained in a synchronous, coordinated, eye–hand task; the other group trained with a 304 ms temporal offset between hand and eye tracking movements. After training, different patterns of performance were observed for the groups, and different functional activation profiles. Significant change in the relationship between functional activation levels and eye–hand task conditions was predominantly restricted to visuo-motor areas of the lateral and vermal cerebellum. In an additional test with one of the subject groups, we show that there was increased cerebellar activation after learning, irrespective of change in performance error. These results suggest that two factors contribute to the measured blood oxygen level-dependent (BOLD) signal. One declined with training and may be directly related to performance error. The other increased after training, in the test conditions nearest to the training condition, and may therefore be related to acquisition of experience in the task. The loci of activity changes suggest that improved performance is because of selective modified processing of ocular and manual control signals within the cerebellum. These results support the suggestion that coordination between eye and hand movement is based on an internal model acquired by the cerebellum that provides predictive signals linking the control of the two effectors.     

IFNγ-producing, virus-specific CD8 effector cells acquire the ability to produce IL-10 as a result of entry into the infected lung environment

It has become clear that T cells with the potential to negatively regulate the immune response are normal constituents of the immune system. These cells often mediate their effects through the production of immunosuppressive factors. At present our understanding of how these cells are generated is limited. Here we report the presence of a population of IL-10-producing, virus-specific CD8⁺ T cells in the lungs of mice following acute respiratory infection. These cells were only found at minimal levels in the spleen and draining lymph node; instead they were restricted primarily to the infected lung tissue. A major finding from this study is demonstration that the ability to produce IL-10 can be acquired by IFNγ-producing effector cells following entry into the infected lung. These studies suggest IL-10 production is the result of further differentiation of an antigen-specific CD8⁺ T cell that is governed by signals present in infected lung tissue.     

Evaluation of CD103 (αEβ7) integrin expression by CD8 T cells in blood as a surrogate marker to predict cervical T cell responses in the female genital tract during HIV infection

Mucosal homing receptors expressed by blood T cells may be useful surrogates for measuring mucosal T cell immune responses at the site of HIV transmission. Here, we investigated whether HIV-specific responses by T cells expressing the mucosal integrin receptor CD103 in blood reliably predicted corresponding HIV-specific responses at the cervix. The frequency of CD8+ T cells expressing CD103 in blood correlated significantly with the number of CD103+CD8+ T cells from the cervix suggesting that CD103 was involved in trafficking of T cells from blood to the cervical mucosa. TGF-β concentrations in plasma were significantly associated with the frequency of CD103 expression by blood but not cervical CD8 T cells. The majority of Gag-responsive CD8 T cells were CD103+ in both blood and at the cervix. Despite this, the magnitude of Gag-specific IFN-γ responses by CD103+CD8+ T cells in blood did not predict similar Gag-specific responses at the cervix.