Hypothalamic gonadotropin-releasing hormone (GnRH) receptor neurons fire in synchrony with the female reproductive cycle.

Gonadotropin-releasing hormone (GnRH) controls mammalian reproduction via the hypothalamic-pituitary-gonadal (hpg) axis, acting on gonadotrope cells in the pituitary gland that express the GnRH receptor (GnRHR). Cells expressing the GnRHR have also been identified in the brain. However, the mechanism by which GnRH acts on these potential target cells remains poorly understood due to the difficulty of visualizing and identifying living GnRHR neurons in the central nervous system. We have developed a mouse strain in which GnRHR neurons express a fluorescent marker, enabling the reliable identification of these cells independent of the hormonal status of the animal. In this study, we analyze the GnRHR neurons of the periventricular hypothalamic nucleus in acute brain slices prepared from adult female mice. Strikingly, we find that the action potential firing pattern of these neurons alternates in synchrony with the estrous cycle, with pronounced burst firing during the preovulatory period. We demonstrate that GnRH stimulation is sufficient to trigger the conversion from tonic to burst firing in GnRHR neurons. Furthermore, we show that this switch in the firing pattern is reversed by a potent GnRHR antagonist. These data suggest that endogenous GnRH acts on GnRHR neurons and triggers burst firing in these cells during late proestrus and estrus. Our data have important clinical implications in that they indicate a novel mode of action for GnRHR agonists and antagonists in neurons of the central nervous system that are not part of the classical hpg axis.

Preclinical retinal neurodegeneration in a model of multiple sclerosis.

Neurodegeneration plays a major role in multiple sclerosis (MS), in which it is thought to be the main determinant of permanent disability. However, the relationship between the immune response and the onset of neurodegeneration is still a matter of debate. Moreover, recent findings in MS patients raised the question of whether primary neurodegenerative changes can occur in the retina independent of optic nerve inflammation. Using a rat model of MS that frequently leads to optic neuritis, we have investigated the interconnection between neurodegenerative and inflammatory changes in the retina and the optic nerves with special focus on preclinical disease stages. We report that, before manifestation of optic neuritis, characterized by inflammatory infiltration and demyelination of the optic nerve, degeneration of retinal ganglion cell bodies had already begun and ultrastructural signs of axon degeneration could be detected. In addition, we observed an early activation of resident microglia in the retina. In the optic nerve, the highest density of activated microglia was found within the optic nerve head. In parallel, localized breakdown in the integrity of the blood-retinal barrier and aberrations in the organization of the blood-brain barrier marker aquaporin-4 in the optic nerves were observed during the preclinical phase, before onset of optic neuritis. From these findings, we conclude that early and subtle inflammatory changes in the retina and/or the optic nerve head reminiscent of those suggested for preclinical MS lesions may initiate the process of neurodegeneration in the retina before major histopathological signs of MS become manifest.

Uridine supplementation enhances hepatic mitochondrial function in thymidine-analogue treated HIV-infected patients.

Supplementation with uridine offers the possibility of a new and promising approach to nucleoside analogue reverse transcriptase inhibitor-associated mitochondrial toxicity. We investigated the metabolic effects of short-course treatment with the uridine-enriched food supplement NucleomaxX on hepatic mitochondrial function in thymidine-analogue treated HIV-infected patients. Mitochondrial function was assessed by a recently introduced non-invasive C-methionine breath test. NucleomaxX supplementation enhanced mitochondrial decarboxylation function reversibly but reproducibly in all patients. Repeated administration in shorter treatment intervals may maintain this effect.

Cortical activations associated with auditorily paced finger tapping.

We investigated neuromagnetic responses during an auditorily paced synchronization task using a 122-channel whole-head neuromagnetometer. Eight healthy right handed subjects were asked to synchronize left and right unilateral finger taps to a regular binaural pacing signal. Synchronization of the right hand with an auditory pacing signal is known to be associated with three tap-related neuromagnetic sources localized in the contralateral primary sensorimotor cortex. While the first source represents the neuromagnetic correlate of the motor command the second one reflects somatosensory feedback due to the finger movement. The functional meaning of the third source, which is also localized in the primary somatosensory cortex is still unclear. On the one hand this source represents a neuromagnetic correlate of somatosensory feedback due to the finger tap. On the other hand it has been suggested that the function of this source could additionally represent a cognitive process, which enables the subject to monitor the time distance between taps and clicks. The aim of the present study was to elucidate the function of this source, which would fundamentally reform the meaning of the primary somatosensory cortex in the timing of movements with respect to external events. The data of the present study demonstrate that the three sources in the contralateral sensorimotor cortex are stronger related to the tap than to the click. This result contradicts the assumption of a cognitive process localized in the primary somatosensory cortex. Thus, activation in the primary somatosensory cortex most likely represents exclusively somatosensory feedback and no further cognitive processes.