Testosterone-dependent changes in neurons of hypothalamic arcuate nucleus and reversibility of these changes by modeled male hypogonadism

Актуальность. Значение недостаточности тестостерона для структурного гомеостазиса нейронов, регулирующих выработку гонадотропин-рилизинг гормона (ГнРГ) и синтезирующих данный гормон, мало изучены. Цель. Установить реактивные изменения, количество рецепторов к андрогенам (АР) и особенности их распределения в нейронах медиального аркуатного ядра гипоталамуса (МАЯ) при экспериментальном гипогонадизме, а также обратимость этих изменений после восстановительной терапии тестостероном. Методы. У самцов крыс Вистар (16 особей) моделировали гипогонадизм путем удаления одной гонады на 2-3 день постнатальной жизни и исследовали гистологические срезы каудальной части МАЯ у молодых животных (4 мес.) при отсутствии и осуществлении заместительной терапии. Контрольную группу составляли интактные самцы аналогичного возраста (8 особей). В середине левосторонней части МАЯ на площади 0,01 мм определяли реактивные изменения клеток и площадь тел малоизмененных нейронов (после окрашивания срезов методом Ниссля), а также число и долю тел нервных клеток, различавшихся по степени экспрессии АР. Результаты. Установлено, что нейроны МАЯ содержат большое количество АР, распределенных в различных частях их тела. При гипогонадизме происходит перераспределение АР и снижение степени их экспрессии (количества). Сгущение АР в области оболочки ядра и плазмолеммы, образование конгломератов в ядре и цитоплазме было характерно для нейронов с умеренной экспрессией. В цитоплазме и в области плазматической мембраны рецепторы отсутствовали у клеток со слабой и очень низкой экспрессией. Снижение степени экспрессии АР при гипогонадизме сопряжено с уменьшением площади тела и гибелью части нейронов. Заключение. Выявленные дегенеративные тестостерон-зависимые изменения нейронов МАЯ, которые синтезируют ГнРГ или пептиды, влияющие на его выработку, могут обусловить уменьшение высвобождения гонадолиберина, вторичное снижение синтеза андрогенов и реализацию морфофункциональных проявлений его вторичного дефицита. Заместительная терапия частично компенсирует дегенеративные изменения нейронов, восстанавливает интенсивность экспрессии АР, однако не влияет на процесс гибели нервных клеток. Background. Importance of testosterone deficiency for structural homeostasis of the neurons regulating production of gonadotropin-releasing hormone (GnRH) and synthesizing this hormone is insufficiently understood. Aim. To determine reactive changes, quantity of androgens receptors (AR), and features of their distribution in neurons of hypothalamic medial arcuate nucleus (MAN) in experimental hypogonadism and reversibility of these changes by restorative therapy with testosterone. Methods. Hypogonadism was modeled in 16 Wistar rats by removing one gonad on postnatal days 2-3, and histological sections of caudal MAN were examined in young, 4-month old animals with and without a replacement therapy. The control group consisted of 8 age-matched intact males. Cell reactive changes, areas of slightly changed neuron bodies (Nissl staining of sections), and the number and proportion of nerve cell bodies differing in the degree of AR expression were determined in the middle left-sided part of MAN, on an area of 0.01 mm. Results. MAN neurons contained a large quantity of AR distributed in different parts of the neuron body. In hypogonadism, AR redistributed and their expression (quantity) decreased. Condensation of AR in the region of nucleo- and plasmolemma and formation of conglomerates in the nucleus and cytoplasm were characteristic of neurons with moderate expression. In the regions of cytoplasm and plasma membrane, the receptors were absent in cells with low and very low expression. The reduced AR expression in hypogonadism was associated with a decreased neuron body area and death of a part of neurons. Conclusions. The identified degenerative changes in the testosterone-dependent neuronal MAN that synthesize GnRH or peptides affecting the GnRH production may decrease the release of GnRH, cause a secondary decrease in the androgen synthesis, and mediate morphological and functional manifestations of GnRH secondary deficit. The replacement therapy partially compensated for degenerative changes in neurons and restored the intensity of AR expression, however, it did not influence the process of nerve cell death.

Effect of cytoskeletal element degradation on merging of concentration waves in slow axonal transport

The aim of this paper is to investigate, by means of a numerical simulation, the effect of the half-life of cytoskeletal elements (CEs) on superposition of several waves representing concentrations of running, pausing, and off-track anterograde and retrograde CE populations. The waves can be induced by simultaneous microinjections of radiolabeled CEs in different locations in the vicinity of a neuron body; alternatively, the waves can be induced by microinjecting CEs at the same location several times, with a time interval between the injections. Since the waves spread out as they propagate downstream, unless their amplitude decreases too fast, they eventually superimpose. As a result of superposition and merging of several waves, for the case with a large half-life of CEs, a single wave is formed. For the case with a small half-life the waves vanish before they have enough time to merge.

Modeling Bidirectional Transport of New and Used Organelles in Fast Axonal Transport in Neurons

This paper develops a model for simulating transport of newly synthesized material from the neuron body toward the synapse of the axon as well as transport of misfolded and aggregated proteins back to the neuron body for recycling. The model demonstrates that motor-assisted transport, much similar to diffusion, can occur due to a simple concentration difference between the cell body and the synapse; organelles heading to the synapse do not need to attach preferably to plus-end-directed molecular motors, same as organelles heading to the neuron body for recycling do not need to attach preferably to minus-end-directed molecular motors. The underlying mechanics of molecular-motor-assisted transport is such that organelles would be transported to the right place even if new and used organelles had the same probability of attachment to plus-end-directed (and minus-end-directed) motors. It is also demonstrated that the axon with organelle traps and a region with a reversed microtubule polarity would support much smaller organelle fluxes of both new and used organelles than a healthy axon. The flux of organelles is shown to decrease as the width of organelle traps increases.

American Retrospect

Epilepsy and other Convulsive Diseases: A Study in Neuro-dynamics and Pathogenesis.—Under this title Dr. Langdon, of Cincinnati, reviews (Journ. Nerv. and Mental Disease, September, 1896) the present state of our knowledge upon certain facts in the anatomy and physiology of the central nervous system; and puts forward some propositions to serve as a working hypothesis to explain epilepsy and other convulsive disorders in the light of modern histological research. He lays particular stress upon Cajal's demonstration of the individuality of the neuron as opposed to the older views. Though anatomically distinct units, neurons are in physiological relation with each other, by means of delicate projections termed gemmules or “contact granules.” The neuron-body (or nerve-cell) is to be considered, in his opinion, as mainly trophic in function; while the nervous activities themselves are to be looked for in the neuron processes, and accounted for upon the theory of inter-molecular and inter-atomic motion—this motion being the result of external stimuli acting upon the peripheral arborisations of neurons. In opposition to the many theories that have been advanced in the explanation and location of the epileptic convulsion, it is now almost universally conceded that: (1) the actual origin of the epileptic convulsion is in the cortex cerebri, and (2) that its nature is an “explosive discharge” in “unstable nerve tissue.” While the nerve-cell was considered the sole seat of all nervous activity, naturally the cause of convulsive phenomena was principally sought for within this nerve-cell. But Langdon quotes researches which show that the ultimate fibrillæ of the axis-cylinder may be traced through the neuron-body to finally ramify in “neuro-plexuses” composed of multitudinous interlacing “end-tufts,” with their contactbuds, and it is in this jungle that, in his opinion, any demonstrable lesions of the various convulsive disorders (including chorea, hysteria, and even uræmia) are to be sought. He is further of opinion that the cerebral cortex, instead of being a “centre of action,” has for its main function that of inhibition, in other words, that it is a centre for preventing, checking, directing and combining various activities which might otherwise occur in different order or intensity. The phenomena observed in the case of Goltz’ dog, which lived for eighteen months after having been deprived of its cerebral hemispheres, are cited in confirmation of this view. His propositions are summarised as follows:—(1) That epilepsy, the choreas, and probably most convulsive disorders, are the dynamical expression of an inhibitory insufficiency; not indications of an over production of nerve-energy, nor “explosions” due to a “molecular instability,” per se. (2) That the cause of this inhibitory insufficiency is to be sought for in the end-brushes of collateral processes of various cortical neurons, the situation varying with the type of the disease, whether sensory, psychic, or motor. (3) That the defect consists most probably in a structural incompleteness (small capacity, defective insulation, imperfect contact) or a numerical deficiency, or both, in the collateral processes of the neurons. (4) Defective collaterals may favour occurrence of convulsions in two ways: (a) by impairing connection with other neurons (inhibitory, storage?); (b) by increased “resistance” to overflow currents, causing temporary over-charging of motor axis-cylinders.