Distinct purinergic receptor-mediated currents of rat oculomotor integrator neurons characterized by different firing patterns

The roles of purinergic signaling on vertical (mediated by the interstitial nucleus of Cajal; INC) and horizontal (prepositus hypoglossal nucleus; PHN) gaze control are not understood. Here, we report three current types induced by ATP in INC neurons; the distribution of these current types across different types of INC neurons is different from that in PHN neurons. These results suggest distinct modes of purinergic modulation in horizontal and vertical gaze control centers.

Isolated unilateral lingual paralysis in a supranuclear infarction

Lingual paralysis can result from damage to both upper and lower motor neurons. However, since the hypoglossal nucleus is innervated from both hemispheres simultaneously, unilateral lingual paralysis caused by upper motor neuron has rarely been reported. We report a case which a patient isolated unilateral lingual paralysis due to supranuclear infarction. A 50-year-old right-handed woman was admitted to our hospital due to suddenly developed dysarthria. Her tongue deviated to the right on protrusion without fasciculation or atrophy. A brain MRI showed focal lesion in the left corona radiate and basal ganglia.

Fast Progression in Amyotrophic Lateral Sclerosis Is Associated With Greater TDP-43 Burden in Spinal Cord

Upper and lower motor neuron pathologies are critical to the autopsy diagnosis of amyotrophic lateral sclerosis (ALS). Further investigation is needed to determine how the relative burden of these pathologies affects the disease course. We performed a blinded, retrospective study of 38 ALS patients, examining the association between pathologic measures in motor cortex, hypoglossal nucleus, and lumbar cord with clinical data, including progression rate and disease duration, site of symptom onset, and upper and lower motor neuron signs. The most critical finding in our study was that TAR DNA-binding protein 43 kDa (TDP-43) pathologic burden in lumbar cord and hypoglossal nucleus was significantly associated with a faster progression rate with reduced survival (p < 0.02). There was no correlation between TDP-43 burden and the severity of cell loss, and no significant clinical associations were identified for motor cortex TDP-43 burden or severity of cell loss in motor cortex. C9orf72 expansion was associated with shorter disease duration (p < 0.001) but was not significantly associated with pathologic measures in these regions. The association between lower motor neuron TDP-43 burden and fast progression with reduced survival in ALS provides further support for the study of TDP-43 as a disease biomarker.

Global Neurotoxicity: Quantitative Analysis of Rat Brain Toxicity Following Exposure to Trimethyltin

The organotin, trimethyltin (TMT), is a highly toxic compound. In this study, silver-stained rat brain sections were qualitatively and quantitatively evaluated for degeneration after systemic treatment with TMT. Degenerated neurons were counted using image analysis methods available in the HALO image analysis software. Specific brain areas including the cortex, inferior and superior colliculus, and thalamus were quantitatively analyzed. Our results indicate extensive and widespread damage to the rat brain after systemic administration of TMT. Qualitative results suggest severe TMT-induced toxicity 3 and 7 days after the administration of TMT. Trimethyltin toxicity was greatest in the hippocampus, olfactory area, cerebellum, pons, mammillary nucleus, inferior and superior colliculus, hypoglossal nucleus, thalamus, and cerebellar Purkinje cells. Quantification showed that the optic layer of the superior colliculus exhibited significantly more degeneration compared to layers above and below. The inferior colliculus showed greater degeneration in the dorsal area relative to the central area. Similarly, in cortical layers, there was greater neurodegeneration in deeper layers compared to superficial layers. Quantification of damage in various thalamic nuclei showed that the greatest degeneration occurred in midline and intralaminar nuclei. These results suggest selective neuronal network vulnerability to TMT-related toxicity in the rat brain.

OBSTRUCTIVE APNEAS IN A MOUSE MODEL OF CONGENITAL CENTRAL HYPOVENTILATION SYNDROME

RationaleCongenital Central Hypoventilation Syndrome is characterized by life-threatening sleep hypoventilation, and is caused by PHOX2B gene mutations, most frequently the PHOX2B27Ala/+ mutation. Patients require lifelong ventilatory support. It is unclear whether obstructive apneas are part of the syndrome.ObjectivesTo determine whether Phox2b27Ala/+ mice, which presented main symptoms of Congenital Central Hypoventilation Syndrome and died within hours after birth, also presented obstructive apneas and investigate potential underlying mechanisms.MethodsApneas were classified as central, obstructive or mixed by using an original system combining pneumotachography and laser detection of abdominal movement immediately after birth. Some respiratory nuclei involved in airway patency were analyzed by immunohistochemistry and electrophysiology in brainstem-spinal cord preparation.Measurements and Main ResultsThe median (interquartile range) of obstructive apnea frequency was 2.3/min (1.5-3.3) in Phox2b27Ala/+ pups versus 0.6/min (0.4-1.0) in wildtypes (P < 0.0001). Obstructive apnea duration was 2.7s (2.3-3.9) in Phox2b27Ala/+ pups versus 1.7s (1.1- 1.9) in wildtypes (P < 0.0001). Central and mixed apneas presented similar, significant differences. In Phox2b27Ala/+ preparations, hypoglossal nucleus had fewer neurons (P < 0.05) and smaller size (P < 0.01), compared to wildtypes. Importantly, coordination of phrenic and hypoglossal activities was disrupted, as shown by the longer and variable delay of hypoglossal with respect to phrenic onset, compared to wildtypes (P < 0.001).ConclusionsThe Phox2b27Ala/+ mutation predisposed pups not only to hypoventilation and central apneas, but also obstructive and mixed apneas likely due to hypoglossal dysgenesis. These results call for attention toward obstructive events in infants with Congenital Central Hypoventilation Syndrome.Subject category15.1 Animal Models of Sleep Apnea

Chronic Sleep Restriction Outcome on the Volumetric Correlates, Neuronal and Glial Number of the Hypoglossal Nucleus in a Rat Model (Preprint)

BACKGROUND Chronic sleep restriction (CSR) is known to result in various changes in brain structures including the dorsal respiratory nuclei of the brain stem. Obstructive sleep apnea has partly been resulted from reduced tone of the muscles including the tongue which are involved in maintaining airway patency during sleep. OBJECTIVE This study aimed at investigating whether CSR may result in structural changes in the hypoglossal nerve nuclei. METHODS Three groups of male rats (each comprising 6) were randomly assigned to CSR, cage control and grid-floor control groups. CSR was imposed using the modified multi-platform box containing water for 18 hours/day for 21 days. At the end of 21 days, the rats’ brain was removed and stained through the modified Giemsa method. The hypoglossal nucleus (HGN) was evaluated through stereological approach. RESULTS The volume of HGN as well as the total number of neuronal and glial cells did not show significant differences between the cage control and the other groups (p=0.3). CONCLUSIONS The current study provided evidence to support that CSR induced by the modified multiple platform approach for 18 hours/day over 21 days in rats, neither results in volume reduction, nor neuronal and glial cells loss in the hypoglossal nuclei in the brain stem.

Nitric oxide controls excitatory/inhibitory balance in the hypoglossal nucleus during early postnatal development

Synaptic remodeling during early postnatal development lies behind neuronal networks refinement and nervous system maturation. In particular, the respiratory system is immature at birth and is subjected to significant postnatal development. In this context, the excitatory/inhibitory balance dramatically changes in the respiratory-related hypoglossal nucleus (HN) during the 3 perinatal weeks. Since, development abnormalities of hypoglossal motor neurons (HMNs) are associated with sudden infant death syndrome and obstructive sleep apnea, deciphering molecular partners behind synaptic remodeling in the HN is of basic and clinical relevance. Interestingly, a transient expression of the neuronal isoform of nitric oxide (NO) synthase (NOS) occurs in HMNs at neonatal stage that disappears before postnatal day 21 (P21). NO, in turn, is a determining factor for synaptic refinement in several physiopathological conditions. Here, intracerebroventricular chronic administration (P7–P21) of the broad spectrum NOS inhibitor l-NAME (N(ω)-nitro-l-arginine methyl ester) differentially affected excitatory and inhibitory rearrangement during this neonatal interval in the rat. Whilst l-NAME led to a reduction in the number of excitatory structures, inhibitory synaptic puncta were increased at P21 in comparison to administration of the inactive stereoisomer d-NAME. Finally, l-NAME decreased levels of the phosphorylated form of myosin light chain in the nucleus, which is known to regulate the actomyosin contraction apparatus. These outcomes indicate that physiologically synthesized NO modulates excitatory/inhibitory balance during early postnatal development by acting as an anti-synaptotrophic and/or synaptotoxic factor for inhibitory synapses, and as a synaptotrophin for excitatory ones. The mechanism of action could rely on the modulation of the actomyosin contraction apparatus.