Quantitative evaluation of posture control in rats with inferior olive lesions

Impairment of inferior olivary neurons (IONs) affects whole-body movements and results in abnormal gait and posture. Because IONs are activated by unpredicted motion rather than regular body movements, the postural dysfunction caused by ION lesions is expected to involve factors other than simple loss of feedback control. In this study, we measured the postural movements of rats with pharmacological ION lesions (IO rats) trained to stand on their hindlimbs. The coordination of body segments as well as the distribution and frequency characteristics of center of mass (COM) motion were analyzed. We determined that the lesion altered the peak properties of the power spectrum density of the COM, whereas changes in coordination and COM distribution were minor. To investigate how the observed properties reflected changes in the control system, we constructed a mathematical model of the standing rats and quantitatively identified the control system. We found an increase in linear proportional control and a decrease in differential and nonlinear control in IO rats compared with intact rats. The dystonia-like changes in body stiffness explain the nature of the linear proportional and differential control, and a disorder in the internal model is one possible cause of the decrease in nonlinear control.

Magnetic Resonance Image of Neonatal Acute Bilirubin Encephalopathy: A Diffusion Kurtosis Imaging Study

Background and Objective: The abnormal T1-weighted imaging of MRI can be used to characterize neonatal acute bilirubin encephalopathy (ABE) in newborns, but has limited use in evaluating the severity and prognosis of ABE. This study aims to assess the value of diffusion kurtosis imaging (DKI) in detecting ABE and understanding its pathogenesis.Method: Seventy-six newborns with hyperbilirubinemia were grouped into three groups (mild group, moderate group, and severe group) based on serum bilirubin levels. All the patients underwent conventional MRI and DKI serial, as well as 40 healthy full-term infants (control group). The regions of interest (ROIs) were the bilateral globus pallidus, dorsal thalamus, frontal lobe, auditory radiation, superior temporal gyrus, substantia nigra, hippocampus, putamen, and inferior olivary nucleus. The values of mean diffusivity (MD), axial kurtosis (AK), radial kurtosis (RK), and mean kurtosis (MK), and fractional anisotropy (FA), radial diffusivity (RD), and axis diffusivity (AD) of the ROIs were evaluated. All newborns were followed up and evaluated using the Denver Development Screening Test (DDST). According to the follow-up results, the patients were divided into the normal group, the suspicious abnormal group, and the abnormal group.Result: Compared with the control group, significant differences were observed with the increased MK of dorsal thalamus, AD of globus pallidus in the moderate group, and increased RD, MK, AK, and RK value of globus pallidus, dorsal thalamus, auditory radiation, superior temporal gyrus, and hippocampus in the severe group. The peak value of total serum bilirubin was moderately correlated with the MK of globus pallidus, dorsal thalamus, and auditory radiation and was positively correlated with the other kurtosis value. Out of 76 patients, 40 finished the DDST, and only 9 patients showed an abnormality. Compared with the normal group, the AK value of inferior olivary nucleus showed significant differences (p < 0.05) in the suspicious abnormal group, and the MK of globus pallidus, temporal gyrus, and auditory radiation; RK of globus pallidus, dorsal thalamus, and auditory radiation; and MD of globus pallidus showed significant differences (p < 0.05) in the abnormal group.Conclusion: DKI can reflect the subtle structural changes of neonatal ABE, and MK is a sensitive indicator to indicate the severity of brain damage.

Stress Adaptation and the Brainstem with Focus on Corticotropin-Releasing Hormone

Stress adaptation is of utmost importance for the maintenance of homeostasis and, therefore, of life itself. The prevalence of stress-related disorders is increasing, emphasizing the importance of exploratory research on stress adaptation. Two major regulatory pathways exist: the hypothalamic–pituitary–adrenocortical axis and the sympathetic adrenomedullary axis. They act in unison, ensured by the enormous bidirectional connection between their centers, the paraventricular nucleus of the hypothalamus (PVN), and the brainstem monoaminergic cell groups, respectively. PVN and especially their corticotropin-releasing hormone (CRH) producing neurons are considered to be the centrum of stress regulation. However, the brainstem seems to be equally important. Therefore, we aimed to summarize the present knowledge on the role of classical neurotransmitters of the brainstem (GABA, glutamate as well as serotonin, noradrenaline, adrenaline, and dopamine) in stress adaptation. Neuropeptides, including CRH, might be co-localized in the brainstem nuclei. Here we focused on CRH as its role in stress regulation is well-known and widely accepted and other CRH neurons scattered along the brain may also complement the function of the PVN. Although CRH-positive cells are present on some parts of the brainstem, sometimes even in comparable amounts as in the PVN, not much is known about their contribution to stress adaptation. Based on the role of the Barrington’s nucleus in micturition and the inferior olivary complex in the regulation of fine motoric—as the main CRH-containing brainstem areas—we might assume that these areas regulate stress-induced urination and locomotion, respectively. Further studies are necessary for the field.

Anoctamin 2-chloride channels reduce simple spike activity and mediate inhibition at elevated calcium concentration in cerebellar Purkinje cells

Modulation of neuronal excitability is a prominent way of shaping the activity of neuronal networks. Recent studies highlight the role of calcium-activated chloride currents in this context, as they can both increase or decrease excitability. The calcium-activated chloride channel Anoctamin 2 (ANO2 alias TMEM16B) has been described in several regions of the mouse brain, including the olivo-cerebellar system. In inferior olivary neurons, ANO2 was proposed to increase excitability by facilitating the generation of high-threshold calcium spikes. An expression of ANO2 in cerebellar Purkinje cells was suggested, but its role in these neurons remains unclear. In the present study, we confirmed the expression of Ano2 mRNA in Purkinje cells and performed electrophysiological recordings to examine the influence of ANO2-chloride channels on the excitability of Purkinje cells by comparing wildtype mice to mice lacking ANO2. Recordings were performed in acute cerebellar slices of adult mice, which provided the possibility to study the role of ANO2 within the cerebellar cortex. Purkinje cells were uncoupled from climbing fiber input to assess specifically the effect of ANO2 channels on Purkinje cell activity. We identified an attenuating effect of ANO2-mediated chloride currents on the instantaneous simple spike activity both during strong current injections and during current injections close to the simple spike threshold. Moreover, we report a reduction of inhibitory currents from GABAergic interneurons upon depolarization, lasting for several seconds. Together with the role of ANO2-chloride channels in inferior olivary neurons, our data extend the evidence for a role of chloride-dependent modulation in the olivo-cerebellar system that might be important for proper cerebellum-dependent motor coordination and learning.

Bilateral Hypertrophic Olivary Degeneration Following Brainstem Insult: A Retrospective Review and Examination of Causative Pathology

Hypertrophic olivary degeneration is a rare condition caused by a lesion in the Guillain-Mollaret triangle which leads to trans-synaptic degeneration resulting in the degenerative hypertrophy of the inferior olivary nucleus. This condition presents clinically with palatal tremor but can also produce ocular myoclonus or cerebellar signs. While any lesion that occurs within the Guillian-Mollaret triangle and results in the deafferentation of the inferior olive can lead to hypertrophic olivary degeneration, the most common etiologies include ischemic and hemorrhagic stroke, vascular malformation, neoplasm, and iatrogenic injury related to surgery. We report a series of 7 patients who presented with this condition bilaterally on MRI imaging, including 1 case which represents the first report of toxoplasmosis leading to the development of bilateral hypertrophic olivary degeneration and only the third reported case, unilateral or bilateral, related to an infectious etiology.

Hypertrophy of the Anterior External Arcuate Fasciculus: A Rare Variant With Implications for the Development of the Arcuate Nucleus

A rare anatomic variant of a markedly enlarged anterior external arcuate fasciculus (AEAF) on the ventral medullary surface is reported and compared to two controls. The hypertrophic AEAF was nine times larger in diameter than normal, whereas the arcuate nucleus (AN) and inferior olivary nucleus (ION) appeared histologically normal in size and neuronal distribution, and morphometric analysis of the AN confirmed that it was within the normal range. Calbindin-2 (calretinin, CALB2) expression was identified in the AN and in the fibers of the normal AEAF. The hypertrophic AEAF did not contain calbindin-2–expressing fibers. CALB2 expression was also present in the ventrolateral portion of the ION, both in the index case and in one of the control cases. The origin of the additional fibers was not identified; however, the potential origin of these fibers and its implications for the development of the AEAF are discussed.

Gsx2 is required for specification of neurons in the inferior olivary nuclei from Ptf1a-expressing neural progenitors in zebrafish

ABSTRACTNeurons in the inferior olivary nuclei (IO neurons) send climbing fibers to Purkinje cells to elicit functions of the cerebellum. IO neurons and Purkinje cells are derived from neural progenitors expressing the proneural gene ptf1a. In this study, we found that the homeobox gene gsx2 was co-expressed with ptf1a in IO progenitors in zebrafish. Both gsx2 and ptf1a zebrafish mutants showed a strong reduction or loss of IO neurons. The expression of ptf1a was not affected in gsx2 mutants, and vice versa. In IO progenitors, the ptf1a mutation increased apoptosis whereas the gsx2 mutation did not, suggesting that ptf1a and gsx2 are regulated independently of each other and have distinct roles. The fibroblast growth factors (Fgf) 3 and 8a, and retinoic acid signals negatively and positively, respectively, regulated gsx2 expression and thereby the development of IO neurons. mafba and Hox genes are at least partly involved in the Fgf- and retinoic acid-dependent regulation of IO neuronal development. Our results indicate that gsx2 mediates the rostro-caudal positional signals to specify the identity of IO neurons from ptf1a-expressing neural progenitors.