Retinal lesions induce fast intrinsic cortical plasticity in adult mouse visual system

Neuronal activity plays an important role in the development and structural–functional maintenance of the brain as well as in its life‐long plastic response to changes in sensory stimulation. We characterized the impact of unilateral 15° laser lesions in the temporal lower visual field of the retina, on visually driven neuronal activity in the afferent visual pathway of adult mice using in situ hybridization for the activity reporter gene zif268. In the first days post‐lesion, we detected a discrete zone of reduced zif268 expression in the contralateral hemisphere, spanning the border between the monocular segment of the primary visual cortex (V1) with extrastriate visual area V2M. We could not detect a clear lesion projection zone (LPZ) in areas lateral to V1 whereas medial to V2M, agranular and granular retrosplenial cortex showed decreased zif268 levels over their full extent. All affected areas displayed a return to normal zif268 levels, and this was faster in higher order visual areas than in V1. The lesion did, however, induce a permanent LPZ in the retinorecipient layers of the superior colliculus. We identified a retinotopy‐based intrinsic capacity of adult mouse visual cortex to recover from restricted vision loss, with recovery speed reflecting the areal cortical magnification factor. Our observations predict incomplete visual field representations for areas lateral to V1 vs. lack of retinotopic organization for areas medial to V2M. The validation of this mouse model paves the way for future interrogations of cortical region‐ and cell‐type‐specific contributions to functional recovery, up to microcircuit level.     

Progression to hypertension in the non-hypertensive participants in the Flemish Study on Environment, Genes and Health Outcomes

OBJECTIVE: To evaluate the consistency between a randomly recruited Western European population and the participants of the Framingham Heart Study, with respect to the rates and determinants of progression to hypertension. METHODS: Among the non-hypertensive individuals enrolled in the Flemish Study on Environment, Genes and Health Outcomes, we assessed progression from optimal (< 120/80 mmHg), normal (120-129/80-84 mmHg) and high-normal (130-139/85-89 mmHg) blood pressure to hypertension (> or = 140/90 mmHg). Our analysis included 781 women and 675 men (age range 10-77 years) who were followed up for a median of 4.6 years (interquartile range 2.4-8.1 years). Our statistical methods included Kaplan-Meier survival function estimates, the log-rank test and multiple Cox regression. RESULTS: In individuals younger than 50 years, 4-year progression rates associated with optimal, normal and high-normal blood pressure were 7.4% [95% confidence interval (CI) 5.5-9.3], 17.9% (95% CI 14.3-21.6) and 24.5% (95% CI 18.7-30.2), respectively. Corresponding 4-year rates of progression for individuals aged 50 years or older were 16.4% (95% CI 11.2-22.5), 26.3% (95% CI 19.8-32.9) and 54.0% (95% CI 45.7-62.3), respectively. In multivariate Cox regression, blood pressure category and body mass index at baseline were strong predictors of hypertension. Before the age of 50 years, male sex and a fast heart rate were also forerunners of hypertension. CONCLUSIONS: The stepwise increase in incidence of hypertension across the three non-hypertensive blood pressure categories in our cohort was similar to that observed in the Framingham Heart Study. The Framingham findings, which have informed several guidelines, can be extrapolated to a Western European population.     

Neuronal Gonadotrophin‐Releasing Hormone (GnRH) and Astrocytic Gonadotrophin Inhibitory Hormone (GnIH) Immunoreactivity in the Adult Rat Hippocampus

Gonadotrophin‐releasing hormone (GnRH) and gonadotrophin inhibitory hormone (GnIH) are neuropeptides secreted by the hypothalamus that regulate reproduction. GnRH receptors are not only present in the anterior pituitary, but also are abundantly expressed in the hippocampus of rats, suggesting that GnRH regulates hippocampal function. GnIH inhibits pituitary gonadotrophin secretion and is also expressed in the hippocampus of a songbird; its role outside of the reproductive axis is not well established. In the present study, we employed immunohistochemistry to examine three forms of GnRH [mammalian GnRH‐I (mGnRH‐I), chicken GnRH‐II (cGnRH‐II) and lamprey GnRH‐III (lGnRH‐III)] and GnIH in the adult rat hippocampus. No mGnRH‐I and cGnRH‐II+ cell bodies were present in the hippocampus. Sparse mGnRH‐I and cGnRH‐II+ fibres were present within the CA1 and CA3 fields of the hippocampus, along the hippocampal fissure, and within the hilus of the dentate gyrus. No lGnRH‐III was present in the rodent hippocampus. GnIH‐immunoreactivity was present in the hippocampus in cell bodies that resembled astrocytes. Males had more GnIH+ cells in the hilus of the dentate gyrus than females. To confirm the GnIH+ cell body phenotype, we performed double‐label immunofluorescence against GnIH, glial fibrillary acidic protein (GFAP) and NeuN. Immunofluorescence revealed that all GnIH+ cell bodies in the hippocampus also contained GFAP, a marker of astrocytes. Taken together, these data suggest that GnRH does not reach GnRH receptors in the rat hippocampus primarily via synaptic release. By contrast, GnIH might be synthesised locally in the rat hippocampus by astrocytes. These data shed light on the sites of action and possible functions of GnRH and GnIH outside of the hypothalamic‐pituitary‐gonadal axis.     

Benefits and Burdens of Using a SNP Array in Pregnancies at Increased Risk for the Common Aneuploidies

We present the nature of pathogenic SNP array findings in pregnancies without ultrasound (US) abnormalities and show the additional diagnostic value of SNP array as compared with rapid aneuploidy detection and karyotyping. 1,330 prenatal samples were investigated with a 0.5‐Mb SNP array after the exclusion of the most common aneuploidies. In 2.7% (36/1,330) of the cases, pathogenic chromosome aberrations were found; a microscopically detectable abnormality in 0.7% and a submicroscopic aberration in 2%. Our results show that in addition to the age‐ or screening‐related aneuploidy risk, in pregnancies without US abnormalities, there is a risk of 1:148 (9/1,330) for a (sub)microscopic abnormality associated with an early‐onset often severe disease, 1:222 (6/1,330) for a submicroscopic aberration causing an early‐onset disease, 1:74 (18/1,330) for carrying a susceptibility locus for a neurodevelopmental disorder, and 1:443 (3/1,330) for a late‐onset disorder (hereditary neuropathy with liability to pressure palsies in all three cases). These risk figures are important for adequate pretest counseling so that prospective parents can make informed individualized choices between targeted prenatal testing and broad testing with SNP array. Based on our results, we believe if invasive testing is performed, SNP array should be the preferred cytogenetic technique irrespective of the indication.     

Identification of cGnRH-II in the median eminence of Japanese quail (Coturnix coturnix japonica)

In a previous paper, we described the presence of cGnRH-II in the quail (Coturnix coturnix japonica) and chicken (Gallus gallus) median eminence using highly specific antibodies directed against a polypeptide corresponding to the C-terminal portion of cGnRH-II (van Gils et al., 1993). This finding remained very controversial, since no other study, with any other antibody, had ever reported the presence of cGnRH-II immunoreactive fibers in the median eminence of birds. In this study, the cGnRH-II immunoreactive substances in quail median eminence were isolated by RP-HPLC and identified by RIA. To eliminate the possibility that the cGnRH-II-like immunoreactivity in the median eminence was due to a cross-reaction of our anti-cGnRH-II antiserum with an unknown peptide, the cGnRH-II immunoreactive substances, present in a quail median eminence extract, were isolated by immunoaffinity chromatography using immunoaffinity-purified antibodies. In the eluate of the immunoaffinity column only one peptide could be detected by mass spectrometry. This peptide had a mass of 1235.56 Da, which is the same as synthetic cGnRH-II. In addition, MS/MS fragmentation generated an amino acid sequence corresponding to the sequence of cGnRH-II. The present study therefore identified indisputably cGnRH-II in the median eminence of the quail.     

Left ventricular diastolic function in relation to the urinary proteome: A proof-of-concept study in a general population

Background

In previous studies, we identified two urinary proteomic classifiers, termed HF1 and HF2, which discriminated subclinical diastolic left ventricular (LV) dysfunction from normal. HF1 and HF2 combine information from 85 and 671 urinary peptides, mainly up- or down-regulated collagen fragments. We sought to validate these classifiers in a population study.

Methods

In 745 people randomly recruited from a Flemish population (49.8 years; 51.3% women), we measured early and late diastolic peak velocities of mitral inflow (E and A) and mitral annular velocities (e' and a') by conventional and tissue Doppler echocardiography, and the urinary proteome by capillary electrophoresis coupled with mass spectrometry.

Results

In the analyses adjusted for sex, age, body mass index, blood pressure, heart rate, LV mass index and intake of medications, we expressed effect sizes per 1-SD increment in the classifiers. HF1 was associated with 0.204 cm/s lower e' peak velocity (95% confidence interval, 0.057–0.351; p = 0.007) and 0.145 higher E/e' ratio (0.023–0.268; p = 0.020), while HF2 was associated with a 0.174 higher E/e' ratio (0.046–0.302; p = 0.008). According to published definitions, 67 (9.0%) participants had impaired LV relaxation and 96 (12.9%) had elevated LV filling pressure. The odds of impaired relaxation associated with HF1 was 1.38 (1.01–1.88; p = 0.043) and that of increased LV filling pressure associated with HF2 was 1.38 (1.00–1.90; p = 0.052).

Conclusions

In a general population, the urinary proteome correlated with diastolic LV dysfunction, proving its utility for early diagnosis of this condition.     

AMIGO2 mRNA expression in hippocampal CA2 and CA3a

AMIGO2, or amphoterin-induced gene and ORF (open reading frame) 2, belongs to the leucine-rich repeats and immunoglobulin superfamilies. The protein is a downstream target of calcium-dependent survival signals and, therefore, promotes neuronal survival. Here, we describe the mRNA distribution pattern of AMIGO2 throughout the mouse brain with special emphasis on the hippocampus. In the Ammon’s horn, a detailed comparison between the subregional mRNA expression patterns of AMIGO2 and Pcp4 (Purkinje cell protein 4)—a known molecular marker of hippocampal CA2 (Cornu Ammonis 2)—revealed a prominent AMIGO2 mRNA expression level in both the CA2 and the CA3a (Cornu Ammonis 3a) subregion of the dorsal and ventral hippocampus. Since this CA2/CA3a region is particularly resistant to neuronal injury and neurotoxicity [Stanfield and Cowan (Brain Res 309(2):299–307 1984); Sloviter (J Comp Neurol 280(2):183–196 1989); Leranth and Ribak (Exp Brain Res 85(1):129–136 1991); Young and Dragunow (Exp Neurol 133(2):125–137 1995); Ochiishi et al. (Neurosci 93(3):955–967 1999)], we suggest that the expression pattern of AMIGO2 indeed fits with its involvement in neuroprotection.