Development and heritability of subcortical brain volumes at ages 9 and 12

Subcortical brain structures are involved in a variety of cognitive and emotional functions and follow different trajectories of increase and decrease in volume from childhood to adulthood. The heritability of development of subcortical brain volumes during adolescence has not been studied comprehensively. In a longitudinal twin study, we estimated to what extent subcortical brain volumes are influenced by genetic factors at ages 9 and 12. In addition, we assessed whether new genes are expressed at age 12 and whether there is evidence for genotype by sex interaction. Brain scans were acquired for 112 and 89 twin pairs at 9 and 12 years of age. In both boys and girls, there was an increase in volumes of the thalamus, hippocampus, amygdala and pallidum, and a decrease in volumes of the caudate and nucleus accumbens. The putamen showed a decrease in boys bilaterally and an increase in girls in the left hemisphere. Heritability was high (>50%) for all structures – except for the left nucleus accumbens – with heritabilities ranging from 0.50 to 0.91 at age 9, and from 0.59 to 0.88 at age 12. There were no significant new genetic effects coming into play at age 12, and there was no evidence for genotype by sex interactions. These findings suggest that despite their sensitivity to environmental effects, the heritability of subcortical brain structures is high from childhood on, resembling estimates found in adult samples.     

Macrostructural alterations of subcortical grey matter in psychogenic erectile dysfunction

Psychogenic erectile dysfunction (ED) has been defined as the persistent inability to attain and maintain an erection sufficient to permit sexual performance. It shows a high incidence and prevalence among men, with a significant impact on the quality of life. Few neuroimaging studies have investigated the cerebral basis of erectile dysfunctions observing the role played by prefrontal, cingulate, and parietal cortices during erotic stimulation. In spite of the well-known involvement of subcortical regions such as hypothalamus and caudate nucleus in male sexual response, and the key role of nucleus accumbens in pleasure and reward, poor attention was paid to their role in male sexual dysfunction. In this study, we determined the presence of grey matter (GM) atrophy patterns in subcortical structures such as amygdala, hippocampus, nucleus accumbens, caudate nucleus, putamen, pallidum, thalamus, and hypothalamus in patients with psychogenic ED and healthy men. After Rigiscan evaluation, urological, general medical, metabolic and hormonal, psychological and psychiatric assessment, 17 outpatients with psychogenic ED and 25 healthy controls were recruited for structural MRI session. Significant GM atrophy of nucleus accumbens was observed bilaterally in patients with respect to controls. Shape analysis showed that this atrophy was located in the left medial-anterior and posterior portion of accumbens. Left nucleus accumbens volumes in patients correlated with low erectile functioning as measured by IIEF-5 (International Index of Erectile Function). In addition, a GM atrophy of left hypothalamus was also observed. Our results suggest that atrophy of nucleus accumbens plays an important role in psychogenic erectile dysfunction. We believe that this change can influence the motivation-related component of sexual behavior. Our findings help to elucidate a neural basis of psychogenic erectile dysfunction.     

Heritability of Subcortical Volumetric Traits in Mesial Temporal Lobe Epilepsy

Objectives

We aimed to 1) determine if subcortical volume deficits are common to mesial temporal lobe epilepsy (MTLE) patients and their unaffected siblings 2) assess the suitability of subcortical volumetric traits as endophenotypes for MTLE.

Methods

MRI-based volume measurements of the hippocampus, amygdala, thalamus, caudate, putamen and pallidium were generated using an automated brain reconstruction method (FreeSurfer) for 101 unrelated ‘sporadic’ MTLE patients [70 with hippocampal sclerosis (MTLE+HS), 31 with MRI-negative TLE], 83 unaffected full siblings of patients and 86 healthy control subjects. Changes in the volume of subcortical structures in patients and their unaffected siblings were determined by comparison with healthy controls. Narrow sense heritability was estimated ipsilateral and contralateral to the side of seizure activity.

Results

MTLE+HS patients displayed significant volume deficits across the hippocampus, amygdala and thalamus ipsilaterally. In addition, volume loss was detected in the putamen bilaterally. These volume deficits were not present in the unaffected siblings of MTLE+HS patients. Ipsilaterally, the heritability estimates were dramatically reduced for the volume of the hippocampus, thalamus and putamen but remained in the expected range for the amygdala. MRI-negative TLE patients and their unaffected siblings showed no significant volume changes across the same structures and heritability estimates were comparable with calculations from a healthy population.

Conclusions

The findings indicate that volume deficits for many subcortical structures in ‘sporadic’ MTLE+HS are not heritable and likely related to acquired factors. Therefore, they do not represent suitable endophenotypes for MTLE+HS. The findings also support the view that, at a neuroanatomical level, MTLE+HS and MRI-negative TLE represent two distinct forms of MTLE.     

Cocaine regulates protein kinase B and glycogen synthase kinase-3 activity in selective regions of rat brain

Protein kinase B (also known as Akt) signaling regulates dopamine-mediated locomotor behaviors. Here the ability of cocaine to regulate Akt and glycogen synthase kinase 3 (GSK3) was studied. Rats were injected with cocaine or saline in a binge-pattern, which consisted of three daily injections of 15 mg/kg cocaine or 1 mL/kg saline spaced 1 h apart for 1, 3, or 14 days. Amygdala, nucleus accumbens, caudate putamen, and hippocampus tissues were dissected 30 min following the last injection and analyzed for phosphorylated and total Akt and GSK3(alpha and beta) protein levels using western blot analysis. Phosphorylation of Akt on the threonine-308 (Thr308) residue was significantly reduced in the nucleus accumbens and increased in the amygdala after 1 day of cocaine treatment; however, these effects were not accompanied by a significant decrease in GSK3 phosphorylation. Phosphorylation of Akt and GSK3 was significantly reduced after 14 days of cocaine administration, an effect that was only observed in the amygdala. Cocaine did not alter Akt or GSK3 phosphorylation in the caudate putamen or hippocampus. The findings in nucleus accumbens may reflect dopaminergic motor-stimulant activity caused by acute cocaine, whereas the effects in amygdala may be associated with changes in emotional state that occur after acute and chronic cocaine exposure.     

Reduced Hippocampal Volume in Healthy Young ApoE4 Carriers: An MRI Study

The E4 allele of the ApoE gene has consistently been shown to be related to an increased risk of Alzheimer''s disease (AD). The E4 allele is also associated with functional and structural grey matter (GM) changes in healthy young, middle-aged and older subjects. Here, we assess volumes of deep grey matter structures of 22 healthy younger ApoE4 carriers and 22 non-carriers (20–38 years). Volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen, thalamus and brain stem were calculated by FMRIB''s Integrated Registration and Segmentation Tool (FIRST) algorithm. A significant drop in volume was found in the right hippocampus of ApoE4 carriers (ApoE4+) relative to non-carriers (ApoE4−), while there was a borderline significant decrease in the volume of the left hippocampus of ApoE4 carriers. The volumes of no other structures were found to be significantly affected by genotype. Atrophy has been found to be a sensitive marker of neurodegenerative changes, and our results show that within a healthy young population, the presence of the ApoE4+ carrier gene leads to volume reduction in a structure that is vitally important for memory formation. Our results suggest that the hippocampus may be particularly vulnerable to further degeneration in ApoE4 carriers as they enter middle and old age. Although volume reductions were noted bilaterally in the hippocampus, atrophy was more pronounced in the right hippocampus. This finding relates to previous work which has noted a compensatory increase in right hemisphere activity in ApoE4 carriers in response to preclinical declines in memory function. Possession of the ApoE4 allele may lead to greater predilection for right hemisphere atrophy even in healthy young subjects in their twenties.     

Inhibition of Succinate Dehydrogenase by Malonic Acid Produces an "Excitotoxic" Lesion in Rat Striatum

Abstract: Clinical and preclinical evidence supports a possible role for thyrotropin-releasing hormone (TRH) in cocaine action. However, the interaction between cocaine and TRH has not been directly examined. In the following report we describe a solution hybridization RNase protection assay that can sensitively detect mRNA for the TRH precursor, prepro-TRH (ppTRH). Using this assay, we examined ppTRH mRNA levels in rat brain regions implicated in cocaine reinforcement, including the nucleus accumbens, hypothalamus, amygdala, hippocampus, and thalamus. Acute cocaine treatment (15 mg/kg) resulted in significant decreases in ppTRH mRNA levels in the amygdala and hippocampus, but not in the hypothalamus, nucleus accumbens, or thalamus, 45 min postinjection. Chronic cocaine treatment (15 mg/kg twice daily for 14 days) resulted in marked regulation in all regions but the thalamus. Regulation was strongly dependent on the length of cocaine withdrawal and persisted up to 72 h postinjection in the amygdala. These studies support the hypothesis that TRH or other ppTRH-derived peptides are involved in cocaine action, especially in the extrahypothalamic regions of the amygdala and hippocampus.     

Role of the caudate nucleus in the development of evoked synchronized activity

Synchronized activity (spindles, augmentation response) evoked by stimulation of thalamic nonspecific, association, and specific nuclei was investigated in chronic experiments on 11 cats before and after successive destruction of the caudate nuclei. After destruction of the caudate nuclei the duration of spindle activity in the frontal cortex and subcortical formations (thalamic nuclei, globus pallidus, putamen) was reduced to only three or four oscillations. In the subcortical nuclei its amplitude fell significantly (by 50±10%); in the cortex the decrease in amplitude was smaller and in some cases was not significant. Different changes were observed in the amplitude of the augmentation response, depending on where it was recorded. In the subcortical formations it was considerably and persistently reduced (by 50±10%); in the cortex these changes were unstable in character. Unilateral destruction of the caudate nucleus inhibited synchronized activity evoked by stimulation of the thalamic nuclei on the side of the operation only. Destruction of the basal ganglia (caudate nucleus, globus pallidus, entopeduncular nucleus, and putamen) did not prevent the appearance of synchronized activity; just as after isolated destruction of the caudate nucleus, after this operation synchronized activity was simply reduced in duration and amplitude. It is suggested that the caudate nucleus exerts an ipsilateral facilitatory influence on the nonspecific system of the thalamus during the development of evoked synchronized activity.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 9, No. 3, pp. 239–248, May–June, 1977.     

Studies on genomic DNA topology and stability in brain regions of Parkinson's disease

DNA damage has been postulated as a mechanism of neuronal death in Parkinson's disease (PD). In the present study, genomic DNA was isolated from eight brain regions (frontal, temporal, and occipital cortex, hippocampus, caudate/putamen, thalamus, cerebellum, and midbrain) from five neuropathologically confirmed cases of Parkinson's disease and six control brains and analyzed for the presence of single and double strand breaks, melting temperature, EtBr intercalation, DNAse digestion pattern, and DNA conformations. The results showed that DNA from midbrain in PD accumulated significantly higher number of strand breaks than age-matched controls. Caudate nucleus/putamen, thalamus, and hippocampus also showed more DNA fragmentation compared to control brains. Circular dichroism studies showed that DNA conformation was altered with imprecise base stacking in midbrain, caudate nucleus/putamen, thalamus, and hippocampus in PD. However, DNA from frontal, temporal, and occipital cortex, and cerebellum was not affected significantly in PD group as compared to controls. This study provides a comprehensive database on stability, damage, and conformations of DNA in different regions in brains of PD patients.     

The mechanism of electrically stimulated adenosine release varies by brain region

Adenosine plays an important role in neuromodulation and neuroprotection. Recent identification of transient changes in adenosine concentration suggests adenosine may have a rapid modulatory role; however, the extent of these changes throughout the brain is not well understood. In this report, transient changes in adenosine evoked by one second, 60 Hz electrical stimulation trains were compared in the caudate–putamen, nucleus accumbens, hippocampus, and cortex. The concentration of evoked adenosine varies between brain regions, but there is less variation in the duration of signaling. The highest concentration of adenosine was evoked in the dorsal caudate–putamen (0.34?±?0.08 μM), while the lowest concentration was in the secondary motor cortex (0.06?±?0.02 μM). In all brain regions, adenosine release was activity-dependent. In the nucleus accumbens, hippocampus, and prefrontal cortex, this release was partly due to extracellular ATP breakdown. However, in the caudate–putamen, release was not due to ATP metabolism but was ionotropic glutamate receptor-dependent. The results demonstrate that transient, activity-dependent adenosine can be evoked in many brain regions but that the mechanism of formation and release varies by region.     

Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain

We present a technique for automatically assigning a neuroanatomical label to each voxel in an MRI volume based on probabilistic information automatically estimated from a manually labeled training set. In contrast to existing segmentation procedures that only label a small number of tissue classes, the current method assigns one of 37 labels to each voxel, including left and right caudate, putamen, pallidum, thalamus, lateral ventricles, hippocampus, and amygdala. The classification technique employs a registration procedure that is robust to anatomical variability, including the ventricular enlargement typically associated with neurological diseases and aging. The technique is shown to be comparable in accuracy to manual labeling, and of sufficient sensitivity to robustly detect changes in the volume of noncortical structures that presage the onset of probable Alzheimer's disease.     

Family income buffers the relationship between childhood adverse experiences and putamen volume

Adverse experiences and family income in childhood have been associated with altered brain development. While there is a large body of research examining these associations, it has primarily used cross-sectional data sources and studied adverse experiences and family income in isolation. However, it is possible that low family income and adverse experiences represent dissociable and potentially interacting profiles of risk. To address this gap in the literature, we examined brain structure as a function of adverse experiences in childhood and family income in 158 youths with up to five waves of MRI data. Specifically, we assessed the interactive effect of these two risk factors on six regions of interest: hippocampus, putamen, amygdala, nucleus accumbens, caudate, and thalamus. Adverse experiences and family income interacted to predict putamen volume (B = 0.086, p = 0.011) but only in participants with family income one standard deviation below the mean (slope estimate = −0.11, p = 0.03). These results suggest that adverse experiences in childhood result in distinct patterns of brain development across the socioeconomic gradient. Given previous findings implicating the role of the putamen in psychopathology-related behaviors, these results emphasize the importance of considering life events and socioeconomic context when evaluating markers of risk. Future research should include interactive effects of environmental exposures and family income to better characterize risk for psychopathology in diverse samples.     

Structural neuroimaging in autism

Structural neuroimaging studies done by means of magnetic resonance imaging (MRI) have provided important insights into the neurobiological basis for autism. The aim of this article is to review the current state of knowledge regarding structural brain abnormalities in autism. Results of MRI studies dealing with total brain volume, the volume of the cerebellum, caudate nucleus, thalamus, amygdala, hippocampus and the area of the corpus callosum are summarized. Existing research suggests that autistic individuals have larger total brain, cerebellar and caudate nucleus volumes; however, the area of the corpus callosum is reduced. Results of studies involving the amygdala and hippocampus volume in autistic subjects remain inconsistent and no changes have been detected in thalamic volume.     

肾上腺髓质素在正常大鼠脑中的分布-免疫组化及原位杂交分析

目的验证大鼠脑内是否存在ADM及其mRNA。方法取10只健康雄性SD大鼠,体重200-250g,应用免疫组织化学法和原位杂交组织化学法检测正常大鼠脑内ADM及其mRNA的表达情况。结果在大鼠脑内ADM及其mRNA阳性细胞主要表达在大脑皮质、海马结构、齿状回、丘脑、室旁组织、脉络丛、室管膜细胞、基底节、血管内皮细胞,其中脉络丛、室旁组织、丘脑为高表达区,其次为大脑皮质、海马。在大鼠大脑内ADMmRNA的表达与ADM阳性细胞的表达相一致。结论ADM及其mRNA在大脑内广泛表达,提示ADM在中枢神经系统内具有重要的作用。     

肾上腺髓质素在正常大鼠脑中的分布一免疫组化及原位杂交分析

目的验证大鼠脑内是否存在ADM及其mRNA。方法取10只健康雄性SD大鼠,体重200-250g,应用免疫组织化学法和原位杂交组织化学法检测正常大鼠脑内ADM及其mRNA的表达情况。结果在大鼠脑内ADM及其mRNA阳性细胞主要表达在大脑皮质、海马结构、齿状回、丘脑、室旁组织、脉络丛、室管膜细胞、基底节、血管内皮细胞,其中脉络丛、室旁组织、丘脑为高表达区,其次为大脑皮质、海马。在大鼠大脑内ADMmRNA的表达与ADM阳性细胞的表达相一致。结论ADM及其mRNA在大脑内广泛表达,提示ADM在中枢神经系统内具有重要的作用。     

Distribution of calcium-independent phospholipase A<Subscript>2</Subscript> (iPLA<Subscript>2</Subscript>) in monkey brain

The present study was carried out to elucidate the distribution of calcium-independent phospholipase A₂ (iPLA₂) in the normal monkey brain. iPLA₂ immunoreactivity was observed in structures derived from the telencephalon, including the cerebral neocortex, amygdala, hippocampus, caudate nucleus, putamen, and nucleus accumbens, whereas structures derived from the diencephalon, including the thalamus, hypothalamus and globus pallidus were lightly labeled. The midbrain, vestibular, trigeminal and inferior olivary nuclei, and the cerebellar cortex were densely labeled. Immunoreactivity was observed on the nuclear envelope of neurons, and dendrites and axon terminals at electron microscopy. Western blot analysis showed higher levels of iPLA₂ protein in the cytosolic, than the nuclear fraction, but little or no protein in the membrane fraction. Similarly, subcellular fractionation studies of iPLA₂ activity in rat brain cortical cell cultures showed greater enzymatic activity in the cytosolic, than the nuclear fraction, and the least activity in non-nuclear membranes. The association of iPLA₂ with the nuclear envelope suggests a role of the enzyme in nuclear signaling, such as during neuronal proliferation and differentiation or death. In addition, the localization of iPLA₂ in dendrites and axon terminals suggests a role of the enzyme in neuronal signaling.     

Changes of Biogenic Amines and Their Metabolites in Postmortem Brains from Patients with Alzheimer-Type Dementia

Noradrenaline (NA), 3,4-dihydroxyphenylethylamine (dopamine, DA), 5-hydroxytryptamine (serotonin, 5-HT), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were measured in 22 regions of postmortem brains from four histologically verified cases with Alzheimer-type dementia (ATD) and nine histologically normal controls. Compared with the controls, concentrations of 5-HT and 5-HIAA in the ATD brains were significantly reduced in nine regions (superior frontal gyrus, insula, cingulate gyrus, amygdala, putamen, medial and lateral segments of globus pallidus, substantia nigra, lateral nucleus of thalamus) and in eight regions (amygdala, substantia innominata, caudate, putamen, medial and lateral segments of globus pallidus, medial and lateral nuclei of thalamus), respectively. NA concentrations of the ATD brains were significantly reduced in six regions (cingulate gyrus, substantia innominata, putamen, hypothalamus, medial nucleus of thalamus, raphe area). In contrast, significant reductions of DA and HVA concentrations in the ATD brains were found only in putamen and amygdala, respectively. The 5-HIAA/5-HT ratio in the ATD brains decreased significantly in locus coeruleus, while the HVA/DA ratio increased significantly in putamen and medial segment of globus pallidus. These findings suggest that the serotonergic and noradrenergic systems are affected, while the dopaminergic system is relatively unaffected in ATD brains.     

Characterization of a new radioiodinated probe for the alpha2C adrenoceptor in the mouse brain

[125I]17alpha-hydroxy-20alpha-yohimban-16beta-(N-4-p6 hydroxyphenethyl)carboxamide or [125I]rauwolscine-OHPC, a new radioiodinated probe derived from rauwolscine was synthesized and its binding characteristics investigated on sections of the mouse caudate putamen. [125I]rauwolscine-OHPC binding was saturable and revealed interaction with a single class of binding sites (KD= 0.171 nM, Bmax = 3082 pCi/mg of tissue). The kinetically derived affinity was in close agreement with the affinity evaluated by saturation experiments: k(-1)/k(+1)(0.0403 min(-1)/114 10(6) M(-1) min(-1))=0.35 nM. Competition studies revealed interaction with one single class of binding sites for each of the twelve compounds tested. The rank of potency suggested an interaction with alpha2 adrenoceptors (atipamezole > or = RX 821002 > yohimbine > (-)epinephrine). Moreover, the good affinity of [125I] rauwolscine-OHPC binding sites for spiroxatrine, yohimbine, WB 4101, the relatively good affinity for prazosin (Ki =37.4 nM) and the affinity ratio prazosin/oxymetazoline (37.4/43.4=0.86) were consistent with an alpha2C selective labelling of [125I]rauwolscine-OHPC. The distribution of [125I]rauwolscine-OHPC binding sites in mouse brain was characterized by autoradiography. The density of binding sites was high in the islands of Calleja, accumbens nucleus, caudate putamen and olfactory tubercles, moderate in the hippocampus, amygdala and anterodorsal nucleus of the thalamus. These findings demonstrated that [125I]rauwolscine-OHPC is a useful radioiodinated probe to label alpha2C adrenoceptors in mouse brain.     

Analysis of the morphological substrate of information processing in the striatum based on organizational characteristics of its afferent projections

By the method of axonal transport of the retrograde markers, the afferent projections, coming from functionally different cortical and subcortical structures to various segments of the caudate nucleus, were investigated in the putamen and the nucleus accumbens of the dog brain. On the basis of the determined peculiarities of the spatail organization of these projections, the morphological aspects of the segregated and convergent conducting and processing of the information in the striatum, which underlie their functioning, were analyzed.