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Inhibitors of protein phosphatase-2A from human brain structures, immunocytological localization and activities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau.

Protein phosphatase (PP)-2A, which regulates the phosphorylation of tau, is regulated by two endogenous inhibitor proteins, I(1)(PP2A) and I(2)(PP2A), in mammalian tissues. Here, we report the cloning of I(1)(PP2A) and I(2)(PP2A) from human brain, and show that in PC12 cells and in I(1)(PP2A)-GFP or I(2)(PP2A)-GFP transfected NIH3T3 and human neural progenitor cells, I(1)(PP2A) is localized mostly in the cell cytoplasm and I(2)(PP2A) mostly in the nucleus. The recombinant I(1)(PP-2A) and I(2)(PP-2A) inhibit PP-2A activity towards hyperphosphorylated tau in vitro; the dephosphorylation of the hyperphosphorylated tau at specific sites is selectively inhibited. Overexpression of I(1)(PP2A) as well as I(2)(PP2A) results in tau hyperphosphorylation and degeneration of PC 12 cells.

Alzheimer Disease↗

Reliability of in vivo volume measures of hippocampus and other brain structures using MRI.

Volume reductions of the hippocampus are associated with Alzheimer's disease, schizophrenia, and epilepsy. We used clinically available MRI methods (2D acquisition; inversion recovery and calculated T2 images; 3 mm contiguous slices) that optimize image contrast, quality, and resolution and standardized positioning protocols to maximize the in vivo accuracy (test-retest reliability) of brain volume measurements in volunteers who were scanned two or three times. Volunteers were scanned in the same MRI instrument (intrascanner reliability) as well as in two different instruments (interscanner reliability). A single rater obtained brain volume measures of seven contiguous slices centered on the anterior commissure. The in vivo intrascanner reliability for measures of anterior hippocampus and ventricular volumes was very good, with reliability coefficients [intraclass r (rxx)] ranging between .855 and .997, and a median coefficient of variation (CV) of 6.4%. Reliability was good for amygdala (rxx of .740 and .764) and for total frontal and temporal lobe volumes and white matter volume measures (rxx ranging between .640 and .823, median coefficient of variation was 3.2%). Overall, interscanner reliability was also good. We discuss the implications of our results relative to the possible clinical utility of hippocampal quantification and the feasibility of prospective studies aimed at quantifying progressive neurodegeneration.

Adult↗

[Effect of ACTH and hydrocortisone on the functional state and interaction of brain structures].

In chronic experiments on cats ACTH facilitated the development of behavioral responses to gradually increasing electric stimulation of the medial hypothalamus, hippocampus and the midbrain reticular formation as well as potentiated the reticulo-hypothalamic influence. The effect of hydrocortisone was opposite. The reciprocal reticular and hormonal influences on the basal and anterior amygdala were revealed as well as some hormonal changes due to unspecific thalamic effects upon the limbic structures. The revealed systemic hormonal effect on the state and interaction of cerebral structures seems to be the base for integration of neural and hormonal mechanisms of some behavioral responses.

Adrenocorticotropic Hormone↗

Defining the course of brain structural change and plasticity in schizophrenia.

Recent evidence from controlled CT and MRI longitudinal studies suggests that some cerebral ventricular enlargement and hemispheric volumetric reductions (e.g. cerebral atrophy) may have a progressive component in patients with schizophrenia. These studies vary in cohort composition, stage of illness examined, duration of follow-up interval, imaging techniques used, and specific brain regions with findings. They also conflict with earlier evidence suggesting that schizophrenia is a neurodevelopmental disorder with brain pathological deviance occurring prior to the illness onset. The newer brain imaging reports may be detecting subtle brain plasticity that results from a continuing cortical disruptive process, may be epi-phenomena caused by scanning and image analysis artifacts or may possibly reflect systemic physiological fluctuations. Future longitudinal studies of subjects at all stages of illness using a variety of new technologies are needed to clarify these findings.

Atrophy↗

Structural brain abnormalities in first-episode mania.

Using magnetic resonance imaging (MRI), we studied brain morphometric differences between patients with first-episode mania (n = 17) and normal control subjects (n = 16). Patients were admitted for their first psychiatric hospitalization and met DSM-III-R criteria for bipolar disorder, manic or mixed. Diagnoses were made using the Structured Clinical Interview for DSM-III-R. Patients and control subjects were matched for age, gender, height, past history of substance abuse, and handedness, although control subjects had attained higher levels of education. MRI inversion recovery coronal scans were used for measurements. Volumetric measurements were obtained for cerebral hemispheres, lateral and third ventricles, caudate, thalamus, and cingulate gyrus. Patients with first-episode mania demonstrated significantly larger third-ventricular volumes, possibly increased lateral ventricular volumes, and differences in gray/white matter distribution compared with normal control subjects. The possible pathophysiological meaning of these findings is discussed.

Adolescent↗

Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin-Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning.

Coffin-Lowry syndrome (CLS) is characterized by cognitive impairment, characteristic facial and digital findings and skeletal anomalies. The gene implicated in CLS encodes RSK2, a serine/threonine kinase acting in the Ras/MAPK signalling pathway. In humans, RSK2 belongs to a family of four highly homologous proteins (RSK1-RSK4), encoded by distinct genes. RSK2 mutations in CLS patients are extremely heterogeneous. No consistent relationship between specific mutations and the severity of the disease or the expression of uncommon features has been established. Together, the data suggest an influence of environmental and/or other genetic components on the presentation of the disease. Obvious modifying genes include those encoding other RSK family members. In this study we have determined the expression of RSK1, 2 and 3 genes in various human tissues, during mouse embryogenesis and in mouse brain. The three RSK mRNAs were expressed in all human tissues and brain regions tested, supporting functional redundancy. However, tissue specific variations in levels suggest that they may also serve specific roles. The mouse Rsk3 gene was prominently expressed in the developing neural and sensory tissues, whereas Rsk1 gene expression was the strongest in various other tissues with high proliferative activity, suggesting distinct roles during development. In adult mouse brain, the highest levels of Rsk2 expression were observed in regions with high synaptic activity, including the neocortex, the hippocampus and Purkinje cells. These structures are essential components in cognitive function and learning. Based on the expression levels, our results suggest that in these areas, the Rsk1 and Rsk3 genes may not be able to fully compensate for a lack of Rsk2 function.

Animals↗

Effect of leptin replacement on brain structure in genetically leptin-deficient adults.

The hormone leptin profoundly affects body weight and metabolism. Three human adults (two women, 35 and 40 yr old; one man, age 27) have been identified with a recessive mutation in the ob gene, which is homologous to the mutation in ob/ob mice, and produces leptin deficiency and morbid obesity. Because leptin replacement increases brain weight and changes brain protein and DNA content in ob/ob mice, we hypothesized that analogous treatment of leptin-deficient humans would alter brain tissue composition. Volumetric T1-weighted magnetic resonance images of the brain were acquired before and at 6 and 18 months after initiation of replacement therapy (daily sc injections of recombinant methionyl human leptin), which produced dramatic loss in body weight. We used voxel-based morphometry to test for increased gray matter tissue concentration after initiation of leptin replacement and detected increases at 6 months in the anterior cingulate gyrus, the inferior parietal lobule, and the cerebellum. These increases were maintained for over 18 months, with identical stereotaxic coordinates of the maxima for the effects. Our findings suggest that leptin can have sustained effects on tissue composition in the human brain and broaden the potential spectrum of leptin's influence beyond feeding behavior and endocrine function.

Adult↗

[Glutamate decarboxylase activity and GABA binding by synaptic membranes of brain structure under stress in intact rats and rats with hormonal blockade of the hypothalamo-hypophyseal-adrenal cortex system].

Under the inhibition of hypothalamo-pituitary-adrenal system function, as a result of prolonged hydrocortisone administration, the normal neurochemical reaction to stress, i.e. stimulating the formation of GABA (mediator that is basic among responsible ones for the realization of stress-limiting brain function) was absent. In the medulla under such conditions an increase in the degree of GABA reception processes activation of comparing with the intact stressed rats was revealed and in the hippocamp of their changes was directivity reverse.

Adrenal Cortex↗

Role of enkephalinergic brain structures in regulating motivated behavior in rats with lesioned serotoninergic neurons.

The behavioral effects of injections of enkephalin into the substantia nigra or dorsal raphe nucleus were studied in rats with lesioned serotoninergic structures. Lesions were produced by intracerebral administration of the neurotoxin 5,7-dihydroxytryptamine. Treated rats showed normalization of conditioned drinking reflex extinction. It is proposed that there is a tight connection between the normalizing effects of enkephalin on rat behavior in conditions of deficient brain serotoninergic system function and increases in the efficiency of presynaptic inhibition of dopaminergic neurons.

5,7-Dihydroxytryptamine↗

The structural brain correlates of cognitive deficits in adults with Klinefelter's syndrome.

CONTEXT: Adults with Klinefelter's syndrome (KS) are known to present disturbances of language skills and delayed learning abilities. OBJECTIVES: The aim of this study was to assess brain morphometry in KS and to correlate eventual volumetric changes with performance on neuropsychological tests. PATIENTS: Patients included 18 KS adults and 20 age-matched controls. METHODS: All participants underwent prospectively double-spin-echo brain magnetic resonance imaging and neuropsychological testing of verbal and nonverbal domains. On the axial stack of magnetic resonance imaging slices, regional brain volumes were measured either by automated segmentation (full brain, total cerebrospinal fluid, and ventricular volume) or manual drawing with help of a neuroanatomy atlas (frontal, temporal, and parietal lobes, gray matter component of the lobes, cerebellar hemispheres, and hippocampal complexes). RESULTS: KS patients performed significantly lower than controls on language-related tasks exploring verbal processing speed and verbal executive function. They were diagnosed with significant enlargement of ventricular volume and bilateral reduction of cerebellar hemispheres. Furthermore, after separation of participants according to handedness and after correction of regional brain volumes for atrophy, a significant reduction of left temporal lobe volume was found in KS compared with controls. Ventricular volume was inversely correlated with cognitive function, whereas left temporal lobe volume was positively correlated with language-related tasks. CONCLUSION: This study hypothesizes that supernumerary X-chromosome and/or congenital hypogonadism provoke structural alterations in the subcortical pathways involved in language processing, thus providing a neurobiological substrate for cognitive deficits in KS.

Adolescent↗

An fMRI study of the role of suprapontine brain structures in the voluntary voiding control induced by pelvic floor contraction.

We have learned that micturition is comprised of two basic phases: storage and emptying; during bladder emptying, the pontine and periaqueductal gray (PAG) micturition center ensures coordinated inhibition of striated sphincter and pelvic floor muscles and relaxation of the internal urethral sphincter while the detrusor muscle contracts. Due to several disorders of the brain and spinal cord, the achieved voluntary control of bladder function can be impaired, and involuntary mechanisms of bladder activation again become evident. However, little has been discovered so far how higher brain centers strictly regulate the intricate process of micturition. The present functional magnetic resonance imaging (fMRI) study attempted to identify brain areas involved in such voluntary control of the micturition reflex by performing functional magnetic resonance imaging during a block design experiment in 12 healthy subjects. The protocol consisted of alternating periods of rest and pelvic muscle contraction during empty-bladder condition (EBC) and full-bladder condition (FBC). Repeated pelvic floor muscle contractions were performed during full bladder to induce a stronger contrast of bladder sensation, desire to void and inhibition of the micturition reflex triggering, since the subjects were asked not to urinate. Empty-bladder conditions were applied as control groups. Activation maps calculated by contrast of subtracting the two different conditions were purposed to disclose these brain areas that are involved during the inhibition of the micturition reflex, in which contrast, the SMA, bilateral putamen, right parietal cortex, right limbic system, and right cerebellum were found activated. The combined activation of basal ganglia, parietal cortex, limbic system, and cerebellum might support the assumption that a complex visceral sensory-motor program is involved during the inhibitory control of the micturition reflex.

Adult↗

Prenatal stress alters Fos protein expression in hippocampus and locus coeruleus stress-related brain structures.

Prenatal stress (PS) durably influences responses of rats from birth throughout life by inducing deficits of the hypothalamo-pituitary-adrenal (HPA) axis feedback. The neuronal mechanisms sustaining such alterations are still unknown. The purpose of the present study was to determine whether in PS and control rats, the exposure to a mild stressor differentially induces Fos protein in hippocampus and locus coeruleus, brain areas involved in the feedback control of the HPA axis. Moreover, Fos protein expression was also evaluated in the hypothalamic paraventricular nucleus (PVN) that reflect the magnitude of the hormonal response to stress. Basal plasma corticosterone levels were not different between the groups, while, PS rats exhibited higher number of Fos-immunoreactive neurons than controls, in the hippocampus and locus coeruleus in basal condition. A higher basal expression of a marker of GABAergic synapses, the vGAT, was also observed in the hypothalamus of PS rats. Fifteen minutes after the end of the exposure to the open arm of the elevated plus-maze (mild stress) a similar increased plasma corticosterone levels was observed in both groups in parallel with an increased number of Fos-immunoreactive neurons in the PVN. Return to basal plasma corticosterone values was delayed only in the PS rats. On the contrary, after stress, no changes in Fos-immunoreactivity were observed in the hippocampus and locus coeruleus of PS rats compared to basal condition. After stress, only PS rats presented an elevation of the number of activated catecholaminergic neurons in the locus coeruleus. In conclusion, these results suggest for the first time that PS alters the neuronal activation of hippocampus and locus coeruleus implicated in the feedback mechanism of the HPA axis. These data give anatomical substrates to sustain the HPA axis hyperactivity classically described in PS rats after stress exposure.

Animals↗

[The electrical activity of the brain structures in an experimental depressive syndrome induced by the systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to rats].

In rats injected with neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) the development of experimental depressive syndrome was accompanied by local epileptiform activity in the caudate-putamen complex and by reorganization of electrical processes in the brain. The spectral power density in the caudate-putamen in the delta range was increased in the formative stage of depressive syndrome (day 3-4 from the beginning of MPTP administration) and in the stage of behaviour recovery (a week after the withdrawal) as compared to control rats. On the contrary, the spectral power in the alpha range was decreased at the peak of depression (day 11-12 from the beginning of neurotoxin administration) and a week after the withdrawal as compared to the initial value. In the formative stage of depressive syndrome the spectral power in the delta range was increased in hippocampus whereas in sensorimotor cortex it was decreased at the frequency 6 Hz compared to control. It is suggested that a new pathodynamical organization is formed in the CNS of animals in response to MPTP administration, which is thought to be a neuropathophysiological basis of depressive syndrome.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

[Effect of histological technics on the volume and weight of various brain structures of rats at the early stages of life].

The aim of the studies was to elaborate technical procedure of material preparation for quantitative studies and determination of correction coefficients of morphometric parameters in dependence on histological procedures. Moreover, volume changes of the rat substantia nigra and striatum (structures degenerating in Parkinson's disease) during the first half year of life were estimated. As fixatives 4 and 8% formaldehyde in 4 and 20 degrees C were used. Irrespective of applied variant of fixation formaldehyde produced during first 48 hrs rapid increase of the brain weight and volume up to 52% of that of the fresh brain, which was followed by slow decrease of brain weight of about 1-3%/24 hrs. The most pronounced changes caused 4% formaldehyde in 20 degrees C. The best conditions for morphometric studies were obtained with the use of 8% formaldehyde in 20 degrees C. Dehydration in ethyl alcohol produced violent decrease of brain volume and weight (from 32% up to 39% of the fresh brain weight). Clearing in methyl bensoesane increases again the brain weight by a few percentage. The obtained results make possible to estimate error size in morphometric studies conducted on the formaldehyde-fixed material. It was stated also that the above histological procedure causes more pronounced changes in fetal rat brain and in brain of 1-2-day-old rats. Stabilization of changes caused by histological procedure is achieved between first and sixth months of rat life.

Age Factors↗

Neonatal 5HT activity antagonizes the masculinizing effect of testosterone on the luteinizing hormone release response to gonadal steroids and on brain structures in rats.

Hypothalamic 5HT concentrations are transiently lower in male compared to female Wistar rats in the second week post partum (pp) and our previous findings have shown that pharmacologically potentiating 5HT activity over this period feminizes certain aspects of sexually differentiated behaviours in adult males and androgenized females. In order to investigate whether neonatal testosterone and 5HT interact to influence physiological and morphological brain sexual differences, females, androgenized females and males were treated with the 5HT2 agonist (-) [2,5 dimethoxy-4-iodophenyl]-2-amino propane HCl [(-) DOI], over days 8-16 pp. In androgenized females (250 microg testosterone proprionate, day 2 pp) (-) DOI prevented the delay in vaginal opening, but did not prevent the androgen-induced constant oestrus in females treated with 100 microg TP, day 2 pp. (-) DOI overcame the neonatal androgen effect in suppressing the positive feedback of ovarian steroids in a few males and androgenized females. (-) DOI had a feminizing effect on the volume of the anteroventral periventricular nucleus (normally smaller in males), by significantly increasing its volume in male and androgenized females. It also had a significant antagonistic effect on the testosterone-induced increase in the volume of the sexually dimorphic nucleus of the preoptic area in males and androgenized females. These findings support the view that raised 5HT activity in the second week of life antagonizes the masculinizing effect of neonatal testosterone.

Animals↗