Jürgen K. Mai

Dynamics of expression of apoptosis-regulatory proteins Bid, Bcl-2, Bcl-X, Bax and Bak during development of murine nervous system

We have used immunohistochemistry and immunoblotting to examine the expression of Bid and four other Bcl-2 family proteins (Bcl-2, Bcl-X, Bax and Bak) in the developing and adult murine central nervous system (CNS). Bid protein is widespread in embryonic and postnatal brain, and its expression is maintained at a high level late into the adulthood. Bid is expressed both in the germ disc, early neural tube, proliferating stem cells of ventricular zones, and in postmitotic, differentiated neurons of the developing central and peripheral nervous system. As the differentiation proceeds, the neurons express higher levels of Bid than the stem cells of the paraventricular zone. Both in embryonic and postnatal life, Bid protein is present in the most vital regions of brain, such as the limbic system, basal ganglia, mesencephalic tectum, Purkinje cells in cerebellum, and the ventral columns of spinal cord. The p15 cleaved form of Bid was detectable in the brain specimens at fetal stages of development, consistent with caspase-mediated activation of this pro-apoptotic Bcl-2 family protein. Among the Bcl-2 family proteins only Bid and Bcl-XL continue to be expressed at high levels in the adult brain.

Cognitive Functions in a Patient With Parkinson-Dementia Syndrome Undergoing Deep Brain Stimulation

BACKGROUND Dementia represents one of the most challenging health problems. Despite intense research, available therapies have thus far only achieved modest results. Deep brain stimulation (DBS) is an effective treatment option for some movement disorders and is under study for psychiatric applications. Recently, diencephalic DBS revealed selective effects on memory functions, another facet of subcortical DBS. OBJECTIVE To report a new DBS strategy for the modification of cognitive functions in a patient with severe Parkinson-dementia syndrome. DESIGN Prospective study with double-blinded sham stimulation period. SETTING Departments of Stereotaxy and Functional Neurosurgery and Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany. PATIENT A 71-year-old man with slowly progressive Parkinson-dementia syndrome. Intervention We inserted 2 electrodes into the nucleus basalis of Meynert in addition to electrodes in the subthalamic nucleus. Main Outcome Measure Improvement of cognitive functions. RESULTS Turning on the subthalamic nucleus electrodes improved motor symptoms but left cognitive performance almost unchanged. Turning on electrical stimulation of the nucleus basalis of Meynert resulted in markedly improved cognitive functions. The improvement in attention, concentration, alertness, drive, and spontaneity resulted in the patients renewed enjoyment of former interests and enhanced social communication. CONCLUSIONS Such a broad effect on cognition is consistent with ample experimental evidence revealing that the nucleus basalis of Meynert provides cholinergic innervation to the cortical mantle, complemented by glutaminergic and gamma-aminobutyric acid-transmitting projections from the basal forebrain. These projections provide background tuning facilitating cortical operations. Furthermore, nucleus basalis of Meynert stimulation paired with sensory stimuli can accomplish persistent reorganization of specific processing modules. The improvements in cognitive and behavioral performance in our patient are likely to be related to the effects of stimulating residual cholinergic projections and cell bodies in the nucleus basalis of Meynert.

Organization of human hypothalamus in fetal development

The organization of the human hypothalamus was studied in 33 brains aged from 9 weeks of gestation (w.g.) to newborn, using immunohistochemistry for parvalbumin, calbindin, calretinin, neuropeptide Y, neurophysin, growth‐associated protein (GAP)‐43, synaptophysin, and the glycoconjugate 3‐fucosyl‐ N‐acetyl‐lactosamine. Developmental stages are described in relation to obstetric trimesters. The first trimester (morphogenetic periods 9–10 w.g. and 11–14 w.g.) is characterized by differentiating structures of the lateral hypothalamic zone, which give rise to the lateral hypothalamus (LH) and posterior hypothalamus. The PeF differentiates at 18 w.g. from LH neurons, which remain anchored in the perifornical position, whereas most of the LH cells are displaced laterally. A transient supramamillary nucleus was apparent at 14 w.g. but not after 16 w.g. As the ventromedial nucleus differentiated at 13–16 w.g., three principal parts, the ventrolateral part, the dorsomedial part, and the shell, were revealed by distribution of calbindin, calretinin, and GAP43 immunoreactivity. The second trimester (morphogenetic periods 15–17 w.g., 18–23 w.g., and 24–33 w.g.) is characterized by differentiation of the hypothalamic core, in which calbindin‐ positive neurons revealed the medial preoptic nucleus at 16 w.g. abutted laterally by the intermediate nucleus. The dorsomedial nucleus was clearly defined at 10 w.g. and consisted of compact and diffuse parts, an organization that was lost after 15 w.g. Differentiation of the medial mamillary body into lateral and medial was seen at 13–16 w.g. Late second trimester was marked by differentiation of periventricular zone structures, including suprachiasmatic, arcuate, and paraventricular nuclei. The subnuclear differentiation of these nuclei extends into the third trimester. The use of chemoarchitecture in the human fetus permitted the identification of interspecies nuclei homologies, which otherwise remain concealed in the cytoarchitecture. J. Comp. Neurol. 446:301–324, 2002.

Hypothalamus of the human fetus

The organization of the human hypothalamus was studied in 31 brains aged from 9 weeks of gestation (w.g.) to newborn, using immunohistochemistry for parvalbumin, calbindin, calretinin, neuropeptideY, neurophysin, growth associated protein GAP43, synaptophysin and glycoconjugate, 3-fucosyl-N-acetyl-lactosamine. Morphogenetic periods 9-10 and 11-14 w.g. are characterized by differentiating structures of the lateral hypothalamic zone, which give rise to the lateral hypothalamus (LH) and posterior hypothalamus. The perifornical nucleus differentiates at 18 w.g., from LH neurons which remain anchored in the perifornical position while most of the LH cells are displaced laterally. A transient supramamillary nucleus was apparent at 14 w.g. but not after 16 w.g. As the ventromedial nucleus differentiated at 13-16 w.g., three principal parts; the ventrolateral, the dorsomedial and the shell were revealed by distribution of calbindin, calretinin and GAP43 immunoreactivity. Morphogenetic periods 15-17, 18-23 and 24-33 w.g. are characterized by differentiation of the hypothalamic core, in which calbindin positive neurons revealed the medial preoptic nucleus at 16 w.g. abutted laterally by the intermediate nucleus. The dorsomedial nucleus was clearly defined at 10 w.g. and consisted of compact and diffuse parts, an organization that was lost after 15 w.g. Differentiation of the medial mamillary body into lateral and medial was seen at 13-16 w.g. Morphogenetic period after 34 w.g. was marked by differentiation of midline zone structures including suprachiasmatic, arcuate and paraventricular nuclei. The findings of the present study provide for a better understanding of the structural organization of the adult human hypothalamus, produce new evidence for homologies with the better studied rat hypothalamus and underpin staging system for fetal human hypothalamic development.

Disappearance of self-aggressive behavior in a brain-injured patient after deep brain stimulation of the hypothalamus: technical case report.

OBJECTIVE Self-mutilation is a severe symptom of diseases with varying etiologies. It can be observed in the context of mental retardation and after traumatic brain injury. Pharmacological treatment approaches often prove ineffective. CLINICAL PRESENTATION We report the case of a 22-year-old woman with repetitive self-mutilating behavior in the mouth area after severe traumatic brain injury. RESULTS Bilateral deep brain stimulation of the posterior hypothalamus was conducted and resulted in the complete elimination of self-mutilation during a 4-month observation period. CONCLUSION This technical case report indicates that deep brain stimulation of the posterior hypothalamus could be a promising approach in the treatment of severe self-mutilating behavior.

Bag1 is a regulator and marker of neuronal differentiation

Bag 1 acts as a co-chaperone for Hsp70/Hsc70. We report here that stable over-expression of Bag1 in immortalized neuronal CSM14.1 cells prevents death following serum deprivation. Bag1 over-expression slowed the proliferative rate of CSM14.1 cells, resulted in increased levels of phospo-MAP kinases and accelerated neuronal differentiation. Immunocytochemistry revealed mostly nuclear localization of Bag1 protein in these cells. However, during differentiation in vitro, Bag1 protein shifted from predominantly nuclear to mostly cytosolic in CSM14.1 cells. To explore in vivo parallels of these findings, we investigated Bag1 expression in the developing mouse nervous system using immunohistochemical methods. Early in brain development, Bag1 was found in nuclei of neuronal precursor cells, whereas cytosolic Bag1 staining was observed mainly after completion of neuronal precursor migration and differentiation. Taken together, these findings raise the possibility that the Bag1 protein is expressed early in neurogenesis in vivo and is capable of modulating neuronal cell survival and differentiation at least in part from a nuclear location.

DBS in the basolateral amygdala improves symptoms of autism and related self-injurious behavior: a case report and hypothesis on the pathogenesis of the disorder

We treated a 13-year-old boy for life-threatening self-injurious behavior (SIB) and severe Kanners autism with deep brain stimulation (DBS) in the amygdaloid complex as well as in the supra-amygdaloid projection system. Two DBS-electrodes were placed in both structures of each hemisphere. The stimulation contacts targeted the paralaminar, the basolateral (BL), the central amygdala as well as the supra-amygdaloid projection system. DBS was applied to each of these structures, but only stimulation of the BL part proved effective in improving SIB and core symptoms of the autism spectrum in the emotional, social, and even cognitive domains over a follow up of now 24 months. These results, which have been gained for the first time in a patient, support hypotheses, according to which the amygdala may be pivotal in the pathogeneses of autism and point to the special relevance of the BL part.

Localization of the CD15 carbohydrate epitope in the vertebrate retina.

The distribution of the carbohydrate epitope CD15, a putative cell adhesion molecule, was studied in adult vertebrate retinas by light-microscopic immunohistochemistry. Except for Old World primates, in which no immunoreactivity was detectable, all other species expressed the epitope on retinal interneurones. Subpopulations of stratified amacrine cells were found in all species with the exception of bats and marmoset monkeys, and bipolar cells were immunoreactive in frogs and all amniotic animals. Ganglion cells were labelled in urodelian, in all sauromorphian, as well as in some mammalian species. In some species, the distribution of immunoreactive neurones was correlated to areas of retinal specialization such as the visual streak in frogs and the dorsotemporal field in birds. In these parts of the retina with enhanced visual acuity, more CD15 glycosylated bipolar cells were found than in other parts. Among mammals, labelled bipolar cells were found exclusively in species with cone-dominated retinas. This comparative study shows that CD15 expression is consistently membrane associated in morphologically defined subsets of amacrine, bipolar, and ganglion cells throughout the vertebrate phylum. Its distribution pattern was found to depend more on the visual behavior of a given species (cone-dominated or rod-dominated retina) than on phylogenetic proximity between species.

Expression of the carbohydrate epitope 3-fucosyl-N-acetyl-lactosamine (CD15) in the vertebrate cerebellar cortex

SummaryThe distribution of the carbohydrate epitope CD15 was investigated on paraffin sections of the brains of man and mammals (monkey, dog, rabbit, rat, mouse, dolphin), reptile, bird and fish by means of immunohistochemistry. This paper demonstrates a differential expression of the CD15 epitope in the cerebella of these various vertebrates. CD15 positivity was found on glial cells and neuronal structures. In adult brains two major distribution patterns were distinguished: one with very intense labelling of the molecular layer, for which the rat is representative, the other with very low immunoreactivity in this layer (mouse). Amongst the rodents (mouse, rat and rabbit), as well as the monkey and human, the positivity in the molecular layer could be attributed to Bergmann fibres of the Golgi epithelial cells. A typical parasagittal band pattern, present in the mouse molecular layer for CD15, which is absent in rat and rabbit molecular layer, is present during human cerebellar development. CD15 positivity on neuronal structures is found on parallel fibres in the developing human, on the lower stellate cells in the dog, and in climbing fibres of the dolphin and, presumably, the catfish too. Moreover, within the parrot cerebellum, large CD15-positive mossy fibre-like endings are found just at the infraplexiform layer.

Distribution of the 3-fucosyl-N-acetyl-lactosamine (FAL) epitope in the adult mouse brain

SummaryThe distribution of the 3-fucosyl-N-acetyl-lactosamine (FAL) epitope within the adult mouse brain was studied by immunohistochemistry using the monoclonal antibody Leu-M1. Leu-M1-positive elements comprised astrocytes and neurons. FAL-positive astrocytes were particularly abundant in barrier structures of the brain, but were also prominent at the periphery of most medullated fiber tracts. Their intracerebral distribution led to a distinct pattern of organization, which in some locations, including the cerebral cortex, could be used for an extended regional architectonic description. Since only some FAL-positive astrocytes were also positive for glial fibrillary acid protein (GFAP), the emerging topography of the FAL-positive astrocytes often differed from the GFAP-distribution. In the cerebellum, Bergmann glia cells expressed the FAL epitope and, in the vermis, their arrangement had a band-like appearance. Positive oligodendrocytes could not be identified. The common ependymal cells were negative, whereas tanycytes were highly immunoreactive. The Leu-M1 antibody also stained some neurons. These occurred in selected neocortical regions, within the dorsal and ventral striatum, in the globus pallidus, the nucleus basalis of Meynert, the nucleus diagonalis and some hypothalamic areas. In some instances, their morphology and location indicated an association with neurochemically specified cell groups.