Biomedical subjects

R O Kuljis

Publications and source records attributed to R O Kuljis.

At least 19 recordsLinked to original sources

PubMed2003

Regulation of gonadotropin releasing hormone release by neuropeptide Y at the median eminence during the preovulatory period in ewes.

The median eminence (ME) of the hypothalamus is known to be an important brain site where hypophysiotropic release might be regulated by excitatory and inhibitory signals impinging on their neuronal terminals. Since a role for neuropeptide Y (NPY) on preovulatory luteinizing hormone (LH) release has been suggested, we hypothesized that NPY might act at the ME to control preovulatory gonadotropin-releasing hormone (GnRH) release and thus the onset of the preovulatory surge of LH. To examine this possibility, we used the ewe as an animal model to determine: (a) immunocytochemical distribution of GnRH and NPY in the ewe ME; (b) changes in in vivo release of NPY and GnRH using ME push-pull cannula (PPC) perfusate samples, as well as in plasma LH, during the luteal, follicular and preovulatory phases of a synchronized estrous cycle, and (c) effects of ME perfusion of NPY or a Y1-NPY antagonist, or an NPY antiserum on in vivo release of ME-GnRH and plasma LH during a synchronized follicular phase. Immunolocalization reveals a dense plexus of beaded GnRH-containing neurites in the arcuate nucleus and in its vicinity, the pituitary stalk and the palisade. In contrast, a dense plexus of NPY-containing neurites occurs in the internal layer, with occasional fibers found in the intermediate and lateral external zone of the ME. In the area between the lateral internal and lateral external layers, both NPY and GnRH-containing processes were found, thus providing opportunities for synaptic and/or paracrine interactions between NPY- and GnRH-containing neurons. Hormonal analysis indicated that a synchronized preovulatory surge of LH is elicited within a 2-hour window by the sequential implantation and removal of silastic-encased estradiol (E2) or progesterone (P4) implants. In this paradigm, there was a parallel increase in ME release of both NPY and GnRH preceding the synchronized LH surge. The onset of this synchronized LH surge was advanced by ME perfusion of exogenous NPY and was both delayed and blunted by ME perfusion with the NPY antagonist (both were perfused through the PPC probe for 2 h, starting 2-3 h before the expected onset of the LH surge). In addition, NPY perfusion in the ME increases, while perfusion of the Y1-NPY antagonist or of the NPY antiserum decreases ME-PPC GnRH content and plasma levels of LH in early follicular ewes. Finally, perfusion of NPY antiserum during an ongoing LH surge disrupted LH release. These results suggest that interactions between NPY and GnRH neurons are important in controlling the timing, magnitude and maintenance of the preovulatory LH surge.

Animals↗

PubMed2000

Familial Creutzfeldt-Jakob disease: a neuropsychological case study.

The spectrum of neuropsychological features of familial Creutzfeldt-Jakob disease (CJD) have seldom been reported, possibly because of (a) the rarity of this hereditary form of prion disease; (b) frequent delays in diagnosis, and; (c) the typically rapid demise of the patient, which affords little opportunity for comprehensive testing or serial analysis. Here we describe the neurobehavioral characteristics of a 48-year-old right-handed male (JD) who presented with complaints of poor depth perception, unsteady gait, and unusual sensory experiences in his face and neck. JD was followed serially over the final 4 months of his 5-month illness. Immediately following hospital admission, he underwent a neuropsychological evaluation that revealed moderate to severe impairment of delayed (30-minute) verbal memory, tactual performance in his right hand, and word-finding ability. In contrast, other abilities that are commonly classified within the verbal, visuospatial, and memory domains showed minimal or no compromise. Parallel studies of electroencephalographic activity revealed diffuse slowing and, later, 1-Hz rhythmical discharges over the left hemisphere, and mild prominence of the lateral ventricles and cerebral sulci on magnetic resonance imaging. Autopsy revealed spongiform changes and reactive astrocytosis, and genetic testing demonstrated a codon 200 mutation in the prion protein gene. These findings indicate that CJD can result in clinical manifestations compatible with multifocal asymmetric cerebral involvement before more diffuse neurodegeneration ensues, providing a strong impetus for the study of additional cases. This long-term understanding can help to determine whether the multiple loci of clinical involvement are specified by genetic or epigenetic factors, or both.

Clinical Conference↗

PubMed1999

ATM immunolocalization in mouse neuronal endosomes: implications for ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is a human disorder with pleiotropic manifestations that include neoplasms, immune dysfunction and neurodegeneration. The disorder is due to mutations in the gene known as ATM (A-T, mutated), which causes a deficiency in its protein product (Atm in mice) that is necessary for DNA damage surveillance. This nuclear function of Atm explains in principle the propensity to cancer and immunodeficiency in A-T, but not the neurodegeneration which results in the earliest clinical manifestations and causes progressive disability. Here we report ultrastructural evidence of cytoplasmic localization of Atm-like immunoreactivity (ALI) within endosomes in murine cerebellocortical neurons, one of the principal targets of A-T. The ALI was obtained with two separate monoclonal antibodies that recognize Atm specifically. By contrast, electron-dense endosomes that could be confused with ALI occur in negligible amounts in both wild-type mice and in mice deficient in Atm ("knockout" mice). Furthermore, there was a marked preferential distribution of Atm-immunopositive endosomes in the granule cell layer - where they are present in granule neurons - with a much lower density in the Purkinje and molecular layers. These observations suggest that endosome-bound Atm may be more important for the function of certain neurons than others - or that it is processed differently among them - and that this protein may be involved in molecular sorting in the cytoplasm. This is relevant to elucidating the role of Atm deficiency in the pathobiology of neurodegeneration in A-T.

Animals↗

PubMed1999

Degeneration of NO-synthesizing cerebrocortical neurons in transgenic mice expressing mutated superoxide dismutase is not due to elevated nitric oxide levels.

Nitric oxide (NO) synthase (NOS)-containing cerebrocortical neurons degenerate in patients with amyotrophic lateral sclerosis (ALS) and dementia, and in transgenic mice expressing a mutated superoxide dismutase gene (G93A) associated with familial ALS. The cerebral cortex of transgenic mice displayed decreased NOS activity (p<0.001) and cGMP levels (p<0.01), but no changes in NOS content indicating that less NO is produced. Therefore, NOSN degeneration is not caused by elevated NO.

Amino Acid Substitution↗

PubMed1999

Neurodegeneration in ataxia-telangiectasia is caused by horror autotoxicus.

Ataxia-telangiectasia (A-T) is a pleiotropic, multi-system disorder with manifestations that include immune deficiency, sensitivity to ionizing radiation and neoplasms. Many of these manifestations are understood in principle since the identification in A-T patients of mutations in a gene encoding a protein kinase that plays a key role in signaling and repair of DNA damage. However, the cause of the neurodegeneration that afflicts patients with A-T for at least a decade before they succumb to overwhelming infections or malignancy remains mysterious. Based on our work in a mouse model of A-T and previous evidence of extra-neural autoimmune disorders in A-T, we postulate that the neurodegenerative process in A-T is not due to a function for A-T mutated (ATM) essential for the postnatal brain, but to an autoimmune process (hence 'horror autotoxicus', Paul Ehrlich's term for autoimmune disorder). This hypothetical mechanism may be analogous to that in the so-called 'paraneoplastic' neurodegenerative syndromes in patients with various malignancies. Thus, alterations in the balance between cellular and humoral immunity in A-T probably result in autoantibodies to cerebral epitopes shared with cells of the immune system. This hypothesis has important implications for the understanding and development of effective palliative and even preventative strategies for A-T, and probably for other so far relentlessly progressive neurodegenerative disorders.

Animals↗

PubMed1997

Degeneration of neurons, synapses, and neuropil and glial activation in a murine Atm knockout model of ataxia-telangiectasia.

Neural degeneration is one of the clinical manifestations of ataxia-telangiectasia, a disorder caused by mutations in the Atm protein kinase gene. However, neural degeneration was not detected with general purpose light microscopic methods in previous studies using several different lines of mice with disrupted Atm genes. Here, we show electron microscopic evidence of degeneration of several different types of neurons in the cerebellar cortex of 2-month-old Atm knockout mice, which is accompanied by glial activation, deterioration of neuropil structure, and both pre- and postsynaptic degeneration. These findings are similar to those in patients with ataxia-telangiectasia, indicating that Atm knockout mice are a useful model to elucidate the mechanisms underlying neurodegeneration in this condition and to develop and test strategies to palliate and prevent the disease.

Animals↗

PubMed1997

Discontinuous distribution of senile plaques within striate cortex hypercolumns in Alzheimer's disease.

Tangential sections of the primary visual (striate) cerebral cortex from five patients with histopathologically verified Alzheimer's disease were used to study the laminar and tangential disposition of senile plaques. These lesions were visualized with thioflavin S or the modified Bielschowsky method, and classified into four different, purely morphological types: "classical", (predominantly) "neuritic", (primarily amyloid) "core" and "diffuse", which were charted and analyzed using computer-assisted three- and two-dimensional reconstruction and mapping methods. These analyses reveal a tendency for a selective laminar disposition of the lesions (preferentially in layers II/III and V) which is generally consistent with previous reports performed at lower resolution, yet the specific pattern is highly variable among patients, and among plaque subtypes within individual patients. In addition, we observed a clustering of senile plaques in the tangential domain (i.e. parallel to the pial surface) in layers II/III, that suggests a selective involvement of iterated circuits within the "units", "modules", or "hypercolumns" that some believe compose this region of the cortex. These findings also imply an intriguing relative sparing of immediately adjacent components of the modular circuitry of the cerebral cortex, in the same cytoarchitectonic layers. Taken together, these findings indicate that: (1) senile plaques may arise in functionally and anatomically distinct subsets of iterated neuronal circuits that cannot be reduced to schemes based on traditional cytoarchitectonic layers; and (2) that individual variability in the patterns of striate cortex involvement and clinical manifestations must be taken into consideration when addressing the specific mechanisms underlying visual dysfunction in Alzheimer's disease.

Alzheimer Disease↗

PubMed1997

Alexia and agraphia in posterior cortical atrophy.

A 65-year-old woman with progressive visuospatial dysfunction for 2 years complained of later-onset associated memory impairment. MRI revealed diffuse cerebrocortical atrophy, which was especially severe in both parieto-occipital regions but spared the calcarine and pericalcarine cortices. Examination 5 years after onset revealed left visual hemi-neglect, oculomotor apraxia, optic ataxia, simultanagnosia, verbal alexia, lexical and spatial agraphia, and anterograde amnesia. This patient's disorder is considered in the context of previous reports on the array of cognitive disturbances associated with posterior cortical atrophy (pCA). Special emphasis is made on her reading and writing disturbances, because their prevalence and range of individual variability have not been established in pCA. This array of neuropsychological manifestations may help to distinguish among different clinical and etiological types of pCA, and to elucidate the pathophysiology of a syndrome that has been associated with conditions as diverse as Alzheimer's disease, subcortical gliosis, and prion diseases. The parameters described in our case may thus help to address these issues in clinico-pathological studies with large numbers of patients with pCA.

Aged↗

PubMed1996

Alterations in nitrogen monoxide-synthesizing cortical neurons in amyotrophic lateral sclerosis with dementia.

Cognitive impairment in the absence of lesions indicative of Alzheimer's disease and other dementing conditions has long been recognized in a subgroup of patients with motor neuron disease MND), including amyotrophic lateral sclerosis. However, the mechanisms underlying this cognitive deterioration and its relationship with the relatively selective involvement of motor neurons remains elusive. We used histo- and immunocytochemical labeling methods to study the nitrogen monoxide (NO; a.k.a. nitric oxide) synthase (NOS)-/NADPH diaphorase-containing neurons (NOSN) in three patients with MND and dementia (MND+D), two patients with MND without dementia, and 19 controls that included patients with Alzheimer and non-Alzheimer dementias. Patients with MND+D, but not those with MND without dementia, exhibit numerous dystrophic perikarya and neurites throughout all sensory, motor, association, and limbic neocortices examined. Interestingly, affected NOSN appear to correspond to some subtypes (smooth stellate and spiny neurons), while other neurons containing the same molecular phenotype (such as layer I local circuit neurons and layer II granule cells) are either spared or significantly less affected. These observations indicate that cognitive impairment and dementia in MND may be due, at least in part, to a pancortical involvement of certain types of NOSN. Consequently, the elucidation of the factors that make NOSN vulnerable in MND, and the prevention or pharmacological palliation of their loss, may eventually help to prevent or ameliorate cognitive impairment in MND and may also shed some light on the nature of the insult that targets motor neurons.

Adolescent↗

PubMed1994

Multiple types of nitrogen monoxide synthase-/NADPH diaphorase-containing neurons in the human cerebral neocortex.

Nitrogen monoxide (NO) synthase (NOS)-containing neurons (NOSN) were identified by means of reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry in nine areas of the human cerebral neocortex from patients 9-74 years of age. Labeled neurons were analyzed according to their disposition in the various layers of the cortical gray and immediately subjacent white matter, and classified according to their cytological features. The vast majority of NOSN (about 80%) are situated in the subcortical white matter and not in the cortical gray proper. Nevertheless, these NOSN extend their processes into the cortical gray and thus appear to participate in intracortical circuits, along with the minority of NOSN situated in all cortical layers. Although many NOSN are small aspiny local circuit neurons, as reported previously, additional distinct cytological types of NADPH diaphorase-positive neurons were also identified, including: (a) local circuit neurons in layer I; (b) granule cells in layer II, and (c) non-pyramidal neurons with densely spinous dendrites in the white matter immediately under the cortical gray. Processes fulfilling light microscopic criteria for axons were seen in many of the above cell types originating from proximal dendrites and, less frequently, from a presumed axon hillock. Taken together, these observations indicate that NOSN belong to several distinct morphological and presumably functional classes, some of which have a unique or restricted laminar location, raising the possibility that some of these various classes of neurons may be selectively affected or spared in neurodegenerative disorders.

Adult↗

PubMed1994

Lesions in the pulvinar in patients with Alzheimer's disease.

The pulvinar nucleus of the thalamus has been implicated in visual attention and in the control of eye movements, and may also help mediate attention-dependent tasks in the auditory and somatosensory systems. Consequently, a hypothetical disruption of functions mediated by the pulvinar may help understand common visual and nonvisual symptoms in patients with Alzheimer's disease. To test this hypothesis, the pulvinar nuclei of nine patients with histologically confirmed Alzheimer's disease and twelve young (9-28 years of age) and age-matched controls (without dementia and with non-Alzheimer dementias) were examined using a battery of histopathological methods. All patients with Alzheimer's disease had numerous amyloid plaques and some neuritic plaques throughout the various subdivisions of the pulvinar. Neuropil threads were also present among the senile plaques, and neurofibrillary tangles occurred in clusters throughout the nucleus. Control patients with and without dementia had very few Alzheimer lesions, which should be expected in normal elderly individuals. The lesions in the pulvinar may help understand some of the clinical manifestations of Alzheimer's disease, including deficits in attention and in a host of visual disturbances. Such deficits may be the result of involvement of reciprocal thalamo-cortical and corticothalamo-cortical circuits that appear to be critical for the function of a vast expanse of association cortices interconnected with the pulvinar, which are heavily laden with lesions themselves.

Adolescent↗

PubMed1993

Environmental deprivation delays the maturation of motor pyramids during the early postnatal period.

The effects of environmental deterioration upon the development of motor cortex was studied in 30 Sprague-Dawley albino rats during lactation (1st-18th postnatal days). The use of Golgi-Cox-Sholl methodology allowed qualitative and particularly quantitative evaluations since impregnation of neurons take place at random without any selectivity. Morphometric studies were assessed by measuring layers II-III pyramidal neurons, basal dendritic branching, under camera lucida. Early environmental impoverishment results in a highly significant decrease in the number and length of peripherical branches and terminal dendrites. These results extend previous observations made predominantly in non-motor cortices which indicate that during early postnatal life restrictions or enrichments of the environment may be associated with quantitative changes in the differentiation of cerebrocortical neurons. It is of upmost importance to consider that the potential effects of different types of epigenetic cues are highly selective since pyramids of pups subjected to mild nutritional manipulation during the same developmental period remained unaffected.

Animals↗

PubMed1993

Beta-endorphin regulation of luteinizing hormone-releasing hormone release at the median eminence in ewes: immunocytochemical and physiological evidence.

Beta-endorphin (beta-END) is an inhibitory factor in the neuroendocrine control of luteinizing hormone (LH) release and thus, presumably also of hypophysiotropic luteinizing hormone-releasing hormone (LHRH) release. In order to address if the median eminence (ME) is a site of beta-END action, we studied its functional role in ewes by assessing: (a) the hypothalamic distribution of beta-END using immunolabeling and by comparing this distribution with our data on the localization of LHRH; (b) the ME in vivo release of LHRH and beta-END during the luteal (day 12) and the follicular (day 15) phases of the estrous cycle; (c) the in vivo release of LHRH from the posterior-lateral ME, as assessed by push-pull cannula (PPC) sampling, before, during, and after infusion of increasing doses of beta-END or naloxone through the PPC, during the follicular phase; and (d) the in vivo release of ME-LHRH and serum LH, before, during, and after infusion of beta-END or naloxone in luteal and follicular ewes. In the ewe, beta-END-containing perikarya are located in and around the arcuate nucleus. Their processes are also present in the diagonal band, medial septal nucleus, and medial and lateral hypothalamic areas, including the preoptic region and posterior ME. Perikarya containing LHRH are located in the preoptic area and project also to the ME, providing opportunities for synaptic interactions between beta-END and LHRH-containing perikarya and processes at these levels. ME in vivo release of LHRH and beta-END increase from the luteal (low LH/high progesterone, P4) to the follicular phase (high LH/low P4). In follicular ewes, in vivo LHRH and LH release is decreased, in a dose-dependent manner, by beta-END infused through the PPC probe into the posterior-lateral ME. In contrast, infusion of naloxone under similar conditions increases LHRH and LH release, also in a dose-dependent fashion. The inhibitory effect of beta-END on LHRH and LH, as well as the stimulatory effect of naloxone on LHRH and LH, were only marginally apparent in luteal ewes. These results suggest that the ME is a major control site where beta-END exerts its influence on hypophysiotropic LHRH release. The strength of this inhibitory effect apparently increases throughout the follicular phase, and might prevent the premature onset of the preovulatory surge of LHRH and LH.

Animals↗

PubMed1992

Vibrissaeless mutant rats with a modular representation of innervated sinus hair follicles in the cerebral cortex.

Specialized areas in the cerebral cortex are essential to mediate the various sensory modalities and are crucial to their recovery in disease. We recently observed that prenatal photoreceptor cues are not indispensable for the development of the elaborate modular organization of the primate primary visual (striate) cortex (Kuljis, R. O. and P. Rakic. 1990. Proc. Natl. Acad. Sci. USA 87: 5303-5306). By contrast, the elegant experiments of Woolsey, Van der Loos, and collaborators (Van der Loos, H., and T. A. Woolsey. 1973. Science 179: 395-398; Van der Loos, H. and J. Dörfl. 1978. Neurosci Lett. 7: 23-30; Woolsey, T. A. 1967. John Hopkins Med. J. 121: 91-112; Woolsey, T. A. and H. Van der Loos. 1970. Brain Res. 17: 205-242) indicate that postnatal vibrissal receptor input is necessary for the development of modular organization in the posteromedial barrel subfield (PMBSF) of the rodent somatosensory cortex. The present report is part of a series of studies designed to address the variables that result in seemingly different results in these two models. Here, I address the role of pre- and postnatal tactile experience in the development of the rat homologue of the mouse PMBSF using mutants that lack vibrissae. Mutants exhibit cytoarchitectonic units in layer IV similar to those in controls, as revealed by NissI stains and histochemistry for succinate dehydrogenase and cytochrome oxidase. Sections from flat mounts of the vibrissal pad reveal that all mutants contain vibrissal follicles with stumps of sinus hairs in a geometric array and number similar to that in controls, and that the follicles are innervated heavily by fascicles of fibers from the infraorbital nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Hypercolumns in primate visual cortex can develop in the absence of cues from photoreceptors.

The visual cortex in primates consists of an array of anatomically and chemically identifiable cellular modules (hypercolumns) with distinct physiological properties. For example, layers II/III in the macaque monkey contain a regular array of cytochrome oxidase-rich blobs. Furthermore, the surrounding cytochrome oxidase-poor interblob regions have a higher density of neuropeptide Y-positive aspiny stellate cells. Neurons in the blobs are thought to mediate predominantly low spatial frequencies and color vision, while those in the interblobs appear to be engaged in pattern vision and high spatial frequency analysis. In this study we examined the role of the retina in the development of hypercolumns. A bilateral retinal ablation was performed in embryos at midgestation, before any photoreceptors had established contacts with other retinal neurons and before layers II/III of the cortex--or their synaptic connection--had been generated. We found that the cortex in operated animals had cytochrome oxidase blobs and that their size and spacing were normal. In addition, neuropeptide Y-containing neurons were preferentially distributed in the interblob region as in control animals. Our findings indicate that some basic aspects of the cyto- and chemoarchitectonic organization of the cerebral cortex, which presumably evolved for the analysis of form and color, can emerge in the absence of cues from the retinal photoreceptors that mediate these attributes of vision.

Aging↗

PubMed1989

Lewy bodies in tyrosine hydroxylase-synthesizing neurons of the human cerebral cortex.

A population of neurons situated in the human cerebral neocortex contains mRNA coding for tyrosine hydroxylase, the key enzyme for catecholamine biosynthesis. Phosphorylated neurofilament-containing cytoplasmic inclusions occur in these neurons in diffuse Lewy body disease, indicating a tendency for selective involvement that is shared with subcortical catecholamine-containing neurons. These findings are relevant to the pathophysiology of several neurologic and psychiatric illnesses in which the monoamine-containing neurons of the neocortex may participate.

Antibodies, Monoclonal↗

PubMed1989

Distribution of neuropeptide Y-containing perikarya and axons in various neocortical areas in the macaque monkey.

The laminar and areal distribution of neuropeptide Y (NPY)-containing perikarya and their processes was analyzed immunocytochemically in Brodmann's neocortical areas 17, 18, 7, 22, 3, 4, 24, and 9 (Walker's area 46) in seven macaque monkeys. Most NPY-containing cells are distributed in two broad bands in layers II-III and V-VI in all areas; relatively few cells can be found in layer I and virtually none in layer IV. Numerous NPY-containing cells are situated in the white matter immediately subjacent to the cortical gray. Severalfold regional and individual differences in the density of NPY-positive somata were found in supra- and infragranular layers. However, the interareal variations in the density of NPY-containing somata do not conform to a universal pattern, because of either individual variability or inherent difficulties in standardizing immunocytochemical labeling. In contrast, the laminar differences in the distribution of NPY-containing axons among cortical areas are consistent in all animals. In general, primary sensory and motor areas have a lesser density of NPY-containing axons than association and limbic areas. Within the general pattern, area-specific laminar segregation of NPY-containing axons occurs. The regional differences in the distribution of NPY-like immunoreactivity in the neocortex may reflect innate characteristics of local neuronal circuits serving specialized functions.

Animals↗

PubMed1989

Multiple types of neuropeptide Y-containing neurons in primate neocortex.

The avidin-biotin-peroxidase method was used at the light and electron microscopic levels to analyze neuropeptide Y (NPY)-containing neurons in the neocortex of six adult macaque monkeys. Regions studied included various sensory, motor, limbic, and association areas, designated as 17, 18, 7, 22, 3, 4, 6, 24, and 9 by Brodmann (Beiträge zur Histologischen Lokalisation der Grosshirnrinde. Leipzig: Barth, '06). Several types of NPY-containing neurons can be distinguished by their laminar location, by the size of their perikarya, and by the size, shape, and pattern of ramification of their processes: 1) layer I small local circuit neurons; 2) layer II granule cells; 3) aspiny stellate cells located in layers II-III and V-VI, with long, slender dendrites; 4) sparsely spiny stellate cells; 5) aspiny stellate cells with long, horizontally oriented dendrites, whose cell body is situated in layer VI; 6) Martinotti cells in areas 9, 7, and 24; and 7) multipolar neurons situated in the white matter subjacent to the cortical gray. The possibility of additional neuronal types containing NPY is suggested by labeled densely spinous dendrites in area 6 and recurving axons and axonal loops in the supragranular layers in areas 7 and 9. No NPY-containing neurons were found in layer IV of any area, except layers IVA and B of the visual cortex. Likewise, nonneuronal elements were not labeled. The regional differences in the distribution of some NPY-containing neuron types may reflect adaptations of local neuronal circuits for specialized functions.

Animals↗