Age-related reduction in microcolumnar structure correlates with cognitive decline in ventral but not dorsal area 46 of the rhesus monkey.

The age-related decline in cognitive function that is observed in normal aging monkeys and humans occurs without significant loss of cortical neurons. This suggests that cognitive impairment results from subtle, sub-lethal changes in the cortex. Recently, changes in the structural coherence in mini- or microcolumns without loss of neurons have been linked to loss of function. Here we use a density map method to quantify microcolumnar structure in both banks of the sulcus principalis (prefrontal cortical area 46) of 16 (ventral) and 19 (dorsal) behaviorally tested female rhesus monkeys from 6 to 33 years of age. While total neuronal density does not change with age in either of these banks, there is a significant age-related reduction in the strength of microcolumns in both regions on the order of 40%. This likely reflects a subtle but definite loss of organization in the structure of the cortical microcolumn. The reduction in strength in ventral area 46 correlates with cognitive impairments in learning and memory while the reduction in dorsal area 46 does not. This result is congruent with published data attributing cognitive functions to ventral area 46 that are similar to our particular cognitive battery which does not optimally tap cognitive functions attributed to dorsal area 46. While the exact mechanisms underlying this loss of microcolumnar organization remain to be determined, it is plausible that they reflect age-related alterations in dendritic and/or axonal organization which alter connectivity and may contribute to age-related declines in cognitive performance.

Automated identification of neurons and their locations.

Individual locations of many neuronal cell bodies (>10(4)) are needed to enable statistically significant measurements of spatial organization within the brain such as nearest-neighbour and microcolumnarity measurements. In this paper, we introduce an Automated Neuron Recognition Algorithm (ANRA) which obtains the (x, y) location of individual neurons within digitized images of Nissl-stained, 30 microm thick, frozen sections of the cerebral cortex of the Rhesus monkey. Identification of neurons within such Nissl-stained sections is inherently difficult due to the variability in neuron staining, the overlap of neurons, the presence of partial or damaged neurons at tissue surfaces, and the presence of non-neuron objects, such as glial cells, blood vessels, and random artefacts. To overcome these challenges and identify neurons, ANRA applies a combination of image segmentation and machine learning. The steps involve active contour segmentation to find outlines of potential neuron cell bodies followed by artificial neural network training using the segmentation properties (size, optical density, gyration, etc.) to distinguish between neuron and non-neuron segmentations. ANRA positively identifies 86 +/- 5% neurons with 15 +/- 8% error (mean +/- SD) on a wide range of Nissl-stained images, whereas semi-automatic methods obtain 80 +/- 7%/17 +/- 12%. A further advantage of ANRA is that it affords an unlimited increase in speed from semi-automatic methods, and is computationally efficient, with the ability to recognize approximately 100 neurons per minute using a standard personal computer. ANRA is amenable to analysis of huge photo-montages of Nissl-stained tissue, thereby opening the door to fast, efficient and quantitative analysis of vast stores of archival material that exist in laboratories and research collections around the world.

Extragenic suppressors of the nimX2(cdc2) mutation of Aspergillus nidulans affect nuclear division, septation and conidiation.

The Aspergillus nidulans NIMX(CDC2) protein kinase has been shown to be required for both the G(2)/M and G(1)/S transitions, and recent evidence has implicated a role for NIMX(CDC2) in septation and conidiation. While much is understood of its G(2)/M function, little is known about the functions of NIMX(CDC2) during G(1)/S, septation, and conidiophore development. In an attempt to better understand how NIMX(CDC2) is involved in these processes, we have isolated four extragenic suppressors of the A. nidulans nimX2(cdc2) temperature-sensitive mutation. Mutation of these suppressor genes, designated snxA-snxD for suppressor of nimX, affects nuclear division, septation, and conidiation. The cold-sensitive snxA1 mutation leads to arrest of nuclear division during G(1) or early S. snxB1 causes hyperseptation in the hyphae and sensitivity to hydroxyurea, while snxC1 causes septation in the conidiophore stalk and aberrant conidiophore structure. snxD1 leads to slight septation defects and hydroxyurea sensitivity. The additional phenotypes that result from the suppressor mutations provide genetic evidence that NIMX(CDC2) affects septation and conidiation in addition to nuclear division, and cloning and biochemical analysis of these will allow a better understanding of the role of NIMX(CDC2) in these processes.

Review of immune function, healing of pressure ulcers, and nutritional status in patients with spinal cord injury.

The immune, neural, and endocrine systems do not act autonomously; rather, multiple communicative pathways exist among the nervous, endocrine, and immune systems that facilitate physiological immunoregulation. Patients with spinal cord injury (SCI) have decreased natural and adaptive immune responses by 2 weeks after injury. In patients with SCI, adrenocorticotropic hormone (ACTH) and urine-free cortisol levels were increased while zinc and albumin levels were decreased, respectively. In addition, the surface markers alpha 2, alpha 3, alpha 4, CD11a, CD11b, CD18, CD54, and CD8 found on lymphocytes and alpha 3, alpha 4, CD11a, CD18, and CD8 surface markers found on granulocytes were also decreased in the patient population. Finally, the adhesion molecules binding ability in the SCI group was also decreased when compared with a control group. Overall, the investigation showed that patients with SCI have a decreased immune function, especially succeeding the SCI injury, an impaired nutrition status, and a decreased number of adhesion molecules, all of which contribute to delayed wound healing.

Association of HLA-DQ and -DR alleles with protection from or infection with HIV-1.

Infection with human immunodeficiency virus type 1 (HIV-1) and progression to acquired immune deficiency syndrome (AIDS) are controlled by both host genetic factors and viral factors. The HLA (human leukocyte antigen) region in humans controls immune response functions and tissue rejection and influences susceptibility to neoplasia, autoimmune diseases, and infectious diseases including HIV. Twenty-eight African American and 12 Caucasian patients participated in the study. HLA-DQB1 and HLA-DRB1 genotyping was performed using PCR and sequence-specific oligonucleotide probe reverse hybridization and analyzed with the LiPA Key Typing System and LiPA software. DQB1*0603 was found to be positively associated with HIV-1 infection and with HIV-1 infection in Caucasians but not African Americans. DQB1*03032 frequencies indicate a positive association with protection from HIV-1 infection. It was further found to be protective against HIV-1 infection in Caucasians but not in African Amens. DQB1*0201 was observed more frequently in HIV(+) African Americans than HIV(-) African Americans, suggesting a positive association with HIV-1 infection in this ethnic group. HLA-DRB1*04 exhibited a positive association with HIV-1 infection in Caucasians. These data show that there are HLA class II alleles associated with susceptibility to and protection from HIV-1 infection and that these differ between ethnic groups.

Facilitation of immune function, healing of pressure ulcers, and nutritional status in spinal cord injury patients.

Multiple communicative pathways among nervous, endocrine, and immune systems facilitate physiological immunoregulation. Spinal cord injury (SCI) patients had strikingly decreased natural and adaptive immune responses by 2 weeks post injury. While NK-cell function was decreased, plasma ACTH and urine-free cortisol levels were increased. T cell function and activation were both diminished. With rehabilitation therapy, NK and T function increased; without rehabilitation, NK levels remained depressed. When rehabilitation ceased, NK function decreased. Cervical SCI patients had less NK and T function than thoracic injury patients. SCI patients also had reduced levels of cellular adhesion molecules (CAMs) that participate in immune function and wound healing. SCI patients with pressure ulcers were compared to those without pressure ulcers. LFA-1, VLA-4, and other surface markers were decreased on the lymphocytes of all SCI patients. SCI patients with pressure ulcers had lower CAM levels than did patients without pressure ulcers. Nutritional status was determined by zinc, albumin, and prealbumin levels. SCI patients had decreased albumin levels. Those with pressure ulcers had decreased prealbumin levels and zinc levels.

Induction of Fos protein by antipsychotic drugs in rat brain following kainic acid-induced limbic-cortical neuronal loss.

Antipsychotic drugs increase expression of the immediate early gene, c-fos, in the striatum, nucleus accumbens and prefrontal cortex of rat brain. Since intracerebro-ventricular (i.c.v.) infusion of kainic acid (KA) produces loss of limbic-cortical neurons that project to these brain areas, we postulated that the c-fos responses to antipsychotics in these brain areas would be altered following i.c.v. KA administration. To produce limbic-cortical lesions, rats received i.c.v. infusions of either KA (4.5 nmol) or vehicle. Then, 25 28 days later, rats received 0.13, 0.35, or 1.5 mg/kg haloperidol, 6.3, 17.5, or 30.0 mg/kg clozapine, or saline. In both KA-lesioned and control animals, haloperidol produced greater increases in Fos protein immunoreactivity in the striatum than in limbic-cortical areas, while clozapine produced greater increases in Fos protein immunoreactivity in limbic-cortical areas than in the striatum. In both KA-lesioned and control animals, haloperidol and clozapine administration also produced similar dose-dependent increases in Fos protein immunoreactivity in the striatum and nucleus accumbens. However, the ability of clozapine to increase Fos protein immunoreactivity in the infralimbic prefrontal cortex was significantly enhanced in KA-lesioned rats compared to controls. Since limbic-cortical pathology has been implicated in the negative symptoms of schizophrenia, the enhanced effect of clozapine on limbic-cortical expression of c-fos in KA-lesioned rats may be relevant to understanding clozapine's unusual therapeutic actions in patients with schizophrenia.

From DOPA to Parkinson's disease: the early history of dopamine research.

Dopamine is among the most well-researched neurotransmitters at the present time. For the first half-century of neurotransmitter research, however, interest in dopamine was minimal, and only a few scattered groups of researchers studied it. It was their research that stimulated current interest, and provided the background for our present understanding of this important substance. By the late 1950s, it was clear to these individuals that dopamine served an important physiological role in mammalian brains, and that its role was most likely that of a central nervous system agonist. Soon after this, dopamine, or more specifically the depletion of dopamine, was clearly implicated in Parkinson's disease. This paper looks at the early history of the physiological roles of this intriguing compound.