Biomedical subjects

Dwight C German

Publications and source records attributed to Dwight C German.

11 recordsLinked to original sources

PubMed2006

5HTTLPR polymorphism and enlargement of the pulvinar: unlocking the backdoor to the limbic system.

BACKGROUND: The 5HTTLPR genetic variant of the serotonin transporter (SERT), which consists of a long (SERT-l) and short (SERT-s) allele, has emerged as a major factor influencing emotional behavior and brain anatomy. The pulvinar nucleus of the thalamus projects to important limbic nuclei including the amygdala and cingulate cortex, is involved in the processing of stimuli with emotional content, and contains an abundance of SERT. METHODS: Stereological methods were used to measure pulvinar neuron number in postmortem tissue from major depressive disorder (n = 11), bipolar disorder (n = 11), schizophrenia (n = 12), and control (n = 15) specimens from the Stanley Foundation Neuropathology Consortium. The effect of SERT genotype on pulvinar volume and neuron number was investigated by using analysis of covariance. RESULTS: Analysis of covariance with diagnosis, SERT genotype, age, hemisphere, postmortem interval, and time-in-formalin covariates identified a 20% increase in pulvinar neuron number and volume in SERT-ss subjects. CONCLUSIONS: The elevated number of pulvinar neurons in subjects with a SERT-ss genotype may serve to enhance subcortical input of emotionally relevant stimuli to the limbic system, providing a mechanism for the 5HTTLPR genetic variant to affect predisposition to conditions such as major depression.

Alleles↗

PubMed2006

Mitochondria mass is low in mouse substantia nigra dopamine neurons: implications for Parkinson's disease.

In Parkinson's disease (PD) there is a selective loss of certain midbrain dopaminergic (DA) neurons. The most vulnerable neurons reside in the substantia nigra zona compacta (SNC), whereas the DA neurons in the ventral tegmental area (VTA) and interfascicular (IF) nucleus are less vulnerable to degeneration. Many sporadic PD patients have a defect in mitochondria respiration, and some of the genes that cause PD are mitochondrial-related (e.g., PINK1, Parkin, DJ1). The present study sought to determine whether mitochondria mass is different in SNC neurons compared to other midbrain DA neurons and to non-DA neurons in the mouse. At the electron microscopic level, mitochondria in the SN DA neurons occupy 40% less of the soma and dendritic area than in the SN non-DA neurons. The area occupied by mitochondria in the SN DA neurons is also lower than in the VTA neurons, although not different from the IF neurons. The red nucleus somata have the largest percentage of the somata occupied by mitochondria (12%). Mitochondria size is related to somata size; the largest mitochondria are found in the red nucleus neurons and the smallest mitochondria are found in the IF neurons. At the light microscopic level, SNC, VTA and IF DA neurons have <50% of the cytoplasm immunostained with the mitochondrial antibody 1D6, whereas non-DA neurons in the same midbrain regions contain mitochondria areas up to >65% of the cytoplasm area. These data indicate that mitochondria size and mass are not the same for all neurons, and the SNC DA neurons have relatively low mitochondria mass. The low mitochondria mass in SNC DA neurons may contribute to the selective vulnerability of these neurons in certain rodent models of PD.

Animals↗

PubMed2006

Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease.

Abnormal subgranular zone (SGZ) neurogenesis is proposed to contribute to Alzheimer's disease (AD)-related decreases in hippocampal function. Our goal was to examine hippocampal neurogenesis in the PDAPP mouse, a model of AD with age-dependent accumulation of amyloid-beta(42) (Abeta(42))-containing plaques that is well studied with regard to AD therapies. A secondary goal was to determine whether altered neurogenesis in the PDAPP mouse is associated with abnormal maturation or number of mature cells. A tertiary goal was to provide insight into why hippocampal neurogenesis appears to be increased in AD post-mortem tissue and decreased in most AD mouse models. We report an age-dependent decrease in SGZ proliferation in homozygous PDAPP mice. At 1 year of age, PDAPP mice also had new dentate gyrus granule neurons with abnormal maturation and fewer dying cells relative to control mice. In contrast to decreased SGZ cell birth, PDAPP mice had increased birth of immature neurons in the outer portion of the granule cell layer (oGCL), providing insight into why some studies link AD with increased neurogenesis. However, these ectopic oGCL cells were still rare compared with SGZ proliferating cells, emphasizing that the primary characteristic of PDAPP mice is decreased neurogenesis. The decrease in SGZ neurogenesis was not associated with an age-dependent loss of dentate granule neurons. The altered neurogenesis in the PDAPP mouse may contribute to the age-related cognitive deficits reported in this model of AD and may be a useful adjunct target for assessing the impact of AD therapies.

Aging↗

PubMed2005

The PDAPP mouse model of Alzheimer's disease: locus coeruleus neuronal shrinkage.

Alzheimer's disease is characterized by neuronal degeneration in the cerebral cortex and hippocampus and subcortical neuronal degeneration in such nuclei as the locus coeruleus (LC). Transgenic mice overexpressing mutant human amyloid precursor protein V717F, PDAPP mice, develop several Alzheimer's disease-like lesions. The present study sought to determine whether there is also loss of LC noradrenergic neurons or evidence of degenerative changes in these animals. PDAPP hemizygous and wild-type littermate control mice were examined at 23 months of age, at a time when there are numerous amyloid-beta (Abeta) plaques in the neocortex and hippocampus. Tissue sections were stained immunohistochemically with an antibody against tyrosine hydroxylase (TH) to identify LC neurons. Computer imaging procedures were used to count the TH-immunoreactive somata in sections through the rostral-caudal extent of the nucleus. There was no loss of LC neurons in the hemizygous mice. In a second experiment, homozygous PDAPP and wild-type mice were examined, at 2 months and 24 months of age. Again there was no age-related loss of neurons in the homozygous animals. In the portion of the LC where neurons reside that project to the cortex and hippocampus, however, the neurons were decreased in size selectively in the 24-month-old transgenic animals. These data indicate that overt LC cell loss does not occur following abundant overexpression of Abeta peptide. However, the selective size reduction of the LC neuronal population projecting to cortical and hippocampal regions containing Abeta-related neuropathology implies that these cells may be subjected to a retrograde-mediated stress.

Alzheimer Disease↗

PubMed2005

Molecular, anatomical, and biochemical events associated with neurodegeneration in mice with Niemann-Pick type C disease.

In Niemann-Pick type C (NPC) disease, cholesterol associated with either apoE or apoB100 is taken up by cells in all tissues, including the central nervous system, through clathrin-coated pits and becomes trapped in late endosomes and lysosomes. This study defines the functional, biochemical, and molecular events that ensue as nerve cell death occurs. In mice homozygous for a mutation in NPC1, neuromuscular dysfunction begins at 5 weeks and death occurs at 13 weeks of age. Cholesterol accumulates in every tissue in the body. Purkinje cell loss in the cerebellum begins at 3 to 4 weeks of age and is nearly complete by 11 weeks. This neurodegeneration in the cerebellum is associated with increases in the levels of mRNA for caspase 1, caspase 3, NPC2, LipA, apoE, apoD, glial fibrillary acidic protein, and tumor necrosis factor-alpha, but not for most target genes of the LXR nuclear receptors. The level for apoER2 is significantly reduced. These studies show there is a compensatory increase in NPC2 and LipA in an attempt to overcome the physiological defect caused by the mutation. Nevertheless, neurodegeneration proceeds utilizing apoptosis with activation of glial cells, increased apoE and apoD synthesis, and increased cholesterol turnover across the CNS.

Animals↗

PubMed2004

Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions.

An abundant presynaptic protein, alpha-synuclein, is centrally involved in the pathogenesis of Parkinson's disease. However, conflicting data exist about the normal function of alpha-synuclein, possibly because alpha-synuclein is redundant with the very similar beta-synuclein. To investigate the functions of synucleins systematically, we have now generated single- and double-knockout (KO) mice that lack alpha- and/or beta-synuclein. We find that deletion of synucleins in mice does not impair basic brain functions or survival. We detected no significant changes in the ultrastructure of synuclein-deficient synapses, in short- or long-term synaptic plasticity, or in the pool size or replenishment of recycling synaptic vesicles. However, protein quantitations revealed that KO of synucleins caused selective changes in two small synaptic signaling proteins, complexins and 14-3-3 proteins. Moreover, we found that dopamine levels in the brains of double-KO but not single-KO mice were decreased by approximately 20%. In contrast, serotonin levels were unchanged, and dopamine uptake and release from isolated nerve terminals were normal. These results show that synucleins are not essential components of the basic machinery for neurotransmitter release but may contribute to the long-term regulation and/or maintenance of presynaptic function.

Animals↗

PubMed2004

Inverse relationship between the contents of neuromelanin pigment and the vesicular monoamine transporter-2: human midbrain dopamine neurons.

The dopaminergic neurons in the ventral substantia nigra (SN) are significantly more vulnerable to degeneration in Parkinson's disease (PD) than the dopaminergic neurons in the ventral tegmental area (VTA). The ventral SN neurons also contain significantly more neuromelanin pigment than the dopaminergic neurons in the VTA. In vitro data indicate that neuromelanin pigment is formed from the excess cytosolic catecholamine that is not accumulated into synaptic vesicles by the vesicular monoamine transporter-2 (VMAT2). By using quantitative immunohistochemical methods in human postmortem brain, we sought to examine the relative contents of VMAT2 within neurons that contain different amounts of neuromelanin pigment. The immunostaining intensity (ISI) was measured for VMAT2 and also for the rate-limiting enzyme for the synthesis of dopamine, tyrosine hydroxylase (TH). ISI measures were taken from the ventral SN region where neurons are most vulnerable to degeneration in PD, nigrosome-1 (N1); from the ventral SN region where cells are moderately vulnerable to degeneration in PD, the matrix (M); and from VTA neurons near the exit of the third nerve (subregion III). The data indicate that 1) subregion III neurons have significantly higher levels of VMAT2 ISI compared with N1 neurons (more than twofold) and M neurons (45%); 2) there is an inverse relationship between VMAT2 ISI and neuromelanin pigment in the N1 and III neurons; 3) there is an inverse relationship between VMAT2 ISI and the vulnerability to degeneration in PD in the N1, M, and III subregions; and 4) neurons with high VMAT2 ISI also have high TH ISI. These data support the hypothesis that midbrain dopaminergic neurons that synthesize greater amounts of dopamine have more vesicular storage capacity for action potential-induced release of transmitter and that the ventral SN neurons accumulate the most neuromelanin pigment, in part because they have the least VMAT2 protein.

Adult↗

PubMed2004

Elevated neuron number in the limbic thalamus in major depression.

OBJECTIVE: The mediodorsal and anteroventral/anteromedial nuclei of the thalamus are brain regions of interest in the study of mood disorders because they connect subcortical limbic system structures such as the amygdala with the prefrontal, cingulate, and temporal cortices. Anatomical abnormalities have been observed both in the amygdala and in the aforementioned cortical regions in affective disorder patients. Neuroanatomical studies of the thalamus have rarely been conducted in patients with mood disorders. METHOD: Postmortem tissue from the Stanley Foundation Brain Bank was obtained from subjects diagnosed with major depressive disorder, bipolar disorder, and schizophrenia as well as a nonpsychiatric comparison group (N=10-13 per group). The optical disector stereological procedure was used to count neurons in the mediodorsal and anteroventral/anteromedial nuclei of the thalamus in each brain. RESULTS: There were significantly more neurons in the mediodorsal (37%) and anteroventral/anteromedial (26%) nuclei in subjects with major depressive disorder relative to the nonpsychiatric comparison subjects. Neuron numbers and volumes in these limbic thalamic nuclei were normal in the schizophrenia and bipolar subjects. CONCLUSIONS: The data indicate that there is an elevation in total neuron number in the limbic thalamus that is specific for major depressive disorder. This represents the first report of a neuropsychiatric disorder being associated with an increase in total regional neuron number. The present findings, along with recent data, indicate that significant anatomical and functional abnormalities are present in limbic circuits in major depressive disorder.

Adult↗

PubMed2004

Mouse models of Alzheimer's disease: insight into treatment.

Mice overexpressing mutant Alzheimer's disease (AD)-related proteins exhibit many of the neuropathological and behavioral features of the human disease. Transgenic animals have been created that express mutations in the amyloid precursor protein (APP), presenilin (PS)1, and PS2, and also animals expressing more than one of these mutations. For example, in APP mouse models, there are age-related accumulations of amyloid-beta (Abeta)-containing neuritic plaques in the hippocampus and cerebral cortex, activation of astrocytes and microglial cells in regions containing plaques, and degeneration of cholinergic nerve terminals in brain regions that eventually become plaque containing. Missing in the APP and PS mouse models are neurofibrillary tangles and robust neuronal loss in cerebral cortical and subcortical regions such as the basal forebrain cholinergic and locus coeruleus noradrenergic nuclei. Neurofibrillary tangles can be produced in mice expressing mutant tau protein, and the tangle formation is further enhanced in animals that also express mutant APP. Studies in APP mouse models indicate that, like AD, there are abnormalities in adult hippocampal neurogenesis. The animal models of AD have been used to develop and test treatments that reduce brain levels of the Abeta42 protein, neuritic plaque load and glial activation, and some have been found to restore learning and memory function. If such treatments can be shown to stop the neurodegenerative process and restore hippocampal neurogenesis, damaged brain circuits may be replaceable in patients with AD.

Alzheimer Disease↗

PubMed2003

Cholinergic neuropathology in a mouse model of Alzheimer's disease.

Transgenic mice overexpressing mutant human amyloid precursor protein (PDAPP mice) develop several Alzheimer's disease (AD)-like lesions including an age-related accumulation of amyloid-beta (Abeta)-containing neuritic plaques. Although aged, heterozygous PDAPP mice also exhibit synaptic and glial cell changes characteristic of AD pathology, no evidence of widespread neuronal loss has been observed. The present study sought to determine whether homozygous PDAPP mice, which express very high levels of Abeta peptide, exhibit AD-like cholinergic degenerative changes, and whether the changes parallel the deposition of Abeta plaques. Mice were examined at 2 and 4 months and at 1 and 2 years of age. There was an age-related increase in the density of Abeta plaques in the cortex and hippocampus of the PDAPP animals; at 4 months of age there were very few plaques, and at 2 years there was a very high density of plaques. There was an age-related reduction in the density of cholinergic nerve terminals in the cerebral cortex; at 2 months there was a normal density of nerve terminals, but as early as age 4 months there was an approximately 50% reduction. However, at age 2 years there was no difference in the number or size of basal forebrain cholinergic somata compared with 2-month-old PDAPP mice. These data indicated that the homozygous PDAPP mouse exhibits cholinergic nerve terminal degenerative pathology and that the cortical neurodegenerative changes occur before the deposition of Abeta-containing neuritic plaques.

Acetylcholine↗

PubMed2003

Validation of a near-infrared probe for detection of thin intracranial white matter structures.

OBJECT: The authors have developed an intracranial near-infrared (NIR) probe that analyzes the scattering of light emitted from its tip to measure the optical properties of cerebral tissue. Despite its success in distinguishing graymatter from white matter in humans during stereotactic surgery, the limits of this instrument's resolution remain unclear. In this study, the authors determined the spatial resolution of this new probe by using a rodent model supplemented with phantom measurements and computer simulation. METHODS: A phantom consisting of Intralipid and gelatin was constructed to resemble a layer of white matter overlying a layer of gray matter. Near-infrared measurements were obtained as the probe was inserted through the gray-white matter transition. A computer simulation of NIR measurements through a gray-white matter transition was also performed using Monte Carlo techniques. The NIR probe was then used to study 19 tracks from the cortical surface through the corpus callosum in an in vivo rodent preparation. The animals were killed and histological sections through the tracks were obtained. Data from the phantom models and computer simulations showed that the NIR probe samples a volume of tissue extending 1 to 1.5 mm in front of the probe tip (this distance is termed the "lookthrough" distance). Measurements obtained from an NIR probe passing through a thin layer of white matter consisted of an initial segment of increasing values, a maximum (peak) value, and a trailing segment of decreasing values. The length of the initial segment is the lookthrough distance, the position of the peak indicates the location of the superficial white matter boundary, and the length of the trailing segment is the thickness of the layer. These considerations were confirmed in experiments with rodents. All tracks passed through the corpus callosum, which was demonstrated as a broad peak on each NIR graph. The position of the dorsal boundary of the corpus callosum and its width (based on histological measurements) correlated well with the peak of the NIR curve and its trailing segment, respectively. The initial segments correlated well with estimates of the lookthrough distance. Five of the tracks transected the smaller anterior commissure (diameter 0.2 mm), producing a narrow NIR peak at the correct depth. CONCLUSIONS: Data in this study confirm that the NIR probe can reliably detect and measure the thickness of layers of white matter as thin as 0.2 mm. Such resolution should be adequate to detect larger structures of interest encountered during stereotactic surgery in humans.

Animals↗