Neurons of origin and fiber trajectory of amygdalofugal projections to the medial preoptic area in syrian hamsters

The amygdaloid neurons of origin and the trajectory of amygdaloid fibers to the medial preoptic area of the adult male Syrian hamster were identified by using horseradish peroxidase (HRP) histochemistry. After iontophoresis of HRP into the medial preoptic area, retrogradely labeled amygdaloid neurons were located in the dorsal and caudal parts of the medial amygdaloid nucleus and throughout the amygdalohippocampal area. No amygdaloid neurons were labeled after HRP applications confined to the most rostral portion of the medial preoptic area (anterior to the body of the anterior commissure). Following more caudal medial preoptic area injections (body of the anterior commissure to the suprachiasmatic nucleus) the distribution of retrogradely labeled cells in the medial amygdaloid nucleus and the amygdalohippocampal area revealed no topographic organization of the amygdalopreoptic connections. When amygdaloid neurons were labeled, the amygdalohippocampal area contained two to five times as many HRP-filled cells as the medial amygdaloid nucleus. Retrogradely transported HRP could be followed from the medial preoptic area to the amygdala through fibers in the dorsomedial quadrant of the stria terminalis. In addition, electrolytic lesions of the stria terminalis prior to iontophoresis of HRP into the medial preoptic area prevented retrograde transport to neurons in both the dorsocaudal medial amygdaloid nucleus and the amygdalohippocampal area. These results confirm earlier observations describing the location of autoradiographically labeled efferents from the medial amygdaloid nucleus to the medial preoptic area and provide new information about the restricted region within the medial amygdaloid nucleus from which these projections arise. They also suggest that, unlike the projections from the medial amygdaloid nucleus to the bed nucleus of the stria terminalis, the efferents to the medial preoptic area travel entirely in the stria terminalis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50043/1/902800106_ftp.pd

Reply from W.F. Maragos and colleagues

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26952/1/0000518.pd

Proteomic Analysis of Protein Expression and Oxidative Modification in R6/2 Transgenic Mice A Model of Huntington Disease

Huntington disease (HD) is a hereditary neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. The genetic defect responsible for the onset of the disease, expansion of CAG repeats in exon 1 of the gene that codes for huntingtin on chromosome 4, has been unambiguously identified. On the other hand, the mechanisms by which the mutation causes the disease are not completely understood yet. However, defects in energy metabolism of affected cells may cause oxidative damage, which has been proposed as one of the underlying molecular mechanisms that participate in the etiology of the disease. In our effort to investigate the extent of oxidative damage occurring at the protein level, we used a parallel proteomic approach to identify proteins potentially involved in processes upstream or downstream of the disease-causing huntingtin in a well established HD mouse model (R6/2 transgenic mice). We have demonstrated that the expression levels of dihydrolipoamide S-succinyltransferase and aspartate aminotransferase increase consistently over the course of disease (10-week-old mice). In contrast, pyruvate dehydrogenase expression levels were found to be decreased in 10-week-old HD transgenic mice compared with young (4-week-old) mice. Our experimental approach also led to the identification of oxidatively modified proteins. Six proteins were found to be significantly oxidized in old R6/2 transgenic mice compared with either young transgenic mice or non-transgenic mice. These proteins are alpha-enolase, gamma-enolase (neuron-specific enolase), aconitase, the voltage-dependent anion channel 1, heat shock protein 90, and creatine kinase. Because oxidative damage has proved to play an important role in the pathogenesis and the progression of Huntington disease, our results for the first time identify specific oxidatively modified proteins that potentially contribute to the pathogenesis of Huntington disease

Glutamate dysfunction in Alzheimer's disease: an hypothesis

Glutamate is a major excitatory neurotransmitter that has been implicated in memory formation and learning. This acidic amino acid also has neurotoxic properties, and in animals produces lesions reminiscent of human neurodegenerative diseases. Here we present evidence that supports the hypothesis that glutamate dysfunction is involved in the pathophysiology of Alzheimer's disease and can account for many of the neurochemical and behavioral deficits observed in this disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26817/1/0000375.pd

Glutamate transmission and toxicity in alzheimer's disease

1. 1. Despite intensive research, the cause of Alzheimer's disease is unknown.2. 2. Glutamate is the major excitatory transmitter of the cerebral cortex and hippocampus and it appears to have an important role in learning and memory. In addition to its transmitter function, glutamate is a neurotoxin which has been implicated in the pathogenesis of a variety of neurodegenerative disorders.3. 3. Glutamate toxicity may play a role in the pathogenesis of Alzheimer's disease.4. 4. Disruption of glutamatergic neurotransmission may account, in part, for the learning and memory deficits of Alzheimer's disease.5. 5. Labeling of the glutamate receptor complex may allow in vivo diagnosis by positron emission tomography.6. 6. Glutamate receptor ligands may provide a means of therapeutic intervention in Alzhefmer's disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27563/1/0000607.pd

A study of cortical and hippocampal NMDA and PCP receptors following selective cortical and subcortical lesions

The neuronal localization of glutamate and phencyclidine (PCP) receptors was evaluated in the cerebral cortex and hippocampal formation of rat CNS using quantitative autoradiography. Scatchard analysis of [3H]glutamate binding in the cortex (layers I and II and V and VI) showed no difference in the total number of binding sites (Bmax) or apparent affinity (Kd) 1 week, 1 month and 2 months following unilateral ibotenate lesions to nucleus basalis of Meynert (nbM) compared to the non-lesioned side. Quisqualic acid displacement of [3H]glutamate in layers I and II, 1 week following nbM destruction, revealed both high- and low-affinity binding sites (representing the quisqualate (QA) and (NMDA) sites, respectively). Compared to the control side, there was no difference in binding parameters for either of the receptors sites. In similarly lesioned animals, the NMDA receptor was specifically labelled with [3H]glutamate and the associated PCP receptor labelled with [3H]N-(1-[2-thienyl]cyclohexyl)3,4-piperidine ([3H]TCP) in adjacent brain sections. For both receptors, there was no change in the total number of binding sites in the cortex following destruction of nbM. On the other hand, virtually all binding to NMDA and PCP receptors was eliminated following chemical destruction of intrinsic cortical neurons. These results suggest that the NMDA/PCP receptor complex does not exist on the terminals of cortical cholinergic afferents. One week after knife cuts of the glutamatergic entorhinal pathway to the hippocampal formation only an approximate 10% reduction of NMDA and PCP receptors was seen in the dentate gyrus. Conversely, selective destruction of the dentate granule cells using colchicine caused a near identical loss of NMDA and PCP receptors (84% vs 92% respectively). It is concluded from these experiments that glutamate and PCP receptors exist almost exclusively on neurons intrinsic to the hippocampal formation and that no more than 10% of NMDA and PCP receptors exist as autoreceptors on glutamatergic terminals.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29507/1/0000594.pd

Estrogen protects against the synergistic toxicity by HIV proteins, methamphetamine and cocaine

BACKGROUND: Human immunodeficiency virus (HIV) infection continues to increase at alarming rates in drug abusers, especially in women. Drugs of abuse can cause long-lasting damage to the brain and HIV infection frequently leads to a dementing illness.To determine how these drugs interact with HIV to cause CNS damage, we used an in vitro human neuronal culture characterized for the presence of dopaminergic receptors, transporters and estrogen receptors. We determined the combined effects of dopaminergic drugs, methamphetamine, or cocaine with neurotoxic HIV proteins, gp120 and Tat. RESULTS: Acute exposure to these substances resulted in synergistic neurotoxic responses as measured by changes in mitochondrial membrane potential and neuronal cell death. Neurotoxicity occurred in a sub-population of neurons. Importantly, the presence of 17beta-estradiol prevented these synergistic neurotoxicities and the neuroprotective effects were partly mediated by estrogen receptors. CONCLUSION: Our observations suggest that methamphetamine and cocaine may affect the course of HIV dementia, and additionally suggest that estrogens modify the HIV-drug interactions

Loss of hippocampal [3H]TCP binding in Alzheimer's disease

We have previously demonstrated a marked loss in (NMDA) receptors in the hippocampus and cerebral cortex of patients dying with dementia of the Alzheimer type (DAT). In addition, we have found that the dissociative anesthetic N-(1-[2-thienyl]cyclohexyl)3,4-piperidine ([3H]TCP) binds to a site whose regional distribution is highly correlated with that of NMDA receptor sites. We studied the binding of [3H]TCP to sections of hippocampi from 8 controls, 12 patients with DAT and 7 patients with other dementias. [3H]TCP binding was significantly reduced in strata pyramidalia of CA1/CA2, CA3 and subiculum of DAT hippocampal formation compared to that of control. Labelled dissociative anestheties could potentially be used with positron emission tomography in the diagnosis of DAT.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26773/1/0000325.pd

Quantitative autoradiographic localization of NMDA, quisqualate and PCP receptors in the frog tectum

An organizing role for the (NMDA) receptor/channel has been suggested in the development of the retinotectal projection in Rana pipiens. The regional distributions of NMDA, phencyclidine (PCP) and quisqualic acid (QA) receptors were quantified using in vitro autoradiography in the tectum of normal and surgically produced 3-eyed juvenile frogs. NMDA and QA receptor binding was highest in the pretectum. Of the tectal layers, the superficial retinotectal synaptic zone, layer 9, had the highest amount of NMDA and QA receptor binding. Moderate binding was observed in layer 5, with little binding in the cellular layer 6. No specific [3H]N-(1-[2-thienyl]cyclohexyl piperidine ([3H]TCP) binding was observed in any of the tectal regions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28018/1/0000454.pd

Resistance to nitroprusside neurotoxicity in perinatal rat brain

Nitric oxide (NO) may mediate some of the toxic effects of the excitatory amino acid (EAA) glutamate when there is overactivation of the (NMDA) receptor. In the developing rodent nervous system, NMDA neurotoxicity peaks at postnatal day 7. To assess whether NO toxicity exhibits a similar developmental profile, we injected the NO generator sodium nitroprusside into the immature and adult rodent hippocampal formation and striatum, using a dose known to damage the adult nervous system. Contrary to our expectations, we found the immature brain highly resistant to the toxic effects of sodium nitroprusside.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31573/1/0000501.pd