Ovarian steroid and neurotoxin models of brain aging in rodents.
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Aging↗
Biomedical subjects
C E Finch
Publications and source records attributed to C E Finch.
Chronic estradiol administration did not cause loss of hypothalamic LHRH or TIDA neurons in young or middle-aged C57BL/6J mice.
Age-related decline in estrous cycle frequency and impaired pre-ovulatory gonadotropin surges at mid-life are modelled in young C57BL/6J mice by chronic (3 months) oral administration of estradiol (E2). However, the cellular events that induce damage to the neuroendocrine center that regulate gonadotropins with age or following E2 treatment are unclear. To address this issue, possible neuron loss was examined in relation to the loss of estrous cyclicity in E2-treated mice, in particular neurons of the hypothalamic luteinizing hormone releasing hormone (LHRH) and/or tuberoinfundibular dopaminergic (TIDA) systems. By immunocytochemical methods, there was no change in the number of LHRH or TIDA neurons in mice that have become acyclic due to age or E2 treatment. We conclude that the onset of acyclicity at middle-age or following chronic E2 treatment is not associated with loss of LHRH or TIDA neurons and that other neuroendocrine changes must be considered for the cause of acyclicity, particularly those involved in the synaptic regulation of LHRH secretion.
Aging↗
Absence of c-fos induction in neonatal rat brain after seizures.
Induction of the proto-oncogene c-fos is often considered to be a marker of increased neuronal activity. We have used in situ hybridization to study the pattern of c-fos expression in limbic structures following kainic acid-induced seizures during the postnatal period in the rat. Prior to postnatal day 13 (P13), seizure activity did not result in c-fos induction in any limbic structure. Between P13 and P25, a gradual increase in c-fos expression was observed in hippocampus and cortical structures. These results were corroborated by nuclear run-off transcription assay. Thus, alterations in c-fos transcription that may facilitate stimulus-transcription coupling occur during postnatal development. The possible relationship between the postnatal maturation of c-fos expression and the increase in susceptibility of specific neuronal populations to seizure-induced cell damage is discussed.
Age Factors↗
Complement C1qB and C4 mRNAs responses to lesioning in rat brain.
These data show the presence of mRNAs for two complement components (C) in the adult rat brain and describe their responses to experimental lesions. Cortical deafferentation caused elevations in striatal C1qB and C4 mRNAs that coincided temporally and overlapped anatomically with the course of degeneration of corticostriatal afferent fibers. By in situ hybridization, C1qB mRNA in the lesioned striatum was colocalized to cells immunoreactive for CR3, a complement receptor found on microglia-macrophages. The mRNA for SGP-2, a putative C inhibitor in rat, showed parallel changes. Similarly, in hippocampus and other brain regions, kainic acid lesions increased C1qB mRNA. The data suggest that microglia-macrophages and possibly other cells in rat brain rapidly up-regulate C-mRNAs in response to deafferentation and local neuron injury. These experimental responses provide models to analyze changes in C components during Alzheimer's disease and other chronic neurodegenerative conditions.
Animals↗
New mRNA probes for hippocampal responses to entorhinal cortex lesions in the adult male rat: a preliminary report.
Three new mRNA responses were found in the hippocampus of the adult male rat after entorhinal cortex lesions (ECL) that induce synaptic reorganization. Hippocampus cDNA libraries were screened by a subtractive hybridization strategy designed to detect ECL-induced mRNAs. Partial sequencing showed clones with similarities to mouse vimentin, ferritin, and polypeptide 7B-2. A sequence similar to mouse SNAP-25 sequence was also detected. Using a mouse SNAP-25 probe, rat SNAP-25 mRNA increased in the hippocampus after ECL.
Animals↗
Amyloid precursor protein mRNA encoding the Kunitz protease inhibitor domain is increased by kainic acid-induced seizures in rat hippocampus.
A 168-nucleotide exon, found in alternatively spliced amyloid precursor protein (APP) mRNAs, encodes a Kunitz protease inhibitor (KPI) domain. Kainic acid (ip) caused a selective increase of KPI mRNA in rat hippocampus. By in situ hybridization, KPI mRNA was induced in the neuronal layers of the hippocampus 11-12 h after the onset of kainate-induced seizures. The kainate-induced elevation of the KPI-containing APP-770 mRNA was blocked by pretreatment with the anticonvulsant pentobarbital. These data suggest that kainate-induced seizures cause alterations in APP RNA stability and/or processing in rat hippocampal neurons.
Amino Acid Sequence↗
Sulfated glycoprotein 2: new relationships of this multifunctional protein to neurodegeneration.
Sulfated glycoprotein 2 (SGP-2) from rat, and similar molecules from cow, dog, human, pig, ram and quail are known by 11 or more acronyms. SGP-2 is associated with the responses of brain and other tissues to injury; it and related molecules are also normally secreted by the adrenal gland, the liver and the testes. The mRNA of this protein is found in increased levels in Alzheimer's disease. In rats, after perforant path or excitotoxin lesions, levels of the protein or mRNA are elevated in astrocytes, and also in neurons. In rats, brain SGP-2 is regulated by gonadal and adrenal steroids. However, these increases after brain lesions may relate to a function that is associated with the human protein, namely that of inhibiting complement-mediated cell lysis. Other activities suggested for SGP-2 are lipid transport and cell-cell interactions, which are consistent with sequence data that predict binding of dinucleotides, heparin and lipids. The emerging neurobiology of SGP-2 encompasses the subjects of cell death, synaptic remodelling, neuroendocrinology and neurodegenerative diseases.
Animals↗
Slow changes of tyrosine hydroxylase gene expression in dopaminergic brain neurons after neurotoxin lesioning: a model for neuron aging.
Slow neuron regression develops during the adult phase of life in select brain systems of mammals. We describe a model in adult rats that resolves several phases in a slow atrophic process that differentially influences levels of mRNA and protein for tyrosine hydroxylase (TH). Responses of striatal dopaminergic markers to 6-hydroxydopamine (6-OHDA) lesions in rats indicated that the striatal terminals maintained TH protein, despite greater than 3-fold loss of TH mRNA in the substantia nigra pars compacta (SNC) cell bodies whose axons project to the striatum. The loss of TH mRNA/cell was progressive up to 9 months, whereas SNC cell body shrinkage stabilized by 3 months post-lesioning. Consideration of possible mechanisms in protein turnover motivated a search for PEST motifs in the TH of rats and other vertebrates that could be a point of regulation by altering the rate of TH protein turnover.
3,4-Dihydroxyphenylacetic Acid↗
Mechanisms in senescence: some thoughts in April 1990.
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Aging↗
Estrogen-induced impairments as a mechanism in reproductive senescence of female C57BL/6J mice.
Reproductive senescence in female C57BL/6J mice is characterized by ovarian, neuroendocrine, and other nonovarian impairments. The studies reported here examined the role of the ovarian hormone estradiol in the development of nonovarian impairments during aging. In Study I, intact or ovariectomized 6-month-old mice were given estradiol valerate (EV; 10 micrograms/gm body wt.) or oil. When these mice were 12 months old (MA), their ovaries were exchanged by grafting with ovaries from 6-month-old mice. In mice not given EV, MA ovaries in young hosts and MA hosts with young ovaries both exhibited about 50% fewer cycles than young hosts with young ovaries. In contrast, MA hosts ovariectomized when young exhibited as many cycles as young hosts, suggesting that the presence of the ovaries contributed to the development of neuroendocrine impairments. Intact MA hosts given EV when young were unable to support any estrous cycles when given young ovarian grafts, whereas MA hosts ovariectomized and given EV when young exhibited impairments similar to intact MA hosts not given EV. In Study II, effects of estradiol implants were examined in cycling 6-month-old (Y) and 9-month-old (MA) mice given small (6 mm) or large (18 mm) implants for 6 weeks. The implants caused a monotonically dose-related decrease in the number of cycles mice exhibited while implants were in place as well as after implants were removed. These studies confirm our previous findings that reproductive senescence entails both ovarian and nonovarian impairments. They furthermore suggest that age-correlated reproductive nonovarian impairments are due in part to the cumulative exposure to ovarian estradiol.
Aging↗
Polygenic influences on the length of oestrous cycles in inbred mice involve MHC alleles.
Genetic influences on female reproductive cycles were analysed in histocompatibility-congenic strains of mice. Oestrous cycles of young, virgin mice of inbred-congenic strains, hybrid crosses (F1), and parental-hybrid backcrosses (F2) were monitored for 3 months. Oestrous cycles were categorized by length (inter-oestrous interval): 4, 5, 6, or 7-14 days. Mice with the following H-2 haplotypes had a greater proportion of 5-day oestrous cycles: H-2b, H-2r, H-2h2, H-2h4, and H-2i5. In contrast, the H-2k and H-2d haplotypes had mostly 4-day oestrous cycles. Influences of H-2 haplotype were seen on two genetic backgrounds, C57BL/10Sn and C3H. Non-H-2 alleles were also implied by different patterns of cycles between strains with the same H-2b haplotype: C57BL/10Sn with predominantly 5-day cycles vs. C57BL/6J with a mix of 4- and 5-day cycles. The genetic basis for strain differences was investigation in F1 hybrids and their backcrosses. F1 hybrids of an H-2b (C57BL/10Sn; 5-day cycles) and an H-2k (B10.BR; 4-day cycles) strain had mostly 5-day cycles, indicating dominance of an H-2b allele(s). However, F1 hybrids from the reciprocal B6 x B10 cross (both H-2b) also display a preponderance of 5-day cycles, indicating dominance of a non-H-2 autosomal allele from the C57BL/10Sn strain. Among F2 mice, a '4-day' phenotype segregated with homozygosity for the k haplotype (P < 0.05, chi 2). These findings demonstrate the influence of genetic differences at the major histocompatibility complex on oestrous cycles.
Alleles↗
Dopa accumulates in the hypothalamic-hypophysial portal vessels and is taken into the anterior pituitary of NSD-1015-treated rodents.
DOPA was measured in the anterior pituitary and hypothalamic-hypophysial portal blood after treatment with NSD-1015, a DOPA decarboxylase inhibitor. NSD-1015 caused DOPA to accumulate in the anterior pituitary of mice and rats, and increased DOPA in the hypothalamic-hypophysial portal blood of rat. Serum prolactin was also increased. Interruption of the anterior pituitary blood supply from the hypothalamic-hypophysial system by cannulation of the entire pituitary stalk eliminated the NSD-1015-induced DOPA accumulation in the rat pituitary. We conclude that DOPA can be taken into the anterior pituitary from the portal blood of NSD-1015-treated rodents and that the anterior pituitary lacks tyrosine hydroxylase activity in both mice and rats.
Animals↗
Differential contributions of ovarian and extraovarian factors to age-related reductions in plasma estradiol and progesterone during the estrous cycle of C57BL/6J mice.
The relative contributions of ovarian and extra-ovarian factors to the altered ovarian steroidal profiles of middle-aged mice were assessed by reciprocal, heterochronic ovarian grafting. Ovaries from cycling, young (2 months), and middle-aged (12 months) mice were exchanged by grafting under the renal capsules. Blood samples were obtained daily at midday throughout the estrous cycle for measurement of estradiol (E2) and 3-4 h after lights-out on proestrus to measure the preovulatory elevation of progesterone (P4). Middle-aged intact mice had lower mean concentrations of E2 during the cycle, no detectable midday preovulatory elevation of E2, and an attenuated preovulatory increase of P4 compared to young mice. Ovarian grafts from young donors failed to increase mean E2 levels of middle-aged mice, but did restore the preovulatory elevation of E2 and preovulatory P4 to levels of young controls. Reciprocal grafting confirmed these findings: ovaries from middle-aged donors in young hosts produced mean E2 levels equivalent to those of young mice but were unable to support a preovulatory increase of E2 or a preovulatory P4 level equivalent to that of young controls. These results reveal differential contributions of ovarian and extra-ovarian factors to age changes in E2 and P4. They indicate that ovarian aging plays an important role in attenuating the preovulatory increase of E2 and P4, but extra-ovarian, presumably neuroendocrine, age changes underlie the mean reduction of E2 levels across the estrous cycle.
Aging↗
Increased synthesis of two polypeptides in area CA1 of the hippocampus in response to repetitive electrical stimulation.
Changes in the pattern of newly synthesized polypeptides were investigated in the in vitro hippocampal slice following exposure to repetitive stimulation with and without the induction of long-term potentiation. Using [35S]methionine labeling of polypeptides and two-dimensional gel electrophoresis, we detected an increase in the rate of synthesis of two polypeptides (48 kDa and 89 kDa) in CA1 in response to repetitive stimulation of the Schaffer collaterals. The synthesis of the 48 kDa polypeptide (pI approximately 6.6) increased 240% in response to high-frequency stimulation (100 Hz) relative to the same protein from unstimulated slices (n = 14), and increased 220% in response to low-frequency stimulation (1 Hz) (n = 5). Blockade of the N-methyl-D-aspartate (NMDA) receptor induced the protein 180%, with no further increase following tetanic stimulation. An 89 kDa doublet (pI approximately 6.8) increased 150% following high-frequency and 140% following low-frequency stimulation. Blockade of the NMDA receptor increased this protein as well (180% of the unstimulated control) and no further increase was observed following high-frequency stimulation. Based on physicochemical and electrophysiological properties, these proteins are not identifiable as any of those previously associated with long-term potentiation or repetitive electrical stimulation.
2-Amino-5-phosphonovalerate↗
Striatal responses to decortication. I. Dopaminergic and astrocytic activities.
Unilateral ablation of the frontal cortex induced 30%-50% decrease of dopamine (DA) concentration in the ipsilateral striatum at 10 and 27 days after lesioning. There were increased ratios of dihydroxyphenylacetic acid (DOPAC): DA and homovanillic acid (HVA): DA by 20%-60% at 10 days post-lesioning, which suggest compensatory increases of DA metabolism. While no change in total striatal tyrosine hydroxylase (TH) polypeptide concentration was found at any post-lesion time, TH catalytic activity was decreased slightly (-25%) at 10 days. Among individual rats, at 3, 10 and 27 days post-lesioning, striatal DA concentration was inversely related to striatal glial fibrillary acidic protein (GFAP) concentration, a marker of astrocytic activity. The loss of DA was observed whether or not DA was normalized to striatal protein, which suggests that DA loss cannot be simply attributed to increased astrocytic proteins. These data suggest reciprocal relationships between the extent of astrocytic reactions after cortical deafferentation and striatal DA loss, which could involve local remodelling without primary damage to the nigro-striatal terminals.
3,4-Dihydroxyphenylacetic Acid↗
Sulfated glycoprotein-2 is increased in rat hippocampus following entorhinal cortex lesioning.
Thios study showed responses of sulfated glycoprotein-2 (SGP-2) in the rat hippocampus after deafferenting lesion. SGP-2 is a plasma protein that also occurs in many peripheral tissues. In some circumstances, elevations of SGP-2 mRNA are associated with cell degeneration and responses to injury. This study used entorhinal cortex lesions (ECL) to partially deafferent the hippocampus by damaging the perforant path and to induce synaptic remodeling. SGP-2 mRNA is increased in hippocampal astrocytes after ECL. Western blot analysis of soluble hippocampal proteins identified 3 major forms of rat SGP-2 protein: a precursor (61 kDa) and 2 reduced subunits at 39.5 and 35 kDa. These forms increased at 4 days post ECL ipsilaterally to the lesion. By immunocytochemistry (ICC), SGP-2 showed an increased immunoreactivity on the lesioned side by 2 days post ECL that continued through 14 days post ECL. Besides immunopositive astrocytes, punctate immunochemical reaction products occurred among the degenerating fibers of the perforant path. We conclude that changes of SGP-2 protein in the hippocampus after ECL occur roughly in parallel with increases of SGP-2 mRNA. The punctate immuno-deposits could represent secreted SGP-2 and may be useful as a marker for degenerating pathways.
Animals↗
Sulfated glycoprotein-2 (SGP-2) mRNA is expressed in rat striatal astrocytes following ibotenic acid lesions.
A combination of in situ hybridization and immunocytochemistry (ICC) was used to identify the cells that contained mRNA for sulfated glycoprotein-2 (SGP-2) in adult male rats after striatal ibotenic acid (IA) lesioning. Astrocytic responses were monitored by ICC for glial fibrillary acidic protein (GFAP). IA lesioning that caused death of striatal neurons also stimulated astrocytic responses as monitored by GFAP and SGP-2. The SGP-2 immunoreactivity showed punctate deposits in the lesioned striatum without any apparent cellular localization. By in situ hybridization combined with ICC, SGP-2 mRNA was localized in astrocytes that were GFAP-immunopositive. These data suggest that reactive astrocytes may express SGP-2 which may be eventually secreted.
Animals↗