RESUMEN
The results of the present study indicate that the density of the beta-adrenergic receptors in the skeletal muscle does not decline with age, despite declines in oxidative capacity both in the skeletal muscle and whole body oxygen consumption. When young rats and old rats of equal body weight trained daily at the same duration and speed for 6 months on the treadmill, skeletal muscle of young and old rats reached the same aerobic capacity. The young demonstrated a significant rise in Bmax of the beta receptors, while the old rats did not change their density of receptors. When both young and old rats had the contractile activity of their skeletal muscle raised to the same level through chronic tonic electrical stimulation, the aerobic-capacity and beta receptor density rose to the same levels in the skeletal muscle. Thus, the contraction-dependent pathway in the senescent muscle appears to function normally given a maximal chronic stimulus via electrical stimulation. These data indicate that the relationship between oxidative capacity, beta-adrenergic receptor properties, exercise training, and aging does not appear to be readily explicable by a single unifying mechanism, but probably resides in the interaction of age with a differential responsiveness of the beta-adrenergic and/or contraction dependent pathway for stimulation of aerobic capacity in the aging skeletal muscle.
Asunto(s)
Envejecimiento/fisiología , Contracción Muscular , Músculo Esquelético/fisiología , Condicionamiento Físico Animal , Receptores Adrenérgicos beta/metabolismo , Animales , Citrato (si)-Sintasa/metabolismo , Estimulación Eléctrica , Masculino , Desarrollo de Músculos , Músculo Esquelético/crecimiento & desarrollo , Consumo de Oxígeno , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas F344 , Receptores Adrenérgicos beta/análisis , Sarcolema/fisiologíaRESUMEN
Chronic administration of sodium azide in rats inhibits cytochrome oxidase and produces learning and memory deficits. The present experiment tested the hypothesis that chronic sodium azide treatment might also alter protein kinase C activation. Continuous infusion of sodium azide (400 micrograms/h, sc) in rats for 2 weeks significantly decreases membrane-bound protein kinase C in hippocampus, but not frontal cortex, temporal cortex, or cerebellum. Since protein kinase C activation is correlated with hippocampus-dependent learning, these results suggest a possible biochemical mechanism for azide-induced impairment of learning.
Asunto(s)
Azidas/farmacología , Hipocampo/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Mutágenos/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Membranas Sinápticas/efectos de los fármacos , Animales , Mapeo Encefálico , Cerebelo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Lóbulo Frontal/efectos de los fármacos , Hipocampo/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Azida Sódica , Lóbulo Temporal/efectos de los fármacosRESUMEN
The effects of oxiracetam on hippocampally-mediated learning performance and hippocampal protein kinase C (PKC) were examined in C57BL/6Ibg (C57) and DBA/2Ibg (DBA) mice. C57 and DBA mice were subjected to daily injections of oxiracetam (50 mg/kg i.p.) or vehicle (0.9% saline) for a total of 9 days. C57 and DBA mice were examined on a modified version of the Morris water maze task and the contextual fear conditioning task on the last 5 or 2 days, respectively, of the 9-day treatment schedule. When compared with controls, C57 and DBA oxiracetam-treated mice showed no difference in motor skill capability to perform these complex learning tasks (swim speed or ability to freeze). Hippocampal PKC activity was measured in cytosolic, loosely-bound, and membrane-bound homogenate fractions. Oxiracetam-treated DBA mice demonstrated a significant increase in spatial learning performance as determined by the Morris task. DBA performance was also improved in contextual learning as determined by the fear conditioning task. The increase in spatial learning performance was correlated to an increase in membrane-bound PKC. No substantial improvements in C57 mice were observed on either learning task nor did hippocampal PKC activity change in response to oxiracetam treatment. These data demonstrate that the learning impairment of DBA mice can be reversed by treatment with a nootropic agent and support previous studies suggesting that PKC may be one mechanism of action for oxiracetam.
Asunto(s)
Hipocampo/fisiopatología , Discapacidades para el Aprendizaje/fisiopatología , Discapacidades para el Aprendizaje/psicología , Aprendizaje/fisiología , Proteína Quinasa C/metabolismo , Pirrolidinas/farmacología , Animales , Condicionamiento Psicológico/efectos de los fármacos , Miedo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Psicotrópicos/farmacología , NataciónRESUMEN
We have reported that C57BL/6 and DBA/2 mice differ in spatial learning performance and associated hippocampal protein kinase C (PKC) activity (Upchurch and Wehner, 1989, Behav Neurosci 103:1251-1258; Wehner et al., 1990, Brain Res 523:181-187) and that physical activity enhances spatial learning with related alterations in protein kinase C (PKC) (Fordyce and Wehner, 1993b, Brain Res 619:111-119). To assess whether physical activity induces alterations in gene expression that may underlie these changes in PKC and learning performance, we examined the effect of physical activity on expression of zif268, a transcription regulatory factor linked to stimulus-induced neuronal plasticity. C57 and DBA mice, 3 months of age, were subjected to acute (one bout) or chronic (8 weeks) physical activity. The mice were then tested on the Morris water maze task for 6 days with subsequent analysis of PKC activity and zif268 mRNA expression. Control DBA mice, which have poor hippocampal-specific learning performance compared to C57 mice (Wehner et al., 1990, Brain Res 523-181-187; Fordyce and Wehner, 1993b, Brain Res 619:111-119; Paylor et al., 1993, Psychobiology 27:11-26), displayed lower basal levels of zif268 mRNA (P < .05). As observed previously, chronic physical activity produced an enhancement in spatial learning performance accompanied by alterations in hippocampal PKC activity in both strains of mice (P < .05). In addition, the present investigation demonstrated that acute physical activity increased mRNA levels of zif268 in hippocampal regions CA1, CA3 and overlying cortex (P < .005) of both C57 and DBA mice. Chronic physical activity suppressed the basal expression of zif268 in C57 mice in CA1 and overlying cortex below control levels. These findings suggest that genetic and activity-dependent regulation of zif268 may influence learning performance.
Asunto(s)
Proteínas de Unión al ADN/biosíntesis , Regulación de la Expresión Génica , Hipocampo/metabolismo , Proteínas Inmediatas-Precoces , Aprendizaje por Laberinto , Ratones Endogámicos C57BL/genética , Ratones Endogámicos DBA/genética , Actividad Motora , Proteínas del Tejido Nervioso/biosíntesis , Factores de Transcripción/biosíntesis , Animales , Proteínas de Unión al ADN/genética , Proteína 1 de la Respuesta de Crecimiento Precoz , Hibridación in Situ , Masculino , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal , Proteína Quinasa C/metabolismo , Especificidad de la Especie , Organismos Libres de Patógenos Específicos , Natación , Factores de Transcripción/genéticaRESUMEN
The effects of physical activity on spatial learning performance and associated hippocampal functioning were examined in C57BL/6Ibg (C57) and DBA/2Ibg (DBA) mice. C57 and DBA mice, 3 months of age, were subjected to 8 weeks of a physical activity regime (consisting of moderate-pace treadmill running 5 days/week, 60 min/day, 0% grade, 12 m/min) or remained sedentary in their cages. Mice were then tested on the Morris water maze task for 6 days followed by 12 days of testing on the place learning-set task (8 trials/day with each task). Both C57 and DBA run mice showed no difference in swim speed compared to controls. Hippocampal protein kinase C (PKC) activity was measured in cytosolic, loosely bound, and membrane-bound homogenate fractions. Mice subjected to the physical activity protocol were compared to sedentary controls from the same set of litters. Physical activity produced a 2- to 12-fold enhancement in spatial learning performance on both the Morris (P < 0.0001) and place learning-set (P < 0.02) probe trials in both C57 and DBA mice. DBA mice, which characteristically perform poorly in comparison to C57 mice, were enhanced to perform similarly to C57 control mice. This physical activity-induced enhancement in spatial learning performance was accompanied by alterations in hippocampal bound PKC activity (P < 0.05). These data provide further support for our previous hypotheses of a PKC activity involvement in spatial learning and enhancement of spatial learning performance in rodents by physical activity. In addition, these data indicate that hippocampal PKC activity may be involved in the physical activity-induced enhancement of spatial learning performance.
Asunto(s)
Hipocampo/fisiología , Aprendizaje , Condicionamiento Físico Animal , Proteína Quinasa C/metabolismo , Percepción Espacial , Análisis de Varianza , Animales , Discriminación en Psicología , Hipocampo/enzimología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Especificidad de la Especie , Estrés Psicológico/fisiopatologíaRESUMEN
C57BL/6Nia and F1(B6xD2)Nia mice were tested on the Morris water maze task for 5 days followed by 12 days of testing on the place learning-set task (8 trials/day with each task). Mice were tested at 3, 14, and 25 months of age. C57 mice, 25 months of age, were significantly impaired in both the Morris and place learning-set task probe trial performance compared to mice 3 months of age (p < 0.05). These aged C57 mice also demonstrated a significant reduction in membrane-bound hippocampal protein kinase C (PKC) activity (p < 0.05) with no significant change in cytosolic PKC activity. F1 mice, however, showed no effect of age on probe trial performance on the spatial learning tasks. In addition, in a comparison of C57 and F1 mice within each age group, F1 mice demonstrated superior learning performance which was accompanied by a significant elevation in PKC activity (p < 0.05). Spatial learning performance of both strains significantly correlated with membrane-bound PKC activity (p < 0.01). These data provide additional support for our previous hypothesis of an involvement of hippocampal PKC activity in spatial learning and suggest that the amount of membrane-bound PKC activity may be a determinant of age-related decline in spatial learning.
Asunto(s)
Envejecimiento/metabolismo , Envejecimiento/psicología , Hipocampo/enzimología , Aprendizaje/fisiología , Proteína Quinasa C/metabolismo , Percepción Espacial/fisiología , Animales , Peso Corporal/fisiología , Membrana Celular/enzimología , Citosol/enzimología , Genotipo , Masculino , Memoria/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Tamaño de los Órganos/fisiología , Análisis de Regresión , Especificidad de la EspecieRESUMEN
A slow freeze/fast thaw tissue preparation gave analogous hippocampal protein kinase C (PKC) activity to a fresh tissue preparation in both C57BL/6 and DBA/2 mice. Both the frozen and fresh preparations demonstrated a 28% reduction in membrane-bound PKC activity in DBA compared to C57 mice which supports our previous findings (14). This DBA-associated reduction was found only in total PKC and not synaptosomal PKC activity suggesting that the PKC difference between C57 and DBA mice may be primarily postsynaptic. This investigation shows that (1) PKC activity obtained from a slow freeze/fast thaw preparation is analogous to activity obtained from fresh tissue and (2) analysis of PKC activity in both a total and synaptosomal preparation may provide additional characterization of PKC differences such as that observed between C57 and DBA mice.
Asunto(s)
Hipocampo/enzimología , Proteína Quinasa C/metabolismo , Sinaptosomas/enzimología , Animales , Congelación , Cinética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Especificidad de la EspecieRESUMEN
The effects of physical activity on spatial memory performance and associated cholinergic function were examined in F344 rats. Cholinergic analysis included resting and depolarization-induced activation of high-affinity choline uptake and muscarinic receptor binding in the hippocampus, parietal cortex and frontal cortex. Rats that were physically trained, using chronic treadmill running, demonstrated significantly enhanced performance on the spatial learning task, both in second trial latency and first and second trial proximity ratio scores (P less than 0.002). Concomitant with enhanced behavioral performance were neurochemical changes of a reduction in hippocampal high-affinity choline uptake, an upregulation of muscarinic receptor density, and an increase in high-affinity choline uptake 24 h after spatial memory testing (P less than 0.05). Spatial memory tested rats demonstrated enhanced depolarization-induced activation of high-affinity choline uptake (P less than 0.001). Rats that were yoked for swim time to spatial memory tested rats did not show any spatial learning-induced alterations in high affinity choline uptake. These spatial learning- and physical activity-induced cholinergic alterations were observed only in the hippocampus, not in the parietal or frontal cortex. These data indicate that the chronic running-induced alterations in hippocampal high-affinity choline uptake and upregulation of muscarinic receptor density, in combination with enhancement of high-affinity choline uptake related to spatial learning, may contribute to the enhanced spatial learning performance of chronic-run rats.
Asunto(s)
Nivel de Alerta/fisiología , Corteza Cerebral/fisiología , Fibras Colinérgicas/fisiología , Aprendizaje Discriminativo/fisiología , Hipocampo/fisiología , Recuerdo Mental/fisiología , Actividad Motora/fisiología , Orientación/fisiología , Receptores Colinérgicos/fisiología , Animales , Mapeo Encefálico , Lóbulo Frontal/fisiología , Masculino , Lóbulo Parietal/fisiología , Ratas , Ratas Endogámicas F344 , Retención en Psicología/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
A decline in muscarinic receptor density of the hippocampus during aging has been previously observed. In the present investigation, the physiological treatments of underfeeding (every-other-day feeding) and exercise (daily treadmill running), initiated at 3 months or 10 months of age, compensated for this age-related decline in hippocampal muscarinic receptor density in F344 rats. Muscarinic receptor density in aged rats, 27 or 24 months of age, was maintained to levels comparable to rats 12 or 10 months of age, respectively. In addition, with the protocols used in this study, underfeeding appeared to be more effective than exercise in muscarinic receptor upregulation.
Asunto(s)
Envejecimiento/patología , Privación de Alimentos/fisiología , Hipocampo/patología , Condicionamiento Físico Animal , Receptores Muscarínicos/análisis , Envejecimiento/metabolismo , Animales , Peso Corporal , Dieta , Hipocampo/química , Leucemia Experimental , Longevidad , Masculino , Proteínas/análisis , Ratas , Ratas Endogámicas F344 , Receptores Muscarínicos/metabolismo , Tasa de Supervivencia , Factores de TiempoRESUMEN
In the present investigation, the effects of physical activity on hippocampal cholinergic function, parietal cortical cholinergic function, and spatial memory were examined in F344 rats. Single bouts of physical activity elevated hippocampal and cortical high affinity choline uptake, whereas chronic physical activity significantly reduced only hippocampal high affinity choline uptake (HACU) and elevated muscarinic (QNB) receptor density. Three weeks prior to the end of the 14-week chronic treadmill running protocol, a group of chronic-run rats and their non-run controls were tested on a stringent version of Whishaw's place learning-set task. Chronic-run rats exhibited enhanced performance on the spatial task by significantly reduced second trial latencies and elevated first and second trial proximity ratio scores. Chronic-run spatial memory tested rats also showed enhanced hippocampal HACU and muscarinic receptor binding. These data indicate that chronic physical activity improves spatial learning performance. This improvement may be due, in part, to a chronic running-induced enhancement of hippocampal cholinergic functioning.
Asunto(s)
Fibras Colinérgicas/fisiología , Aprendizaje Discriminativo/fisiología , Hipocampo/fisiología , Recuerdo Mental/fisiología , Actividad Motora/fisiología , Orientación/fisiología , Lóbulo Parietal/fisiología , Receptores Colinérgicos/fisiología , Percepción Espacial/fisiología , Animales , Mapeo Encefálico , Colina/metabolismo , Masculino , Ratas , Ratas Endogámicas F344 , Receptores Muscarínicos/fisiologíaRESUMEN
Normal aging has been associated with a progressive decline in hippocampal cholinergic function. In the present study, specific markers of hippocampal cholinergic function, high-affinity choline uptake (HACU) and muscarinic quinuclidinylbenzilate (QNB) binding, were shown to be altered by endurance training (6 months of treadmill running, 5 days/week, 30 min/day). HACU and QNB binding were determined in synaptosomes of endurance trained F344 rats and their age-matched sedentary controls. Comparison of synaptosomes of sedentary rats ages 3 months, 12 months and 25 months (distinguished in this paper as young (Y), middle age (MA) and old (O), respectively) showed maximum HACU at 12 months and subsequent reduction in HACU and QNB binding at 25 months (P less than 0.05). This decline at 25 months is consistent with previous reports of an age-related decline in cholinergic function. Endurance trained rats (trained from 6 months to 12 months of age) showed a reduction (P less than 0.02) in HACU and an increase (P less than 0.05) in QNB binding compared to their age-matched sedentary controls whereas endurance trained rats (trained from 19 months to 25 months of age) showed no significant difference in either parameter from their age-matched sedentary controls. From these results, it appears that while both training and normal aging reduce HACU, the reductions may be different in presynaptic mechanism and postsynaptic consequence.