NGF gene transfer to intrinsic basal forebrain neurons increases cholinergic cell size and protects from age-related, spatial memory deficits in middle-aged rats

2000 ◽  
Vol 875 (1-2) ◽  
pp. 144-151 ◽  
Author(s):  
Ronald L Klein ◽  
Aaron C Hirko ◽  
Craig A Meyers ◽  
Jeremy R Grimes ◽  
Nicholas Muzyczka ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Spatial Memory ◽  
Cell Size ◽  
Basal Forebrain ◽  
Memory Deficits ◽  
Aged Rats ◽  
Middle Aged ◽  
Age Related ◽  
Cholinergic Cell ◽  
Ngf Gene

scholarly journals Enhanced Calcium Buffering in F344 Rat Cholinergic Basal Forebrain Neurons Is Associated With Age-Related Cognitive Impairment

2009 ◽  
Vol 102 (4) ◽  
pp. 2194-2207 ◽  
Author(s):  
David Murchison ◽  
Angelika N. McDermott ◽  
Candi L. LaSarge ◽  
Kathryn A. Peebles ◽  
Jennifer L. Bizon ◽  
...  
Keyword(s):  
Basal Forebrain ◽  
Cholinergic Neurons ◽  
Cognitive Status ◽  
Cognitively Impaired ◽  
Aged Rats ◽  
Middle Aged ◽  
Cholinergic Basal Forebrain ◽  
Age Related ◽  
Forebrain Neurons ◽  
Firing Properties

Alterations in neuronal Ca2+ homeostasis are important determinants of age-related cognitive impairment. We examined the Ca2+ influx, buffering, and electrophysiology of basal forebrain neurons in adult, middle-aged, and aged male F344 behaviorally assessed rats. Middle-aged and aged rats were characterized as cognitively impaired or unimpaired by water maze performance relative to young cohorts. Patch-clamp experiments were conducted on neurons acutely dissociated from medial septum/nucleus of the diagonal band with post hoc identification of phenotypic marker mRNA using single-cell RT-PCR. We measured whole cell calcium and barium currents and dissected these currents using pharmacological agents. We combined Ca2+ current recording with Ca2+-sensitive ratiometric microfluorimetry to measure Ca2+ buffering. Additionally, we sought changes in neuronal firing properties using current-clamp recording. There were no age- or cognition-related changes in the amplitudes or fractional compositions of the whole cell Ca2+ channel currents. However, Ca2+ buffering was significantly enhanced in cholinergic neurons from aged cognitively impaired rats. Moreover, increased Ca2+ buffering was present in middle-aged rats that were not cognitively impaired. Firing properties were largely unchanged with age or cognitive status, except for an increase in the slow afterhyperpolarization in aged cholinergic neurons, independent of cognitive status. Furthermore, acutely dissociated basal forebrain neurons in which choline acetyltransferase mRNA was detected had the electrophysiological profiles of identified cholinergic neurons. We conclude that enhanced Ca2+ buffering by cholinergic basal forebrain neurons may be important during aging.

Late-onset caloric restriction alters skeletal muscle metabolism by modulating pyruvate metabolism

2015 ◽  
Vol 308 (11) ◽  
pp. E942-E949 ◽  
Author(s):  
Chiao-nan (Joyce) Chen ◽  
Shang-Ying Lin ◽  
Yi-Hung Liao ◽  
Zhen-jie Li ◽  
Alice May-Kuen Wong
Keyword(s):  
Energy Metabolism ◽  
Muscle Mass ◽  
Mitochondrial Biogenesis ◽  
Muscle Metabolism ◽  
Muscle Loss ◽  
Aged Rats ◽  
Middle Aged ◽  
Pyruvate Metabolism ◽  
Age Related ◽  
Age Dependent

Caloric restriction (CR) attenuates age-related muscle loss. However, the underlying mechanism responsible for this attenuation is not fully understood. This study evaluated the role of energy metabolism in the CR-induced attenuation of muscle loss. The aims of this study were twofold: 1) to evaluate the effect of CR on energy metabolism and determine its relationship with muscle mass, and 2) to determine whether the effects of CR are age dependent. Young and middle-aged rats were randomized into either 40% CR or ad libitum (AL) diet groups for 14 wk. Major energy-producing pathways in muscles, i.e., glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), were examined. We found that the effects of CR were age dependent. CR improved muscle metabolism and normalized muscle mass in middle-aged animals but not young animals. CR decreased glycolysis and increased the cellular dependency for OXPHOS vs. glycolysis in muscles of middle-aged rats, which was associated with the improvement of normalized muscle mass. The metabolic reprogramming induced by CR was related to modulation of pyruvate metabolism and increased mitochondrial biogenesis. Compared with animals fed AL, middle-aged animals with CR had lower lactate dehydrogenase A content and greater mitochondrial pyruvate carrier content. Markers of mitochondrial biogenesis, including AMPK activation levels and SIRT1 and COX-IV content, also showed increased levels. In conclusion, 14 wk of CR improved muscle metabolism and preserved muscle mass in middle-aged animals but not in young developing animals. CR-attenuated age-related muscle loss is associated with reprogramming of the metabolic pathway from glycolysis to OXPHOS.

Effects of Intraventricular Encapsulated Hngf-Secreting Fibroblasts in Aged Rats

1996 ◽  
Vol 5 (2) ◽  
pp. 205-223 ◽  
Author(s):  
Mark D. Lindner ◽  
Cristin E. Kearns ◽  
Shelley R. Winn ◽  
Beata Frydel ◽  
Dwaine F. Emerich
Keyword(s):  
Morris Water Maze ◽  
Basal Forebrain ◽  
Water Maze ◽  
Genetically Modified ◽  
Learning Task ◽  
Activity Levels ◽  
Aged Rats ◽  
Semipermeable Membranes ◽  
Age Related ◽  
Forebrain Neurons

Exogenous NGF administered into the central nervous system (CNS) has been reported to improve cognitive function in aged rats. However, concerns have been expressed about the risks involved with supplying NGF to the CNS. In this study, baby hamster kidney cells (BHK) genetically modified to secrete human NGF (hNGF) were encapsulated in semipermeable membranes and implanted intraventricularly. ChAT/LNGFR-positive basal forebrain neurons were shown to atrophy and degenerate with age, especially in cognitively impaired rats. The encapsulated BHK-NGF cells produced less than 10% of doses previously reported to be effective, but this was sufficient to increase the size of ChAT/LNGFR-positive basal forebrain neurons in the aged and learning-impaired rats to the size of the neurons in young healthy rats. The hNGF from these encapsulated cells also improved performance in a repeated-acquisition version of the Morris water maze spatial learning task in learning-impaired 20.6- and 26.7- mo-old rats. Furthermore, there was no evidence that these doses of hNGF impaired Morris water maze performance in the youngest 3.3-5.4 mo rats, and analyses of mortality rates, body weights, somatosensory thresholds, potential hyperalgesia, and activity levels, suggested that these levels of exogenous hNGF are not toxic or harmful to aged rats. These results suggest that CNS-implanted semipermeable membranes, containing genetically modified xenogeneic cells continuously producing these levels of hNGF, attenuate age-related cognitive deficits in nonimmunosuppressed aged rats, and that both the surgical implantation procedure and long-term exposure to low doses of hNGF appear safe in aged rats.

scholarly journals Higher levels of estradiol replacement correlate with better spatial memory in surgically menopausal young and middle-aged rats

2008 ◽  
Vol 90 (1) ◽  
pp. 155-163 ◽  
Author(s):  
Joshua S. Talboom ◽  
Brice J. Williams ◽  
Edmond R. Baxley ◽  
Stephen G. West ◽  
Heather A. Bimonte-Nelson
Keyword(s):  
Spatial Memory ◽  
Aged Rats ◽  
Middle Aged

scholarly journals The Excitatory Peptide Kisspeptin Restores the Luteinizing Hormone Surge and Modulates Amino Acid Neurotransmission in the Medial Preoptic Area of Middle-Aged Rats

Endocrinology ◽  
2009 ◽  
Vol 150 (8) ◽  
pp. 3699-3708 ◽  
Author(s):  
Genevieve Neal-Perry ◽  
Diane Lebesgue ◽  
Matthew Lederman ◽  
Jun Shu ◽  
Gail D. Zeevalk ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Preoptic Area ◽  
Gaba Release ◽  
Medial Preoptic Area ◽  
Aged Rats ◽  
Middle Aged ◽  
Lh Surge ◽  
Age Related ◽  
Lh Release ◽  
Estrogen Positive Feedback

Reproductive success depends on a robust and appropriately timed preovulatory LH surge. The LH surge, in turn, requires ovarian steroid modulation of GnRH neuron activation by the neuropeptide kisspeptin and glutamate and γ-aminobutyric acid (GABA) neurotransmission in the medial preoptic area (mPOA). Middle-aged females exhibit reduced excitation of GnRH neurons and attenuated LH surges under estrogen-positive feedback conditions, in part, due to increased GABA and decreased glutamate neurotransmission in the mPOA. This study tested the hypothesis that altered kisspeptin regulation by ovarian steroids plays a role in age-related LH surge dysfunction. We demonstrate that middle-aged rats exhibiting delayed and attenuated LH surges have reduced levels of Kiss1 mRNA in the anterior hypothalamus under estrogen-positive feedback conditions. Kisspeptin application directly into the mPOA rescues total LH release and the LH surge amplitude in middle-aged rats and increases glutamate and decreases GABA release to levels seen in the mPOA of young females. Moreover, the N-methyl-d-aspartate receptor antagonist MK801 blocks kisspeptin reinstatement of the LH surge. These observations suggest that age-related LH surge dysfunction results, in part, from reduced kisspeptin drive under estrogen-positive feedback conditions and that kisspeptin regulates GnRH/LH release, in part, through modulation of mPOA glutamate and GABA release.

scholarly journals Effects of β-adrenergic receptor agonists on drinking and arterial blood pressure in young and old rats

2011 ◽  
Vol 300 (4) ◽  
pp. R1001-R1008 ◽  
Author(s):  
Robert L. Thunhorst ◽  
Connie L. Grobe ◽  
Terry G. Beltz ◽  
Alan Kim Johnson
Keyword(s):  
Blood Pressure ◽  
Arterial Blood Pressure ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Aged Rats ◽  
Middle Aged ◽  
Young Rats ◽  
Arterial Blood ◽  
Age Related ◽  
Old Rats

These experiments examined water-drinking and arterial blood pressure responses to β-adrenergic receptor activation in young (4 mo), “middle-aged” adult (12 mo), and old (29 mo) male rats of the Brown-Norway strain. We used isoproterenol to simultaneously activate β1- and β2-adrenergic receptors, salbutamol to selectively activate β2-adrenergic receptors, and the combination of isoproterenol and the β2-adrenergic receptor antagonist ICI 118,551 to stimulate only β1-adrenergic receptors. Animals received one of the drug treatments, and water drinking was measured for 90 min. About 1 wk later, animals received the same drug treatment for measurement of arterial blood pressure responses for 90 min. In some rats, levels of renin and aldosterone secretion in response to isoproterenol or salbutamol were measured in additional tests. Old and middle-aged rats drank significantly less after isoproterenol than did young rats and also had greater reductions in arterial blood pressure. Old and middle-aged rats drank significantly less after salbutamol than did young rats, although reductions in arterial blood pressure were equivalent across the ages. The β2-adrenergic antagonist ICI 118,551 abolished drinking after isoproterenol and prevented most of the observed hypotension. Renin secretion after isoproterenol and salbutamol was greater in young rats than in middle-aged rats, and wholly absent in old rats. Aldosterone secretion was reduced in old rats compared with young and middle-aged rats after treatment with isoproterenol, but not after treatment with salbutamol. In conclusion, there are age-related differences in β-adrenergic receptor-mediated drinking that can be explained only in part by age-related differences in renin secretion after β-adrenergic receptor stimulation.

scholarly journals Hypotension- and osmotically induced thirst in old Brown Norway rats

2009 ◽  
Vol 297 (1) ◽  
pp. R149-R157 ◽  
Author(s):  
Robert L. Thunhorst ◽  
Terry G. Beltz ◽  
Alan Kim Johnson
Keyword(s):  
Arterial Pressure ◽  
Brown Norway ◽  
Aged Rats ◽  
Middle Aged ◽  
Young Rats ◽  
Age Related ◽  
Cellular Dehydration ◽  
Old Rats ◽  
Middle Aged Adult ◽  
Norway Rats

Compared to young cohorts, old rats drink less water in response to several thirst-inducing stimuli. In these experiments, we characterized water drinking in response to hypotension and cellular dehydration in young (4 mo), middle-aged adult (12 mo) and old (29–30 mo) male Brown Norway rats. We injected the vasodilator, minoxidil as an intravenous bolus in a range of doses (0–20 mg/kg), so that drinking responses could be compared at equivalent reductions of arterial pressure. Old rats had greatly diminished reflex tachycardia and became significantly more hypotensive after minoxidil compared with young and middle-aged rats. When compared at equivalent reductions of arterial pressure, old rats drank one-third as much as middle-aged rats, and one-fifth as much as young rats. In addition, there were age-related deficits in drinking in response to a range of administered loads of sodium (0.15–2 M NaCl, 2 ml/100 g body wt). Urinary excretion of water and sodium in response to the loads was equivalent across ages. Both middle-aged and old rats were less able than young rats to repair their water deficits after sodium loading, attributable almost entirely to their reduced drinking responses compared with young rats. Lastly, age-related declines in drinking appeared to be more severe in response to hypotension than in response to cellular dehydration.

Age-related changes in carotid vascular responses to adenosine and nitric oxide in the rat: in vitro and in vivo studies

2010 ◽  
Vol 109 (2) ◽  
pp. 305-313 ◽  
Author(s):  
Nisreen Mansour Omar ◽  
Janice M. Marshall
Keyword(s):  
Carotid Artery ◽  
Cerebral Autoregulation ◽  
No Synthase ◽  
Aged Rats ◽  
Middle Aged ◽  
Juvenile Rats ◽  
Age Related ◽  
Carotid Circulation

We investigated how the ability of adenosine to release nitric oxide (NO) from carotid artery in vitro, and dilator responses evoked in carotid circulation in vivo by systemic infusion of adenosine, change with age in rats of 4–5, 10–12, and 42–44 wk (juvenile, mature, and middle aged). A secondary aim was to follow age-related changes in carotid/cerebral autoregulation. In opened carotid artery, graded doses of adenosine evoked graded increases in NO output measured with a NO sensor that were greater in mature and middle-aged than juvenile rats. Infusion of adenosine to reduce mean arterial pressure (ABP) to ∼60 mmHg increased carotid vascular conductance (CVC) in all groups, but the increase was larger in mature rats; carotid blood flow (CBF) was unchanged in juvenile, increased in mature, but fell in 4/8 middle-aged rats. The NO synthase inhibitor nitro l-arginine methyl ester (l-NAME; 10 mg/kg iv) increased baseline ABP in all groups but caused larger percentage reductions in baseline CVC and CBF in mature and middle-aged than juvenile rats. Thereafter, the adenosine-evoked increase in CVC was unchanged in juvenile and middle-aged rats, yet CBF remained constant in juvenile but increased in middle-aged rats. In mature rats, the evoked increases in CVC and CBF were attenuated and further attenuated by l-NAME at 30 mg/kg. We propose that the ability of adenosine to release NO and cause vasodilation in the carotid artery and its circulation is greater in mature, than juvenile or middle-aged rats, but NO has greater tonic dilator influence in carotid circulation of mature and middle-aged than juvenile rats. By middle age, the lower limit of cerebral autoregulation has increased such that the tonic dilator influence of NO on ABP and CVC limits autoregulation of CBF to depressor responses. However, partial NO synthase inhibition overcomes this impairment, raising baseline ABP and allowing adenosine-evoked increases in CVC to increase CBF.

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