Age-Related Changes in Plasma Catecholamine Responses to Acute Swim Stress

Young adult (3 months) and aged (22 months) Fischer 344 male rats were prepared with chronic tail artery catheters. Three days after surgery, rats were exposed acutely to swim stress at 20, 25, 30, or 35°C for 15 min. Blood samples were obtained from each rat under basal conditions, at the end of the swim stress episode, and 15, 30, and 45 min after swim stress. Basal plasma levels of norepinephrine and epinephrine (EPI) were similar for 3- and 22-month-old rats. In contrast, plasma catecholamine responses of aged rats were significantly greater than those of young adult rats following swim stress at 20 and 25°C. Plasma catecholamine responses were similar for rats of the two ages following swim stress at 30 or 35°C. These findings indicate that aged rats have exaggerated sympathetic-adrenal medullary responses to acute swim stress at the lower water temperatures. Given the modulatory effects of plasma EPI on memory, these age-related alterations in plasma catecholamine responses to acute swim stress may influence spatial memory performance of rats in the Morris water maze.     

Leisure activities, caregiving demands and catecholamine levels in dementia caregivers

This study examined whether satisfaction from leisure activities moderates the relationship between caregiving demands (i.e., hours per day spent caring for a spouse with dementia) and resting levels of the catecholamines norepinephrine (NE) and epinephrine (EPI). Spousal caregivers (n?=?107; mean age?=?73.95?±?8.12 years) were assessed in home for plasma levels of NE and EPI, amount of care provided, and leisure satisfaction. Regression was used to determine whether leisure satisfaction moderated the relationship between hours providing care per day and catecholamine levels. A significant interaction was found between hours caregiving and leisure satisfaction for NE, but not for EPI. Post?hoc regressions were conducted for both NE and EPI. At low leisure satisfaction, time spent caring for a spouse was positively associated with plasma NE (β?=?0.41; p?=?0.005) and EPI (β?=?0.44; p?=?0.003). In contrast, at high levels of satisfaction, time caregiving was not significantly associated with plasma NE (β?=?-0.08; p?=?0.57) or EPI (β?=?0.23; p?=?0.12). These findings suggest that leisure satisfaction may protect caregivers from increases in catecholamines, which have been implicated in cardiovascular risk. Further support for these findings may impact psychological treatments for distressed caregivers.     

Leisure activities,caregiving demands and catecholamine levels in dementia caregivers

This study examined whether satisfaction from leisure activities moderates the relationship between caregiving demands (i.e., hours per day spent caring for a spouse with dementia) and resting levels of the catecholamines norepinephrine (NE) and epinephrine (EPI). Spousal caregivers (n?=?107; mean age?=?73.95?±?8.12 years) were assessed in home for plasma levels of NE and EPI, amount of care provided, and leisure satisfaction. Regression was used to determine whether leisure satisfaction moderated the relationship between hours providing care per day and catecholamine levels. A significant interaction was found between hours caregiving and leisure satisfaction for NE, but not for EPI. Post hoc regressions were conducted for both NE and EPI. At low leisure satisfaction, time spent caring for a spouse was positively associated with plasma NE (β?=?0.41; p?=?0.005) and EPI (β?=?0.44; p?=?0.003). In contrast, at high levels of satisfaction, time caregiving was not significantly associated with plasma NE (β?=?–0.08; p?=?0.57) or EPI (β?=?0.23; p?=?0.12). These findings suggest that leisure satisfaction may protect caregivers from increases in catecholamines, which have been implicated in cardiovascular risk. Further support for these findings may impact psychological treatments for distressed caregivers.     

Regional brain catecholamines and memory: effects of footshock, amygdala implantation, and stimulation

Previous findings have revealed a correlation between post-training release of whole brain norepinephrine (NE) and later retention performance. The present experiment examined changes after a training footshock in NE levels, as well as the levels of the major central NE metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), dopamine (DA), and epinephrine (EPI) in eight brain regions. Brain levels of these amines and the metabolite were assessed 10 min after training in a one-trial inhibitory (passive) avoidance task. The results indicate that NE levels decreased significantly in neocortex, neostriatum, hypothalamus, frontal pole, septum, and brainstem, but not in hippocampus or thalamus. The decreases in NE levels were generally accompanied by increases in MHPG; the MHPG/NE ratio increased significantly in all areas in which decreases in NE were observed. DA levels decreased in neostriatum and increased in neocortex and brainstem. Epinephrine levels decreased only in the brainstem sample. Thus, the effects of training on NE are widespread, probably reflecting the release of the amine in most brain regions. Such findings are consistent with the view that posttraining release of brain NE may modulate the storage of new information in many brain regions. One especially potent treatment for modulating memory storage is electrical stimulation of the amygdala. Therefore, we also examined the effects of amygdala implantation and stimulation on brain catecholamine levels to determine whether such changes might be correlated with the effects of amygdala stimulation on memory. The results indicate that electrode implantation into the amygdala results in pervasive changes in NE levels in most brain regions tested. Against this modified baseline, the results of training and electrical stimulation were region specific and very difficult to interpret. The major conclusion which can be derived from this portion of the experiment is that the amygdala damage produced by electrode implantation produces a brain which is substantially different from that of intact animals.     

Neurotransmitter release during delay eyeblink classical conditioning: role of norepinephrine in consolidation and effect of age

Delay classical eyeblink conditioning (EBC) is an important model of associative, cerebellar-dependent learning. Norepinephrine (NE) plays a significant modulatory role in the acquisition of learning; however, other neurotransmitters are also involved. The goal was to determine whether NE, gamma-aminobutyric acid (GABA) and glutamate (GLU) release are observed in cerebellar cortex during EBC, and whether such release was selectively associated with training. Further studies examined the role of the beta-noradrenergic receptor in consolidation of the learned response by local infusion of propranolol at 5-120 min following training into the cerebellar cortex. In vivo microdialysis coupled to EBC was performed to examine neurotransmitter release. An increase in the extracellular level of NE was observed during EBC and was maximal on day 1 and diminished in amplitude with subsequent days of training. No changes in baseline NE release were observed in pseudoconditioning indicating that NE release is directly related to the associative learning process. The extracellular levels of GABA were also increased selectively during paired training however, the magnitude of GABA release increased over days of training. GLU release was observed to increase during both paired and unpaired training, suggesting that learning does not occur prior to the information arriving in the cerebellum. When propranolol was administered at either 5-, 60-, or 120-min post-training, there was an inhibition of conditioned responses, these data support the hypothesis that NE is important for consolidation of learning. In another set of experiments we demonstrate that the timing of release of NE, GABA and glutamate are significantly delayed in onset and lengthened in duration in the 22-month-old F344 rats. Over days of training the timing of release becomes closer to the timing of training and this is associated with increased learning of conditioned responses in the aged rats.     

Predictability of chronic intermittent stress: effects on sympathetic-adrenal medullary responses of laboratory rats

This experiment involved an examination of sympathetic-adrenal medullary responses of laboratory rats following exposure to chronic intermittent stress. Animals were assigned at random to one of three groups: (i) controls, handled briefly each day; (ii) restraint stress (RS), restrained for 30 min per day; or (iii) variable stress (VS), exposure to restraint, cold swim, or intermittent footshock during one of five time periods each day. On the 26th day, rats were prepared with chronic tail artery catheters for remote sampling of blood and direct measurement of mean arterial pressure and heart rate. On Day 28, rats of each group were exposed to 30 min of restraint stress and timed blood samples were collected and later analyzed for content of norepinephrine (NE) and epinephrine (EPI). VS rats gained significantly less body weight compared to control and RS rats. Basal measures of blood pressure and heart rate and of plasma NE and EPI were comparable for rats of the three groups. The plasma catecholamine responses to restraint stress on Day 28 were significantly reduced in RS and VS rats compared to first-time stressed controls. These findings suggest that predictability of the type of stressor and the time of its occurrence does not influence the pattern of diminished sympathetic-adrenal medullary responses of animals exposed to chronic intermittent stress.     

Choline Uptake in the Frontal Cortex Is Proportional to the Absolute Error of a Temporal Memory Translation Constant in Mature and Aged Rats

The relationship between the magnitude of the error in the content of temporal memory and sodium-dependent high-affinity choline uptake (SDHACU) in the frontal cortex and hippocampus was examined in mature (10- to 16-month-old) and aged (24- to 30-month-old) male rats. The peak time of the response rate distribution that relates the probability of a response to signal duration in a 20-s peak-interval timing procedure was used to index the remembered time of reinforcement. Regression analyses indicated that SDHACU in the frontal cortex of both mature and aged rats and in the hippocampus of aged rats is proportional to the absolute error in the content of temporal memory. These biochemical effects of peak-interval training were also compared with biochemical measures taken from control rats that received random-interval training. This comparison indicated that the observed changes in SDHACU were dependent upon the predictability of the programmed time of reinforcement and age-related changes in memory encoding and retrieval.     

Brain catecholamines and memory modulation: effects of footshock, amygdala implantation, and stimulation

The results of previous studies indicate that the extent of a transient decline in brain norepinephrine (NE) levels shortly after training and administration of any of several memory modulating treatments is correlated with later retention performance. The present experiment assessed such changes after one-trial inhibitory (passive) avoidance training and, in addition, measured concentration changes in 3-methoxy-4-hydroxyphenylglycol (MHPG), the major metabolite of brain NE, as well as dopamine (DA) and epinephrine (EPI) levels. The results indicate that the decreases in brain NE after footshock are accompanied by an increase in MHPG, thus providing additional evidence that brain NE is released after training. DA levels were unchanged after training; brainstem EPI levels increased after the training footshock, but forebrain EPI levels were unchanged. A second experiment examined brain catecholamine levels in animals which received post-training electrical stimulation of the amygdala. The findings of this experiment indicate that the amygdala damage which accompanies electrode implantation apparently results in a chronic change in whole brain NE levels and metabolism. After amygdala, NE concentrations in both brainstem and forebrain samples were reduced by 20% and MHPG was increased by 22-34%. Furthermore, NE levels were not responsive to training in implanted animals. Thus, brain NE levels after training were not predictive of retention performance in amygdala-implanted or -stimulated animals. However, the significance of such findings for understanding the possible role of central NE in memory storage is complicated by the severe modification of the dynamics of brain aminergic systems in animals bearing amygdala electrodes.     

Developmental changes in the perception of adult facial age

The author studied children's (aged 5-16 years) and young adults' (aged 18-22 years) perception and use of facial features to discriminate the age of mature adult faces. In Experiment 1, participants rated the age of unaltered and transformed (eyes, nose, eyes and nose, and whole face blurred) adult faces (aged 20-80 years). In Experiment 2, participants ranked facial age sets (aged 20-50, 20-80, and 50-80 years) that had varying combinations of older and younger facial features: eyes, noses, mouths, and base faces. Participants of all ages attended to similar facial features when making judgments about adult facial age, although young children (aged 5-7 years) were less accurate than were older children (aged 9-11 years), adolescents (aged 13-16 years), and young adults when making facial age judgments. Young children were less sensitive to some facial features when making facial age judgments.     

Enhanced release of norepinephrine in rat hippocampus during spontaneous alternation tests

Recent evidence suggests that release of acetylcholine (ACh) in the hippocampus is associated with performance on a spontaneous alternation task and with enhancement of that performance by systemic and central injections of glucose. The present study extended these findings by examining norepinephrine (NE) release in the hippocampus using in vivo microdialysis while rats were tested for spontaneous alternation performance with and without prior injections (ip) of glucose. Microdialysis samples were collected every 12 min and assayed for NE content by HPLC-ECD. Like ACh, NE release in hippocampus increased during spontaneous alternation testing. As in past experiments, administration of glucose (250 mg/kg) significantly enhanced alternation scores. However, glucose did not influence NE release either during behavioral testing or at rest. These findings contrast with prior evidence showing that glucose augments testing-related increases in ACh release. The findings suggest that norepinephrine is released within the hippocampus while rats are engaged in alternation performance. However, increased release of norepinephrine apparently does not contribute to the enhancement of alternation scores produced by glucose.     

Preserved spatial memory in old rats survives 10 months without training

Aged rats with extensive prior training on the radial maze retain the capacity for accurate spatial working memory (WM) for at least 3 months without practice. To investigate the temporal limits of this influence of prior experience we compared the reacquisition of spatial WM by a group of experienced 21.5-month-old rats to the original acquisition by naive 3-month-old rats. The aged rats had received 225 radial maze tests between 3 and 11 months of age. Despite 10 months without practice the old rats rapidly reacquired critical performance. Their reacquisition was markedly superior to original learning by the young rats, even when delays as long as 5 h were imposed between the rats' fourth and fifth choices during the daily tests in the eight-arm maze. Additional tests showed that neither young nor old rats employed a response strategy to maintain accurate spatial WM performance. Experience clearly confers long-lived protection against the otherwise deleterious effects of aging on spatial WM, but the mechanism by which this influence arises is unknown.     

Evidence for a young adult face bias in accuracy and consensus of age estimates

Adults' face processing may be specialized for the dimensions of young adult faces. For example, young and older adults exhibit increased accuracy in normality judgments and greater agreement in attractiveness ratings for young versus older adult faces. The present study was designed to examine whether there is a similar young adult face bias in facial age estimates. In Experiment 1, we created a face age continuum by morphing an averaged young adult face with an averaged older adult face in 5% increments, for a total of 21 faces ranging from 0 to 100% old. Young and older adults estimated facial age for three stimulus age categories [young (morphs 0–30%), middle‐aged (morphs 35–65%), and older adult (morphs 70–100%)]. Both age groups showed the least differentiation in age estimates for young adult faces, despite showing greater consensus across participants in estimates for young faces. In Experiment 2, young and older adults made age estimates for individual young and older adult identities. Both age groups were more accurate and showed greater consensus in age estimates for young faces. Collectively, these results provide evidence for a bias in processing young adult faces beyond that which is often observed in recognition and normality/attractiveness judgment tasks.     

Age differences in within-session habituation of exploratory behavior: effects of stimulus complexity

The effects of age on the habituation of exploratory behavior of 8-month- and 28-month-old male C57BL/NNia mice were examined under three different stimulus complexity conditions. Increases in the degree of stimulus complexity resulted in an attenuation of between-session habituation and an initial disruption of within-session habituation by 8-month-old mice. Although increases in stimulus complexity also resulted in an increase in the overall level of exploration by aged mice, stimulus complexity was not found to have a systematic effect on between- or within-session habituation by aged mice. No between-session habituation was observed in aged mice under any of the stimulus complexity conditions. Further, aged mice exhibited significant within-session increases, rather than decreases, in exploration under each stimulus complexity condition. This disruption of within-session habituation in aged mice was found to persist over four daily test sessions. In view of the specific patterns of exploration by aged mice, the disruption of within-session habituation was attributed to age-related differences in reactivity to the arousal-inducing properties of novel stimuli.     

Plasma membrane ordering agent pluronic F-68 (PF-68) reduces neurotransmitter uptake and release and produces learning and memory deficits in rats

A substantial body of evidence indicates that aged-related changes in the fluidity and lipid composition of the plasma membrane contribute to cellular dysfunction in humans and other mammalian species. In the CNS, reductions in neuronal plasma membrane order (PMO) (i.e., increased plasma membrane fluidity) have been attributed to age as well as the presence of the β-amyloid peptide-25-35, known to play an important role in the neuropathology of Alzheimer's disease (AD). These PMO increases may influence neurotransmitter synthesis, receptor binding, and second messenger systems as well as signal transduction pathways. The effects of neuronal PMO on learning and memory processes have not been adequately investigated, however. Based on the hypothesis that an increase in PMO may alter a number of aspects of synaptic transmission, we investigated several neurochemical and behavioral effects of the membrane ordering agent, PF-68. In cell culture, PF-68 (nmoles/mg SDS extractable protein) reduced [³H]norepinephrine (NE) uptake into differentiated PC-12 cells as well as reduced nicotine stimulated [³H]NE release. The compound (800–2400 μg/kg, i.p., resulting in nmoles/mg SDS extractable protein in the brain) decreased step-through latencies and increased the frequencies of crossing into the unsafe side of the chamber in inhibitory avoidance training. In the Morris water maze, PF-68 increased the latencies and swim distances required to locate a hidden platform and reduced the time spent and distance swam in the previous target quadrant during transfer (probe) trials. PF-68 did not impair performance of a well-learned working memory task, the rat delayed stimulus discrimination task (DSDT), however. Studies with ¹⁴C-labeled PF-68 indicated that significant (pmoles/mg wet tissue) levels of the compound entered the brain from peripheral (i.p.) injection. No PF-68 related changes were observed in swim speeds or in visual acuity tests in water maze experiments, rotorod performance, or in tests of general locomotor activity. Furthermore, latencies to select a lever in the DSDT were not affected. These results suggest that PF-68 induced deficits in learning and memory without confounding peripheral motor, sensory, or motivational effects at the tested doses. Furthermore, none of the doses induced a conditioned taste aversion to a novel 0.1% saccharin solution indicating a lack of nausea or gastrointestinal malaise induced by the compound. The data indicate that increases in neuronal plasma membrane order may have significant effects on neurotransmitter function as well as learning and memory processes. Furthermore, compounds such as PF-68 may also offer novel tools for studying the role of neuronal PMO in mnemonic processes and changes in PMO resulting from age-related disorders such as AD.     

Individual Differences in Spatial Memory and Striatal ChAT Activity among Young and Aged Rats

Individual differences in spatial memory among young and aged rats were assessed using memory tasks related to integrity of the hippocampus and the neostriatum. Relationships were then examined between measures of spatial memory and regional choline acetyltransferase (ChAT) activity, a marker for cholinergic integrity. Twenty-four-month-old Long-Evans rats were impaired in comparisons with 6-month-old rats on measures of place learning, working memory, reference memory, and perseveration in water-maze tasks. Aged rats that were impaired on one measure of memory, however, were not necessarily impaired on other measures. ChAT activity in the ventromedial and dorsolateral neostriatum of aged rats was significantly reduced in comparisons with young rats whereas no difference was found in the hippocampus. Aged rats with the most ChAT activity in the anterior ventromedial neostriatum performed best on the place-learning and reference memory tasks but also made the most perseverative errors on the working memory task. In addition, young and aged rats with the most ChAT activity in the anterior dorsolateral neostriatum were those with the least accurate working memory. No relationships were found between ChAT activity in the hippocampus and spatial memory. Thus age-related memory impairment has components that can be segregated by measuring relationships between cholinergic integrity in subregions of the anterior neostriatum and memory tasks with different strategic requirements.     

The role of the anterodorsal thalami nuclei in the regulation of adrenal medullary function, beta-adrenergic cardiac receptors and anxiety responses in maternally deprived rats under stressful conditions

Maternal separation can interfere with growth and development of the brain and represents a significant risk factor for adult psychopathology. In rodents, prolonged separation from the mother affects the behavioral and endocrine responses to stress for the lifetime of the animal. Limbic structures such as the anterodorsal thalamic nuclei (ADTN) play an important role in the control of neuroendocrine and sympathetic-adrenal function. In view of these findings we hypothesized that the function of the ADTN may be affected in an animal model of maternal deprivation. To test this hypothesis female rats were isolated 4.5 h daily, during the first 3 weeks of life and tested as adults. We evaluated plasma epinephrine (E) and norepinephrine (NE), cardiac adrenoreceptors and anxiety responses after maternal deprivation and variable chronic stress (VCS) in ADTN-lesioned rats. Thirty days after ADTN lesion, in non-maternally deprived rats basal plasma NE concentration was greater and cardiac beta-adrenoreceptor density was lower than that in the sham-lesioned group. Maternal deprivation induced a significant increase in basal plasma NE concentration, which was greater in lesioned rats, and cardiac beta-adrenoreceptor density was decreased in lesioned rats. After VCS plasma catecholamine concentration was much greater in non-maternally deprived rats than in maternally-deprived rats; cardiac beta-adrenoreceptor density was decreased by VCS in both maternally-deprived and non-deprived rats, but more so in non-deprived rats, and further decreased by the ADTN lesion. In the plus maze test, the number of open arm entries was greater in the maternally deprived and in the stressed rats. Thus, sympathetic-adrenal medullary activation produced by VCS was much greater in non-deprived rats, and was linked to a down regulation of myocardial beta-adrenoceptors. The ADTN are not responsible for the reduced catecholamine responses to stress in maternally-deprived rats. Maternal deprivation or chronic stress also induced a long term anxiolytic effect, which was also not affected by ADTN lesion.     

Extinction-induced "despair" in aged and adult rats: links to neurotrophins in frontal cortex and hippocampus

In the search for animal models of human geriatric depression, we found that operant extinction of escape from water results in the expression of immobility in different age groups, indicative of behavioral "despair", which was also associated with the resistance-to-extinction (RTE) expressed by these animals. With respect to the neurotrophin hypothesis of depression, nerve-growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) protein levels in frontal cortex (FC) and hippocampus (HP) were examined and related to behavioral immobility and RTE in the water maze in aged and adult Wistar rats. Age-related increases in levels of NGF were found in HP and of NT-3 in FC. Indices of immobility showed relationships in the aged with NGF and, in adults, with BDNF, pointing to a dissociation of neurotrophic involvement in extinction trial-induced "despair" in aged and adult rats. The present results support the hypothesis, that extinction-induced immobility in the water maze reflects a state akin to behavioral despair and point to age-related differences of neurotrophic involvement in depressive-like symptoms. The concept of extinction-induced behavioral "despair" in the aged subsumes several aspects of human geriatric depression, such as co-morbidity of learning impairment and anxiety, and, thus could represent a useful paradigm to examine the neuronal mechanisms underlying depression, especially in aged rodents.     

Assessment of retention capacities in old rats

Young (3-6 month) and old (24-27 month) barrier reared Wistar rats were tested for their ability to retain an inhibitory (passive) avoidance, acquired immobility, and a conditioned taste aversion response as a function of time. Old rats exhibited accelerated forgetting of both the inhibitory avoidance and acquired immobility response in comparison to young rats. In contrast, old rats displayed good retention of the conditioned taste aversion response at all time intervals tested. It appears that the dynamic aspects of retention are altered in aged rats depending on the task, and in some instances may be expressed as accelerated forgetting.     

Accelerated cognitive aging in diabetic rats is prevented by lowering corticosterone levels

Diabetes and normal aging are both characterized by increases in levels of glucocorticoids. Because long-term exposure to elevated glucocorticoids can be detrimental to hippocampal function, we evaluated the performance of young diabetic rats in the 14-unit T-maze, a task that is sensitive to hippocampal deficits. To assess the contribution of diabetes-induced elevations in corticosterone levels, we examined maze learning in diabetic rats that had levels of corticosterone 'clamped' through adrenalectomy and low-dose corticosterone replacement. For comparison, we also tested a separate group of young and aged rats in the maze. Adrenally intact diabetic rats learned poorly in the 14-unit T-maze. Preventing the increases in corticosterone levels that accompanies the onset of experimental diabetes also prevented deficits in complex maze learning. The pattern of errors made by adrenally intact diabetic rats was similar to the pattern of errors made by aged rats, suggesting that the cognitive profiles of diabetic and aged rats share common features.