Cardiorespiratory fitness predicts effective connectivity between the hippocampus and default mode network nodes in young adults

Rodent and human studies examining the relationship between aerobic exercise, brain structure, and brain function indicate that the hippocampus (HC), a brain region critical for episodic memory, demonstrates striking plasticity in response to exercise. Beyond the hippocampal memory system, human studies also indicate that aerobic exercise and cardiorespiratory fitness (CRF) are associated with individual differences in large‐scale brain networks responsible for broad cognitive domains. Examining network activity in large‐scale resting‐state brain networks may provide a link connecting the observed relationships between aerobic exercise, hippocampal plasticity, and cognitive enhancement within broad cognitive domains. Previously, CRF has been associated with increased functional connectivity of the default mode network (DMN), specifically in older adults. However, how CRF relates to the magnitude and directionality of connectivity, or effective connectivity, between the HC and other DMN nodes remains unknown. We used resting‐state fMRI and conditional Granger causality analysis (CGCA) to test the hypothesis that CRF positively predicts effective connectivity between the HC and other DMN nodes in healthy young adults. Twenty‐six participants (ages 18–35 years) underwent a treadmill test to determine CRF by estimating its primary determinant, maximal oxygen uptake (V^.O_2max), and a 10‐min resting‐state fMRI scan to examine DMN effective connectivity. We identified the DMN using group independent component analysis and examined effective connectivity between nodes using CGCA. Linear regression analyses demonstrated that CRF significantly predicts causal influence from the HC to the ventromedial prefrontal cortex, posterior cingulate cortex, and lateral temporal cortex and to the HC from the dorsomedial prefrontal cortex. The observed relationship between CRF and hippocampal effective connectivity provides a link between the rodent literature, which demonstrates a relationship between aerobic exercise and hippocampal plasticity, and the human literature, which demonstrates a relationship between aerobic exercise and CRF and the enhancement of broad cognitive domains including, but not limited to, memory.     

Physical fitness,hippocampal functional connectivity and academic performance in children with overweight/obesity: The ActiveBrains project

ObjectivesPhysical fitness is a modifiable factor associated with enhanced brain health during childhood. To our knowledge, the present study is the first to examine: (i) whether physical fitness components (i.e., cardiorespiratory, motor and muscular fitness) are associated with resting state functional connectivity of hippocampal seeds to different cortical regions in children with overweight/obesity, and (ii) whether resting state hippocampal functional connectivity is coupled with better academic performance.Patients and methodsIn this cross-sectional study, a total of 99 children with overweight/obesity aged 8–11 years were recruited from Granada, Spain (November 2014 to February 2016). The physical fitness components were assessed following the ALPHA health-related fitness test battery. T1-weighted and resting-state fMRI images were acquired with a 3.0 Tesla Siemens Magnetom Tim Trio system. Academic performance was assessed by the Woodcock-Muñoz standardized test. Hippocampal seed-based procedures with post-hoc regression analyses were performed.ResultsIn the fully adjusted models, cardiorespiratory fitness was independently associated with greater hippocampal connectivity between anterior hippocampus and frontal regions (β ranging from 0.423 to 0.424, p < 0.001). Motor fitness was independently associated with diminished hippocampal connectivity between posterior hippocampus and frontal regions (β ranging from −0.583 to −0.694, p < 0.001). However, muscular fitness was not independently associated with hippocampal functional connectivity. Positive resting state hippocampal functional connectivity was related to better written expression (β ranging from 0.209 to 0.245; p < 0.05).ConclusionsPhysical fitness components may associate with functional connectivity between hippocampal subregions and frontal regions, independent of hippocampal volume, in children with overweight/obesity. Particularly, cardiorespiratory fitness may enhance anterior hippocampal functional connectivity and motor fitness may diminish posterior hippocampal functional connectivity. In addition, resting state hippocampal functional connectivity may relate to better written expression.     

Aerobic fitness is associated with greater hippocampal cerebral blood flow in children

The present study is the first to investigate whether cerebral blood flow in the hippocampus relates to aerobic fitness in children. In particular, we used arterial spin labeling (ASL) perfusion MRI to provide a quantitative measure of blood flow in the hippocampus in 73 7- to 9-year-old preadolescent children. Indeed, aerobic fitness was found to relate to greater perfusion in the hippocampus, independent of age, sex, and hippocampal volume. Such results suggest improved microcirculation and cerebral vasculature in preadolescent children with higher levels of aerobic fitness. Further, aerobic fitness may influence how the brain regulates its metabolic demands via blood flow in a region of the brain important for learning and memory. To add specificity to the relationship of fitness to the hippocampus, we demonstrate no significant association between aerobic fitness and cerebral blood flow in the brainstem. Our results reinforce the importance of aerobic fitness during a critical period of child development.     

Elevated central monoamine receptor mRNA in rats bred for high endurance capacity: implications for central fatigue

Although alteration to peripheral systems at the skeletal muscle level can contribute to one's ability to sustain endurance capacity, neural circuits regulating fatigue may also play a critical role. Previous studies demonstrated that increasing brain serotonin (5-HT) release is sufficient to hasten the onset of exercise-induced fatigue, while manipulations that increase brain dopamine (DA) release can delay the onset of fatigue. These results suggest that individual differences in endurance capacity could be due to factors capable of influencing the activity of 5-HT and DA systems. We evaluated possible differences in central fatigue pathways between two contrasting rat groups selectively bred for high (HCR) or low (LCR) capacity running. Using quantitative in situ hybridization, we measured messenger RNA (mRNA) levels of tryptophan hydroxylase (TPH), 5-HT transporter (5-HTT), 5-HT1A and 5-HT1B autoreceptors, dopamine receptor-D2 (DR-D2) autoreceptors and postsynaptic receptors, and dopamine receptor-D1 (DR-D1) postsynaptic receptors, in discrete brain regions of HCR and LCR. HCR expressed higher levels of 5-HT1B autoreceptor mRNA in the raphe nuclei relative to LCR, but similar levels of TPH, 5-HTT, and 5-HT1A mRNA in these areas. Surprisingly, HCR expressed higher levels of DR-D2 autoreceptor mRNA in the midbrain, while simultaneously expressing greater DR-D2 postsynaptic mRNA in the striatum compared to LCR. There were no differences in DR-D1 mRNA levels in the striatum or cortex between groups. These data suggest that central serotonergic and dopaminergic systems may be involved in the mechanisms by which HCR have delayed onset of exercise-induced fatigue compared to LCR.     

Cognitive and Physical Activity Differently Modulate Disease Progression in the Amyloid Precursor Protein (APP)-23 Model of Alzheimer’s Disease

BACKGROUND: In aging mice, activity maintains hippocampal plasticity and adult hippocampal neurogenesis at a level corresponding to a younger age. Here we studied whether physical exercise and environmental enrichment would also affect brain plasticity in a mouse model of Alzheimer's disease (AD). METHODS: Amyloid precursor protein (APP)-23 mice were housed under standard or enriched conditions or in cages equipped with a running wheel. We assessed beta-amyloid plaque load, adult hippocampal neurogenesis, spatial learning, and mRNA levels of trophic factors in the brain. RESULTS: Despite stable beta-amyloid plaque load, enriched-living mice showed improved water maze performance, an up-regulation of hippocampal neurotrophin (NT-3) and brain-derived neurotrophic factor (BDNF) and increased hippocampal neurogenesis. In contrast, despite increased bodily fitness, wheel-running APP23 mice showed no change in spatial learning and no change in adult hippocampal neurogenesis but a down-regulation of hippocampal and cortical growth factors. CONCLUSIONS: We conclude that structural and molecular prerequisites for activity-dependent plasticity are preserved in mutant mice with an AD-like pathology. Our study might help explain benefits of activity for the aging brain but also demonstrates differences between physical and more cognitive activity. It also suggests a possible cellular correlate for the dissociation between structural and functional pathology often found in AD.     

The signaling mechanisms of hippocampal endoplasmic reticulum stress affecting neuronal plasticity-related protein levels in high fat diet-induced obese rats and the regulation of aerobic exercise

High fat diet (HFD)-induced obesity has been shown to reduce the levels of neuronal plasticity-related proteins, specifically brain-derived neurotrophic factor (BDNF) and synaptophysin (SYN), in the hippocampus. However, the underlying mechanisms are not fully clear. Endoplasmic reticulum stress (ERS) has been reported to play a key role in regulating gene expression and protein production by affecting stress signaling pathways and ER functions of protein folding and post-translational modification in peripheral tissues of obese rodent models. Additionally, HFD that is associated with hyperglycemia could induce hippocampal ERS, thus impairing insulin signaling and cognitive health in HFD mice. One goal of this study was to determine whether hyperglycemia and hyperlipidemia could cause hippocampal ERS in HFD-induced obese SD rats, and explore the potential mechanisms of ERS regulating hippocampal BDNF and SYN proteins production. Additionally, although regular aerobic exercise could reduce central inflammation and elevate hippocampal BDNF and SYN levels in obese rats, the regulated mechanisms are poorly understood. Nrf2-HO-1 pathways play roles in anti-ERS, anti-inflammation and anti-apoptosis in peripheral tissues. Therefore, the other goal of this study was to determine whether aerobic exercise could activate Nrf2-HO-1 in hippocampus to alleviate obesity-induced hippocampal ERS, which would lead to increased BDNF and SYN levels.Male SD rats were fed on HFD for 8 weeks to establish the obese model. Then, 8 weeks of aerobic exercise treadmill intervention was arranged for the obese rats. Results showed that HFD-induced obesity caused hyperglycemia and hyperlipidemia, and significantly promoted hippocampal glucose transporter 3 (GLUT3) and fatty acid transport protein 1 (FATP1) protein expression. These results were associated with the activation of hippocampal ERS and ERS-mediated apoptosis. At the same time, we found that excessive hippocampal ERS not only significantly decreased proBDNF—the precursor of mature BDNF, but also attenuated p38/ERK-CREB signaling pathways and activated NLRP3-IL-1β pathways in obese rats. These results were associated with reduced BDNF and SYN protein production. However, these adverse changes were obviously reversed by aerobic exercise intervention through activating the Nrf2-HO-1 pathways.These results suggest that dietary obesity could induce hippocampal ERS in male SD rats, and excessive hippocampal ERS plays a critical role in decreasing the levels of BDNF and SYN. Moreover, aerobic exercise could activate hippocampal Nrf2 and HO-1 to relieve ERS and heighten BDNF and SYN production in obese rats.     

Aerobic fitness is associated with hippocampal volume in elderly humans

Deterioration of the hippocampus occurs in elderly individuals with and without dementia, yet individual variation exists in the degree and rate of hippocampal decay. Determining the factors that influence individual variation in the magnitude and rate of hippocampal decay may help promote lifestyle changes that prevent such deterioration from taking place. Aerobic fitness and exercise are effective at preventing cortical decay and cognitive impairment in older adults and epidemiological studies suggest that physical activity can reduce the risk for developing dementia. However, the relationship between aerobic fitness and hippocampal volume in elderly humans is unknown. In this study, we investigated whether individuals with higher levels of aerobic fitness displayed greater volume of the hippocampus and better spatial memory performance than individuals with lower fitness levels. Furthermore, in exploratory analyses, we assessed whether hippocampal volume mediated the relationship between fitness and spatial memory. Using a region‐of‐interest analysis on magnetic resonance images in 165 nondemented older adults, we found a triple association such that higher fitness levels were associated with larger left and right hippocampi after controlling for age, sex, and years of education, and larger hippocampi and higher fitness levels were correlated with better spatial memory performance. Furthermore, we demonstrated that hippocampal volume partially mediated the relationship between higher fitness levels and enhanced spatial memory. Our results clearly indicate that higher levels of aerobic fitness are associated with increased hippocampal volume in older humans, which translates to better memory function. © 2009 Wiley‐Liss, Inc.     

Aerobic fitness relates to learning on a virtual Morris Water Task and hippocampal volume in adolescents

In rodents, exercise increases hippocampal neurogenesis and allows for better learning and memory performance on water maze tasks. While exercise has also been shown to be beneficial for the brain and behavior in humans, no study has examined how exercise impacts spatial learning using a directly translational water maze task, or if these relationships exist during adolescence--a developmental period which the animal literature has shown to be especially vulnerable to exercise effects. In this study, we investigated the influence of aerobic fitness on hippocampal size and subsequent learning and memory, including visuospatial memory using a human analogue of the Morris Water Task, in 34 adolescents. Results showed that higher aerobic fitness predicted better learning on the virtual Morris Water Task and larger hippocampal volumes. No relationship between virtual Morris Water Task memory recall and aerobic fitness was detected. Aerobic fitness, however, did not relate to global brain volume or verbal learning, which might suggest some specificity of the influence of aerobic fitness on the adolescent brain. This study provides a direct translational approach to the existing animal literature on exercise, as well as adds to the sparse research that exists on how aerobic exercise impacts the developing human brain and memory.     

Relation between acute and long-term cognitive decline after surgery: Influence of metabolic syndrome

IntroductionThe relationship between persistent postoperative cognitive decline and the more common acute variety remains unknown; using data acquired in preclinical studies of postoperative cognitive decline we attempted to characterize this relationship.MethodsLow capacity runner (LCR) rats, which have all the features of the metabolic syndrome, were compared postoperatively with high capacity runner (HCR) rats for memory, assessed by trace fear conditioning (TFC) on the 7th postoperative day, and learning and memory (probe trial [PT]) assessed by the Morris water-maze (MWM) at 3 months postoperatively. Rate of learning (A_L) data from the MWM test, were estimated by non-linear mixed effects modeling. The individual rat’s TFC result at postoperative day (POD) 7 was correlated with its A_L and PT from the MWM data sets at postoperative day POD 90.ResultsA single exponential decay model best described A_L in the MWM with LCR and surgery (LCR–SURG) being the only significant covariates; first order A_L rate constant was 0.07 s⁻¹ in LCR–SURG and 0.16 s⁻¹ in the remaining groups (p < 0.05). TFC was significantly correlated with both A_L (R = 0.74; p < 0.0001) and PT (R = 0.49; p < 0.01).ConclusionSeverity of memory decline at 1 week after surgery presaged long-lasting deteriorations in learning and memory.     

Downregulation of caveolin-1 contributes to the synaptic plasticity deficit in the hippocampus of aged rats

Caveolin-1 is involved in the regulation of synaptic plasticity, but the relationship between its ex-pression and cognitive function during aging remains controversial. To explore the relationship be-tween synaptic plasticity in the aging process and changes in learning and memory, we examined caveolin-1 expression in the hippocampus, cortex and cerebellum of rats at different ages. We also examined the relationship between the expression of caveolin-1 and synaptophysin, a marker of synaptic plasticity. Hippocampal caveolin-1 and synaptophysin expression in aged （22-24 month old） rats was significantly lower than that in young （1 month old） and adult （4 months old） rats. Ex- pression levels of both proteins were significantly greater in the cortex of aged rats than in that of young or adult rats, and levels were similar between the three age groups in the cerebellum. Linear regression analysis revealed that hippocampal expression of synaptophysin was associated with memory and learning abilities. Moreover, synaptophysin expression correlated positively with caveolin-1 expression in the hippocampus, cortex and cerebellum. These results confirm that caveolin-1 has a regulatory effect on synaptic plasticity, and suggest that the downregulation of hippocampal caveolin-1 expression causes a decrease in synaptic plasticity during physiological aging.     

High mobility group box-1 mediates hippocampal inflammation and contributes to cognitive deficits in high-fat high-fructose diet-induced obese rats

High-fat high-sugar diet-induced obesity can lead to hippocampal inflammation and cognitive deficits, but the detailed underlying mechanism is still not clear. We aim to investigate the role of HMGB1 in hippocampal inflammatory responses and cognitive impairment in high-fat high-fructose diet (HFHFD)-induced obesity. Rats were fed with a normal control diet or an HFHFD diet for 14 weeks. In the last 6 weeks on the diets, the rats were treated with control, or an HMGB1 inhibitor glycyrrhizin, or an anti-HMGB1 neutralizing monoclonal antibody (mAb). Obesity was induced in the HFHFD-fed rats, which had higher body weight, epididymal white adipose tissue (EWAT) weight and caloric efficiency, and lower brain/body weight ratio, glucose tolerance and insulin sensitivity than the ones on normal diets. In the HFHFD-induced obese rats, the HMGB1 levels in plasma and hippocampus were increased, and the nucleus-to-cytoplasm translocation of HMGB1 was promoted. The hippocampal inflammatory responses were enhanced in the HFHFD-induced obesity, including the activation of TLR4 and NF-κB, the production of IL-1β, TNF-α and IL-6, as well as the activation of microglia and astrocytes. In addition, the hippocampal cell apoptosis and cognitive impairment were observed in the HFHFD-fed rats. The treatment with glycyrrhizin or HMGB1 mAb successfully decreased the HMGB1 levels in plasma and hippocampus, and prevented the HMGB1 translocation from the nucleus to cytoplasm. Inhibiting HMGB1 by glycyrrhizin or HMGB1 mAb suppressed the hippocampal inflammatory, alleviated the apoptosis and ameliorated the cognitive impairment in HFHFD-fed rats. These findings indicate that HMGB1 mediates the hippocampal inflammation and contributes to the cognitive deficits in HFHFD-induced obesity. Therefore, inhibition of HMGB1 may have beneficial effect in protecting against hippocampal inflammation and cognitive deficits in dietary obesity.     

Improving fitness increases dentate gyrus/CA3 volume in the hippocampal head and enhances memory in young adults

Converging evidence suggests a relationship between aerobic exercise and hippocampal neuroplasticity that interactively impacts hippocampally dependent memory. The majority of human studies have focused on the potential for exercise to reduce brain atrophy and attenuate cognitive decline in older adults, whereas animal studies often center on exercise‐induced neurogenesis and hippocampal plasticity in the dentate gyrus (DG) of young adult animals. In the present study, initially sedentary young adults (18–35 years) participated in a moderate‐intensity randomized controlled exercise intervention trial ( ClinicalTrials.gov ; NCT02057354) for a duration of 12 weeks. The aims of the study were to investigate the relationship between change in cardiorespiratory fitness (CRF) as determined by estimated _MAX, hippocampally dependent mnemonic discrimination, and change in hippocampal subfield volume. Results show that improving CRF after exercise training is associated with an increased volume in the left DG/CA3 subregion in young adults. Consistent with previous studies that found exercise‐induced increases in anterior hippocampus in older adults, this result was specific to the hippocampal head, or most anterior portion, of the subregion. Our results also demonstrate a positive relationship between change in CRF and change in corrected accuracy for trials requiring the highest level of discrimination on a putative behavioral pattern separation task. This relationship was observed in individuals who were initially lower‐fit, suggesting that individuals who show greater improvement in their CRF may receive greater cognitive benefit. This work extends animal models by providing evidence for exercise‐induced neuroplasticity specific to the neurogenic zone of the human hippocampus.     

Deafferentation enhances neurogenesis in the young and middle aged hippocampus but not in the aged hippocampus

Increased neurogenesis in the dentate gyrus (DG) after brain insults such as excitotoxic lesions, seizures, or stroke is a well known phenomenon in the young hippocampus. This plasticity reflects an innate compensatory response of neural stem cells (NSCs) in the young hippocampus to preserve function or minimize damage after injury. However, injuries to the middle‐aged and aged hippocampi elicit either no or dampened neurogenesis response, which could be due to an altered plasticity of NSCs and/or the hippocampus with age. We examined whether the plasticity of NSCs to increase neurogenesis in response to a milder injury such as partial deafferentation is preserved during aging. We quantified DG neurogenesis in the hippocampus of young, middle‐aged, and aged F344 rats after partial deafferentation. A partial deafferentation of the left hippocampus without any apparent cell loss was induced via administration of Kainic acid (0.5 μg in 1.0 μl) into the right lateral ventricle of the brain. In this model, degeneration of CA3 pyramidal neurons and dentate hilar neurons in the right hippocampus results in loss of commissural axons which leads to partial deafferentation of the dendrites of dentate granule cells and CA1‐CA3 pyramidal neurons in the left hippocampus. Quantification of newly born cells that are added to the dentate granule cell layer at postdeafferentation days 4–15 using 5′‐bromodeoxyuridine (BrdU) labeling revealed greatly increased addition of newly born cells (～three fold increase) in the deafferented young and middle‐aged hippocampi but not in the deafferented aged hippocampus. Measurement of newly born neurons using doublecortin (DCX) immunostaining also revealed similar findings. Analyses using BrdU‐DCX dual immunofluorescence demonstrated no changes in neuronal fate‐choice decision of newly born cells after deafferentation, in comparison to the age‐matched naive hippocampus in all age groups. Thus, the plasticity of hippocampal NSCs to increase DG neurogenesis in response to a milder injury such as partial hippocampal deafferentation is preserved until middle age but lost at old age. © 2010 Wiley‐Liss, Inc.     

Aerobic fitness enhances relational memory in preadolescent children: The FITKids randomized control trial

It is widely accepted that aerobic exercise enhances hippocampal plasticity. Often, this plasticity co‐occurs with gains in hippocampal‐dependent memory. Cross‐sectional work investigating this relationship in preadolescent children has found behavioral differences in higher versus lower aerobically fit participants for tasks measuring relational memory, which is known to be critically tied to hippocampal structure and function. The present study tested whether similar differences would arise in a clinical intervention setting where a group of preadolescent children were randomly assigned to a 9‐month after school aerobic exercise intervention versus a wait‐list control group. Performance measures included eye‐movements as a measure of memory, based on recent work linking eye‐movement indices of relational memory to the hippocampus. Results indicated that only children in the intervention increased their aerobic fitness. Compared to the control group, those who entered the aerobic exercise program displayed eye‐movement patterns indicative of superior memory for face‐scene relations, with no differences observed in memory for individual faces. The results of this intervention study provide clear support for the proposed linkage among the hippocampus, relational memory, and aerobic fitness, as well as illustrating the sensitivity of eye‐movement measures as a means of assessing memory. © 2012 Wiley Periodicals, Inc.     

Chronically elevating plasma Mg2+ improves hippocampal frequency potentiation and reversal learning in aged and young rats

One prediction of the hypothesis that the capacity for hippocampal frequency potentiation is relevant to behavioral plasticity is tested in this study, by chronically elevating magnesium in intact aged and young rats. Elevated extracellular Mg2+ specifically improves frequency potentiation in hippocampal slices, and chronic alterations in plasma Mg2+ can increase brain Mg2+ in intact animals. Aged and young rats on a diet that elevated plasma Mg2+ exhibited stronger frequency potentiation under urethane anesthesia, and showed improved maze reversal learning.     

Cardiometabolic Risk in Adolescents: Associations with Physical Activity, Fitness, and Sleep

Background

Physical activity and fitness are independently associated with cardiometabolic dysfunction, and short sleep duration is an emerging marker of obesity. Few have examined interrelations among these factors in a comprehensive risk model.

Purpose

Investigate the influence of behavioral and lifestyle risk factors on the metabolic syndrome and inflammation.

Methods

A sample of 367 15–17-year-olds (73 % boys) from ethnic minority groups (45.8 % Hispanic, 30.8 % Black), most with elevated blood pressure (72 %), underwent aerobic fitness testing, blood sampling, and completed behavioral questionnaires.

Results

Structural model results are consistent with the notion that short sleep duration, poor sleep quality and fatigue, and decreased physical activity are associated with increased risk of metabolic syndrome and inflammation possibly via effects on reduced cardiorespiratory fitness.

Conclusions

The combination of negative lifestyle and behavioral factors of physical inactivity, sleep loss, and poor fitness has serious implications for cardiovascular health complications in at-risk youth.     

Chronically elevating plasma Mg improves hippocampal frequency potentiation and reversal learning in aged and young rats

One prediction of the hypothesis that the capacity for hippocampal frequency potentiation is relevant to behavioral plasticity is tested in this study, by chronically elevating magnesium in intact aged and young rats. Elevated extracellular Mg²⁺ specifically improves frequency potentiation in hippocampal slices, and chronic alterations in plasma Mg²⁺ can increase brain Mg²⁺ in intact animals. Aged and young rats on a diet that elevated plasma Mg²⁺ exhibited stronger frequency potentiation under urethane anesthesia, and showed improved maze reversal learning.     

The Effects of Aging and Hormonal Manipulation on Amyloid Precursor Protein APP695 mRNA Expression in the Rat Hippocampus

In the rat hippocampus, neuronal morphology and survival are profoundly affected by adrenal steroids, and synaptic plasticity can be modulated by the ovarian sex steroids estrogen and progesterone, β-amyloid peptides, which accumulate in neuritic plaques and are derived from the amyloid precursor protein (APR), have been shown to be both trophic and toxic for hippocampal neurons. Of the various APR isoforms, APP695 is the predominant form found in rat brain and the APP695 mRNA is abundantly expressed in the hippocampus. In order to investigate the hypothesis that APR may serve as a mediator of the steroid effects, we have monitored the hippocampal expression of APP695 mRNA by in situ hybridization, with aging and with steroid manipulation. In aged female rats we observed a decrease in the level of APP695 mRNA relative to young female rats, while no such age difference was evident in male rats. Physiological, surgical and pharmacological manipulation of glucocorticoids appeared to have no effect on APP695 mRNA levels in the hippocampus. Treatment of young, ovariectomized female rats with estrogen and progesterone, resulted in an increase in hippocampal APP695 expression compared to untreated, ovariectomized controls.     

Reactive synaptogenesis in hippocampal area CA1 of aged and young adult rats

Selective lesions that result in a partial loss of neuronal input appear to signal residual, undamaged inputs to sprout and replace synaptic connections that have been lost. Previous investigations have compared this process of reactive synaptogenesis in young and old animals in the hippocampal dentate gyrus and have demonstrated that the aged brain has a diminished capacity for reinnervation following massive denervation of a target area. This investigation has focused on the lesion-induced plasticity of an adjacent area of the hippocampal formation, area CA1 of regio superior, in young adult and aged rats. Young adult aged Fischer 344 rates were subjected to a unilateral, intraventricular injection of kainic acid that selectively destroyed the CA3-CA4 hippocampal pyramidal neurons. Following a 2-day interoperative interval, the rats sustained an ipsilateral transection of the fimbria-fornix. Animals were killed at 4, 10, 30, and 60 days following the second transection and processed for electron microscopic analysis. Photographic montages were constructed of area CA1 extending from the alveus to the hippocampal fissure. The density of synapses, both intact and degenerating, was determined and analyzed as a function of age, days postlesion, and zone of analysis. Synaptic density decreased 30-40% contralaterally and 60-70% ipsilaterally in both aged and young adult rats. While both age groups restored synaptic density to preoperative levels, aged subjects required significantly more time. Aged rats appeared to be retarded in the initial phases of synaptic replacement. The delay in the aged animals' reactive response was not due to any differences in degeneration clearance between the age groups.