Parietal and frontal object areas underlie perception of object orientation in depth

Attention deficit/hyperactivity disorder (ADHD) is a developmental disorder of cognition. Behavioral symptoms of ADHD are inattention, hyperactivity, and impulsivity. We investigated the effects of treadmill exercise and methylphenidate (MPH) on activity and spatial learning memory in relation to dopamine synthesis and brain-derived neurotrophic factor (BDNF) expression using spontaneously hypertensive adult male rats. The rats in the MPH-treated group received 1 mg/kg MPH orally once a day for 28 days. The rats in the treadmill exercise group were made to run on a treadmill for 30 min once a day, five times a week, for 28 days. Activity was determined by an open-field test and spatial learning memory was evaluated by an 8-arm maze test. Immunohistochemistry and Western blotting were conducted to examine the levels of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of dopamine, and BDNF. The rats in the ADHD group showed hyperactivity and spatial learning memory deficit. Reduction of TH in the striatum and substantia nigra and BDNF in the hippocampus was observed of the rats in the ADHD group. Treadmill exercise and MPH alleviated the ADHD-induced hyperactivity and spatial learning memory impairment. Expressions of TH and BDNF in the ADHD rats were also increased by both treadmill exercise and MPH. These findings provide a possibility that exercise may be used as an effective therapeutic intervention for ADHD patients as MPH treatment.     

Long-term regular exercise promotes memory and learning in young but not in older rats

BACKGROUND AND OBJECTIVE: By aging, some functions in nervous system like spatial memory are reduced. It has been shown that short-time physical activity can improve memory but there is much less data on the long-term exercising. In the present study, the aim was to clarify the effect of regular long-term physical activity on spatial memory and learning of young and middle aged and older male Wistar rats. MATERIALS AND METHODS: Sixty 3 months old rats were randomly divided in six equal groups. Experimental groups were treadmill exercised at speed 22m/min for 1h 6 days per week, and the program lasted 3, 6 and 9 months, respectively. At the end of training period, spatial memory of rats was tested using Morris Water Maze. RESULTS: Results indicated that regular physical activity significantly increased spatial memory (p<0.05) in young rats (6 months old) as compared to controls, but not in the older ones (9 and 12 months old). Nonetheless, spatial memory of these rats was significantly better than in younger ones in both groups (p<0.05). CONCLUSION: Spatial memory and learning increased due regular exercise in young rats. With progression of age up to 9 and 12 months the memory improved, but the programmed exercise had no positive effect on learning.     

Influence of late-life exposure to environmental enrichment or exercise on hippocampal function and CA1 senescent physiology

Aged (20-22 months) male Fischer 344 rats were randomly assigned to sedentary (A-SED), environmentally-enriched (A-ENR), or exercise (A-EX) conditions. After 10-12 weeks of differential experience, the 3 groups of aged rats and young sedentary controls were tested for physical and cognitive function. Spatial discrimination learning and memory consolidation, tested on the water maze, were enhanced in environmentally-enriched compared with sedentary. A-EX exhibited improved and impaired performance on the cue and spatial task, respectively. Impaired spatial learning in A-EX was likely due to a bias in response selection associated with exercise training, as object recognition memory improved for A-EX rats. An examination of senescent hippocampal physiology revealed that enrichment and exercise reversed age-related changes in long-term depression (LTD) and long-term potentiation (LTP). Rats in the enrichment group exhibited an increase in cell excitability compared with the other 2 groups of aged animals. The results indicate that differential experience biased the selection of a spatial or a response strategy and factors common across the 2 conditions, such as increased hippocampal activity associated with locomotion, contribute to reversal of senescent synaptic plasticity.     

Effects of treadmill running on spatial learning and memory in streptozotocin-induced diabetic rats

Previous studies have shown an association between diabetes mellitus and impairments in learning and memory. These deficits were partially reversed by the use of insulin. Due to the fact that exercise has positive effects on many physiological systems, including the central nervous system, the present study, evaluated the effects of treadmill running on spatial learning and memory in streptozotocin (STZ)-induced diabetic rats. The exercise program was treadmill running at 17 meters per minute (m/min) at 0° inclination for 40 minutes per day (min/day), 7 days/week, for 12 weeks. Experimental groups were: the control-rest, the control-exercise, the diabetes-rest and the diabetes-exercise. Spatial learning and memory was investigated by Morris water maze test in the rats after 12 weeks of diabetes induction and the exercise period. Our data showed that spatial learning and memory was significantly impaired in the diabetes-rest group with respect to the control-rest group. However, there were no differences between the other groups. The present results suggest that spatial learning and memory is affected under diabetic conditions and that treadmill running prevents these effects. The data correspond to the possibility that treadmill running is helpful in the prevention and alleviation of the cognitive decline in diabetes mellitus.     

Exercise effects stress-induced analgesia and spatial learning in rats

Previous studies indicated that intensity level may be a determining factor in the beneficial or detrimental effects of exercise on spatial memory, as chronic low-intensity level exercise appears to enhance learning and memory which stressful situations may impair. This study examines the effects of different intensity levels of acute exercise (treadmill running) on spatial memory in rats. Using the Morris water maze, spatial learning was measured in animals exposed to treadmill running at low- (20-22 m/min for 25 min daily) and high-intensity (25 m/min for 25 min daily) levels of exercise. A stress control using an electric foot shock was used to examine if the high-intensity exercise was sufficient to serve as a stressor. Stress level was estimated by examining tail flick latencies as a measure of stress-induced analgesia. The results indicate that high-intensity exercise at a level that may not induce an analgesic state is sufficient to impair early acquisition of spatial learning. However, with additional trials, all animals are capable of learning the task. Acute exposure to the electric foot shock impaired learning in the Morris water maze. Surprisingly, across all studies, there was a significantly higher analgesic state post-swim as compared to pre-swim. The results indicate that irrespective of stress level prior to water maze testing, swimming in the Morris water maze repeatedly for short durations of time is enough to induce an analgesic state.     

A high-fat,refined sugar diet reduces hippocampal brain-derived neurotrophic factor,neuronal plasticity,and learning

We have investigated a potential mechanism by which a diet, similar in composition to the typical diet of most industrialized western societies rich in saturated fat and refined sugar (HFS), can influence brain structure and function via regulation of neurotrophins. We show that animals that learn a spatial memory task faster have more brain-derived neurotrophic factor (BDNF) mRNA and protein in the hippocampus. Two months on the HFS diet were sufficient to reduce hippocampal level of BDNF and spatial learning performance. Consequent to the action of BDNF on synaptic function, downstream effectors for the action of BDNF on synaptic plasticity were reduced proportionally to BDNF levels, in the hippocampus of rats maintained on the HFS diet between 2 and 24 months. In particular, animals maintained on the HFS diet showed a decrease in levels of: (i) synapsin I mRNA and protein (total and phosphorylated), important for neurotransmitter release; (ii) cyclic AMP-response element-binding protein (CREB) mRNA and protein (total and phosphorylated); CREB is required for various forms of memory and is under regulatory control of BDNF; (iii) growth-associated protein 43 mRNA, important for neurite outgrowth, neurotransmitter release, and learning and memory. Diet-related changes were specific for the hippocampus consequent to its role in memory formation, and did not involve neurotrophin-3, another member of the neurotrophin family.Our results indicate that a popularly consumed diet can influence crucial aspects of neuronal and behavioral plasticity associated with the function of BDNF.     

BDNF upregulation rescues synaptic plasticity in middle-aged ovariectomized rats

Brain-derived neurotrophic factor (BDNF) has emerged as a possible broad-spectrum treatment for the plasticity losses found in rodent models of human conditions associated with memory and cognitive deficits. We have tested this strategy in the particular case of ovariectomy. The actin polymerization in spines normally found after patterned afferent stimulation was greatly reduced, along with the stabilization of long-term potentiation, in hippocampal slices prepared from middle-aged ovariectomized rats. Both effects were fully restored by a 60-minute infusion of 2 nM BDNF. Comparable rescue results were obtained after elevating endogenous BDNF protein levels in hippocampus with 4 daily injections of a short half-life ampakine (positive modulator of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate [AMPA]-type glutamate receptors). These results provide the first evidence that minimally invasive, mechanism-based drug treatments can ameliorate defects in spine plasticity caused by depressed estrogen levels.     

Daily running promotes spatial learning and memory in rats.

Previous studies on exercise have shown that physical activity improves learning and memory. Present study was performed to determine the effects of acute, chronic and continuous exercise with different periods on spatial learning and memory recorded as the latency and length of swim path in the Morris water maze testing in subsequent 8 days. Four rat groups were included as follows: (1) group C, controls which did not exercise; (2) group A, 30 days treadmill running before and 8 days during the Morris water maze testing period; (3) group B, 30 days exercise before the Morris water maze testing period only; (4) group D, 8 days exercise only during the Morris water maze testing period. The results showed that chronic (30 days) and continuous (during 8 days of Morris water maze testing days) treadmill training produced a significant enhancement in spatial learning and memory which was indicated by decreases in path length and latency to reach the platform in the Morris water maze test (p<0.05). The benefits in these tests were lost in 3 days, if the daily running session was abandoned. In group D with acute treadmill running (8 days exercise only) the difference between the group A disappeared in 1 week and benefit seemed to be obtained in comparison with the controls without running program. In conclusion the chronic and daily running exercises promoted learning and memory in Morris water maze, but the benefits were lost in few days without daily running sessions in adult rats.     

Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition

Omega-3 fatty acids (i.e. docosahexaenoic acid; DHA), similar to exercise, improve cognitive function, promote neuroplasticity, and protect against neurological lesion. In this study, we investigated a possible synergistic action between DHA dietary supplementation and voluntary exercise on modulating synaptic plasticity and cognition. Rats received DHA dietary supplementation (1.25% DHA) with or without voluntary exercise for 12 days. We found that the DHA-enriched diet significantly increased spatial learning ability, and these effects were enhanced by exercise. The DHA-enriched diet increased levels of pro-brain-derived neurotrophic factor (BDNF) and mature BDNF, whereas the additional application of exercise boosted the levels of both. Furthermore, the levels of the activated forms of CREB and synapsin I were incremented by the DHA-enriched diet with greater elevation by the concurrent application of exercise. While the DHA diet reduced hippocampal oxidized protein levels, a combination of a DHA diet and exercise resulted in a greater reduction rate. The levels of activated forms of hippocampal Akt and CaMKII were increased by the DHA-enriched diet, and with even greater elevation by a combination of diet and exercise. Akt and CaMKII signaling are crucial step by which BDNF exerts its action on synaptic plasticity and learning and memory. These results indicate that the DHA diet enhanced the effects of exercise on cognition and BDNF-related synaptic plasticity, a capacity that may be used to promote mental health and reduce risk of neurological disorders.     

Differential effects of treadmill running and wheel running on spatial or aversive learning and memory: roles of amygdalar brain-derived neurotrophic factor and synaptotagmin I

Chronic exercise has been reported to improve cognitive function. However, whether and how different types of exercise affect various learning and memory tasks remain uncertain. To address this issue, male BALB/c mice were trained for 4 weeks under two different exercise protocols: moderate treadmill running or voluntary wheel running. After exercise training, their spatial memory and aversive memory were evaluated by a Morris water maze and by one-trial passive avoidance (PA), respectively. Levels of neural plasticity-related proteins, i.e. brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and synaptotagmin I (Syt I), in hippocampus and amygdala were determined by ELISA or immunoblotting. Finally, the functional roles of these proteins in the basolateral amygdala were verified by locally blocking them with K252a (a TrkB kinase inhibitor), or lentivirus expressing Syt I shRNA. We found that (1) although both moderate treadmill running and wheel running improved the Morris water maze performance, only the former improved PA performance; (2) likewise, both exercise protocols upregulated the BDNF–TrkB pathway and Syt I in the hippocampus, whereas only treadmill exercise upregulated their expression levels in the amygdala; (3) local injection of K252a abolished the treadmill exercise-facilitated PA performance and upregulation of amygdalar TrkB and Syt I; and (4) local administration of Syt I shRNA abolished the treadmill exercise-facilitated PA performance and upregulation of amygdalar Syt I. Therefore, our results support the notion that different forms of exercise induce neuroplasticity changes in different brain regions, and thus exert diverse effects on various forms of learning and memory.     

Effects of treadmill exercise on memory and c-Fos expression in the hippocampus of the rats with intracerebroventricular injection of streptozotocin

Alzheimer's disease is a progressive neurodegenerative disease clinically characterized by dementia and neurobehavioral deterioration. Hippocampal neurons are vulnerable to injury induced by Alzheimer's disease. The immediate early gene c-Fos has been used as a marker of neuronal activity. In the present study, we investigated the effects of treadmill exercise on long-term memory capacity and c-Fos expression in the hippocampus of rats with Alzheimer's disease. The rat model of Alzheimer's disease used in the present study was induced by the intracerebroventricular (ICV) injection of streptozotocin (STZ) using a stereotaxic instrument. The rats in the exercise group were forced to run on a treadmill for 30 min once daily for 14 consecutive days starting at 3 days after the ICV injection of STZ. The results of the present study showed that ICV injection of STZ impaired long-term memory capacity and decreased the number of c-Fos-positive cells in several regions of the rat hippocampus. However, treadmill exercise alleviated long-term memory deficits and enhanced c-Fos expression in the rats with ICV injection of STZ. The results of the present study showed that treadmill exercise could be a useful strategy for treating several neurodegenerative diseases.     

BDNF-exercise interactions in the recovery of symmetrical stepping after a cervical hemisection in rats

Clinical evidence indicates that motor training facilitates functional recovery after a spinal cord injury (SCI). Brain-derived neurotrophic factor (BDNF) is a powerful synaptic facilitator and likely plays a key role in motor and sensory functions. Spinal cord hemisection decreases the levels of BDNF below the injury site, and exercise can counteract this decrease [Ying Z, Roy RR, Edgerton VR, Gomez-Pinilla F (2005) Exercise restores levels of neurotrophins and synaptic plasticity following spinal cord injury. Exp Neurol 193:411-419]. It is not clear, however, whether the exercise-induced increases in BDNF play a role in mediating the recovery of locomotion after a SCI. We performed a lateral cervical ( approximately C4) hemisection in adult rats. Seven days after hemisection, the BDNF inhibitor trkB IgG was injected into the cervical spinal cord below the lesion ( approximately C5-C6). Half of the rats were exposed to voluntary running wheels for 14 days. Locomotor ability was assessed by determining the symmetry between the contralateral (unaffected) vs. the ipsilateral (affected) forelimb at the most optimum treadmill speed for each rat. Sedentary and exercised rats with BDNF inhibition showed a higher level of asymmetry during the treadmill locomotion test than rats not treated with the BDNF inhibitor. In hemisected rats, exercise normalized the levels of molecules important for synaptic function, such as cyclic AMP response element binding protein (CREB) and synapsin I, in the ipsilateral cervical enlargement, whereas the BDNF blocker lessened these exercise-associated effects. The results indicate that BDNF levels play an important role in shaping the synaptic plasticity and in defining the level of recovery of locomotor performance after a SCI.     

Activity-dependent expression of brain-derived neurotrophic factor in dendrites: facts and open questions

Long-lasting synaptic changes in transmission and morphology at the basis of memory storage, require delivery of newly synthesized proteins to affected synapses. Although many of these proteins are generated in the cell body, several key molecules for plasticity can be delivered in the form of silent mRNAs at synapses in extra somatic compartments where they are locally translated. One of such mRNAs encodes brain-derived neurotrophic factor (BDNF), a key molecule in neuronal development, learning and memory. A single BDNF protein is produced from several splice variants having a different 5' untranslated region. These mRNA variants have a different subcellular localization (soma, proximal or distal dendritic compartment) and may represent a spatial code for a local control of BDNF availability. This review will highlight current knowledge on the mechanisms of spatial and temporal regulation of activity-dependent BDNF mRNA localization in dendrites in relation with synaptic plasticity.     

Caloric restriction does not reverse aging-related changes in hippocampal BDNF

Caloric restriction (CR) can attenuate the aging-related decline in learning and memory in rats. Understanding the mechanisms underlying this effect could lead to therapies for human memory impairment. We tested the hypotheses that aging is associated with a decline in hippocampal brain-derived neurotrophic factor (BDNF), a growth factor that enhances learning and memory, and that CR increases hippocampal BDNF. We compared BDNF protein levels in hippocampal subregions of young, middle-aged and old rats fed CR or ad libitum (AL) diets. Mean BDNF levels in the dentate gyrus and CA3 did not differ with diet but increased with age. In CA1, BDNF levels were slightly higher in CR than AL rats at middle and old age but did not change across lifespan. These data suggest that mnemonic impairments with age do not reflect a decrease in hippocampal BDNF. Furthermore, if CRs attenuation of aging-related memory changes is mediated by BDNF, then it must be through a small, CA1-specific increase and does not involve reversal of an aging-related decline in BDNF.     

Suppression of hippocampal plasticity-related gene expression by sleep deprivation in rats

Previous work shows that sleep deprivation impairs hippocampal-dependent learning and long-term potentiation (LTP). Brain-derived neurotrophic factor (BDNF), cAMP response-element-binding (CREB) and calcium–calmodulin-dependent protein kinase II (CAMKII) are critical modulators of hippocampal-dependent learning and LTP. In the present study we compared the effects of short- (8 h) and intermediate-term (48 h) sleep deprivation ( SD ) on the expression of BDNF and its downstream targets, Synapsin I, CREB and CAMKII in the neocortex and the hippocampus. Rats were sleep deprived using an intermittent treadmill system which equated total movement in the SD and control treadmill animals (CT), but permitted sustained periods of rest in CT animals. Animals were divided into SD (treadmill schedule: 3 s on/12 s off) and two treadmill control groups, CT1 (15 min on/60 min off) and CT2 (30 min on/120 min off – permitting more sustained sleep). Real-time Taqman RT-PCR was used to measure changes in mRNA; BDNF protein levels were determined using ELISA . In the hippocampus, 8 h treatments reduced BDNF , Synapsin I, CREB and CAMKII gene expression in both SD and control groups. Following 48 h of experimental procedures, the expression of all these four molecular markers of plasticity was reduced in SD and CT1 groups compared to the CT2 and cage control groups. In the hippocampus, BDNF protein levels after 8 h and 48 h treatments paralleled the changes in mRNA. In neocortex, neither 8 h nor 48 h SD or control treatments had significant effects on BDNF , Synapsin I and CAMKII mRNA levels. Stepwise regression analysis suggested that loss of REM sleep underlies the effects of SD on hippocampal BDNF , Synapsin I and CREB mRNA levels, whereas loss of NREM sleep underlies the effects on CAMKII mRNA.     

Treadmill running improves long-term potentiation (LTP) defects in streptozotocin-induced diabetes at dentate gyrus in rats

ObjectivesIt has been demonstrated that exercise has neuroprotective effects in the central nervous system (CNS), especially in hippocampus. Previous studies have indicated that diabetes mellitus affects synaptic plasticity in the hippocampus leading to impairments in learning and memory. The aim of this study was to evaluate the effects of treadmill running on synaptic plasticity at dentate gyrus (DG) of streptozotocin-induced diabetic rats.Study designExperimental groups were the control, the diabetes and the diabetes-exercise groups. Long-term potentiation (LTP) in perforant path-DG synapses was assessed (by 400 Hz tetanization) in order to investigate the effect of exercise on synaptic plasticity. Field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude were measured.ResultsWith respect to the control group, fEPSP were significantly decreased in the diabetes group. However, there were no differences between responses of the diabetes-exercise group and the control.ConclusionThe present results suggest that LTP induction in the dentate gyrus is affected under diabetic conditions and that treadmill running prevents these effects. The data suggest that treadmill running protect against diabetes-induced decrease of learning ability and memory function of the hippocampus.     

BDNF对慢性应激性大鼠海马神经元损伤的保护作用

目的研究脑源性神经营养因子(BDNF)对大鼠海马神经元的保护作用。方法40只成年Wistar大鼠随机分为对照组、应激组、BDNF低剂量组和高剂量组,每组10只。用电击足底结合噪声建立慢性应激大鼠模型,Morris水迷宫观察动物的空间学习和记忆能力,Nissl染色观察和计数海马神经元数量,Fara-2荧光法测海马突触体内游离钙浓度。结果在双海马注射BDNF后,对于因慢性应激引起的空间学习和记忆能力下降,海马神经元数量减少,海马突触体内游离钙浓度增高有明显保护作用。结论BDNF对应激海马损伤有保护作用,其机制可能是通过调节海马细胞内的钙浓度,防止海马神经细胞丢失有关。     

Dissecting the age-related decline on spatial learning and memory tasks in rodent models: N-methyl-D-aspartate receptors and voltage-dependent Ca²⁺ channels in senescent synaptic plasticity

In humans, heterogeneity in the decline of hippocampal-dependent episodic memory is observed during aging. Rodents have been employed as models of age-related cognitive decline and the spatial water maze has been used to show variability in the emergence and extent of impaired hippocampal-dependent memory. Impairment in the consolidation of intermediate-term memory for rapidly acquired and flexible spatial information emerges early, in middle-age. As aging proceeds, deficits may broaden to include impaired incremental learning of a spatial reference memory. The extent and time course of impairment has been be linked to senescence of calcium (Ca²⁺) regulation and Ca²⁺-dependent synaptic plasticity mechanisms in region CA1. Specifically, aging is associated with altered function of N-methyl-D-aspartate receptors (NMDARs), voltage-dependent Ca²⁺ channels (VDCCs), and ryanodine receptors (RyRs) linked to intracellular Ca²⁺ stores (ICS). In young animals, NMDAR activation induces long-term potentiation of synaptic transmission (NMDAR-LTP), which is thought to mediate the rapid consolidation of intermediate-term memory. Oxidative stress, starting in middle-age, reduces NMDAR function. In addition, VDCCs and ICS can actively inhibit NMDAR-dependent LTP and oxidative stress enhances the role of VDCC and RyR-ICS in regulating synaptic plasticity. Blockade of L-type VDCCs promotes NMDAR-LTP and memory in older animals. Interestingly, pharmacological or genetic manipulations to reduce hippocampal NMDAR function readily impair memory consolidation or rapid learning, generally leaving incremental learning intact. Finally, evidence is mounting to indicate a role for VDCC-dependent synaptic plasticity in associative learning and the consolidation of remote memories. Thus, VDCC-dependent synaptic plasticity and extrahippocampal systems may contribute to incremental learning deficits observed with advanced aging.