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Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves
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The fetal and even the young brain possesses a considerable degree of plasticity. The plasticity and rate of neurogenesis in the adult brain is much less pronounced. The present study was conducted to investigate whether housing conditions affect neurogenesis, learning, and memory in adult rats. Three-month-old rats housed either in isolation or in an enriched environment were injected intraperitoneally with bromodeoxyuridine (BrdU) to detect proliferation among progenitor cells and to follow their fate in the dentate gyrus. The rats were sacrificed either 1 day or 4 weeks after BrdU injections. This experimental paradigm allows for discrimination between proliferative effects and survival effects on the newborn progenitors elicited by different housing conditions. The number of newborn cells in the dentate gyrus was not altered 1 day after BrdU injections. In contrast, the number of surviving progenitors 1 month after BrdU injections was markedly increased in animals housed in an enriched environment. The relative ratio of neurogenesis and gliogenesis was not affected by environmental conditions, as estimated by double-labeling immunofluorescence staining with antibodies against BrdU and either the neuronal marker calbindin D28k or the glial marker GFAp, resulting in a net increase in neurogenesis in animals housed in an enriched environment. Furthermore, we show that adult rats housed in an enriched environment show improved performance in a spatial learning test. The results suggest that environmental cues can enhance neurogenesis in the adult hippocampal region, which is associated with improved spatial memory. © 1999 John Wiley & Sons, Inc. J Neurobiol 39: 569–578, 1999
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... The magnitude of hippocampal neurogenesis can be modulated by experience, and most studies evaluating the effects of exercise and exposure to an enriched environment (EE) support the idea that the addition of newborn adult neurons may be beneficial for learning and memory abilities. For example, voluntary running and exposure to an EE increase hippocampal neurogenesis, which is paralleled by improved spatial memory performance in the Morris Water task [18][19][20]. This increase in neurogenesis is accompanied and, perhaps, mediated by increased levels of BDNF [21,22]. ...
... * indicates p < 0.001.Given the significant decrease in cell survival in the ZnT3 KO-EE group, we next examined the neuronal phenotype of the surviving cells (Figure 2C-C")). There was no significant interaction between genotype and housing condition [F(1,19) = 0.29, p = 0.596]. While there was no significant effect of genotype for neuronal phenotype [F(1, 19) = 0.01, p = 0.910], there was a significant effect of housing condition [F(1, 19) = 92.45, ...
Zinc is highly concentrated in synaptic vesicles throughout the mammalian telencephalon and, in particular, the hippocampal dentate gyrus. A role for zinc in modulating synaptic plasticity has been inferred, but whether zinc has a particular role in experience-dependent plasticity has yet to be determined. The aim of the current study was to determine whether vesicular zinc is important for modulating adult hippocampal neurogenesis in an experience-dependent manner and, consequently, hippocampal-dependent behaviour. We assessed the role of vesicular zinc in modulating hippocampal neurogenesis and behaviour by comparing ZnT3 knockout (KO) mice, which lack vesicular zinc, to wild-type (WT) littermates exposed to either standard housing conditions (SH) or an enriched environment (EE). We found that vesicular zinc is necessary for a cascade of changes in hippocampal plasticity following EE, such as increases in hippocampal neurogenesis and elevations in mature brain-derived neurotrophic factor (mBDNF), but was otherwise dispensable under SH conditions. Using the Spatial Object Recognition task and the Morris Water task we show that, unlike WT mice, ZnT3 KO mice showed no improvements in spatial memory following EE. These experiments demonstrate that vesicular zinc is essential for the enhancement of adult hippocampal neurogenesis and behaviour following enrichment, supporting a role for zincergic neurons in contributing to experience-dependent plasticity in the hippocampus.
... The total distance traveled by the rats in the 4S and 12E groups did not differ, but the time to reach the nearby zone for the first time was shorter in the 12E group. Thus, rearing in EE did not improve short-term memory and cognitive functions of LHRs, despite that many reports have shown that rats reared in EE showed marked improvements in such functions [38,39]. ...
... In ADHD cases, such executive functions of the PFC are frequently impaired, although the impairment is not a typical symptom of ADHD [51]. The MWM test results showed that EE rearing apparently did not affect the short-term memory of the LHRs, despite many reports describing improved memory, learning, and cognitive functions in animals reared in EE conditions by increased expression of brain-derived neurotrophic factor [38], enhanced neurogenesis [39], and so on. Chronic stress can cause cognitive decline [52][53][54] in rats and humans. ...
In addition to genetic factors, environmental factors play a role in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). This study used Lister hooded rats (LHRs) as ADHD model animals to evaluate the effects of environmental factors. Male LHR pups were kept in four rearing conditions from postnatal day 23 (4 rats in a standard cage; 12 rats in a large flat cage; and 4 or 12 rats in an enriched environment [EE]) until 9 weeks of age. EE rearing but not rearing in a large flat cage decreased the activity of LHRs in the open field test that was conducted for 7 consecutive days. In the drop test, most rats reared in an EE remained on a disk at a height, whereas most rats reared in a standard cage fell off. RNA sequencing revealed that the immediate-early gene expression in the medial prefrontal cortex of LHRs reared in an EE was reduced. cFos-expressing neurons were reduced in number in LHRs reared in an EE. These results suggest that growing in an EE improves ADHD-like behaviors and that said improvement is due to the suppression of neuronal activity in the mPFC.
... Previous unpublished experiments from our laboratory provide further support for this. Normally, neurogenesis, cell survival, and learning and memory abilities, including that of spatial memory in rodents, are strongly enhanced when housed in an enriched environment consisting of a larger living space, a greater number of mice living together, climbing ladders, running wheels, tunnels, and a variety of toys [38][39][40][41][42]. However, in our previous experiments, ZnT3 KO mice did not show an increase in neurogenesis nor an improvement of spatial memory following environmental enrichment. ...
In the brain, vesicular zinc, which refers to a subset of zinc that is sequestered into synaptic vesicles by zinc transporter 3 (ZnT3), has extensive effects on neuronal signalling and modulation. Vesicular zinc-focused research has mainly been directed to its role in the hippocampus, particularly in adult neurogenesis. However, whether vesicular zinc is involved in modulating neurogenesis during the early postnatal period has been less studied. As a first step to understanding this, we used ZnT3 knockout (KO) mice, which lack ZnT3 and, thus, vesicular zinc, to evaluate cell proliferation at three different age points spanning postnatal development (P6, P14, and P28). The survival and the neuronal phenotype of these cells was also assessed in adulthood. We found that male ZnT3 KO mice exhibited lower rates of cell proliferation at P14, but a greater number of these cells survived to adulthood. Additionally, significantly more cells labelled on P6 survived to adulthood in male and female ZnT3 KO mice. We also found sex-dependent differences, whereby male mice showed higher levels of cell proliferation at P28, as well as higher levels of cell survival for P14-labelled cells, compared to female mice. However, female mice showed greater percentages of neuronal differentiation for P14-labelled cells. Finally, we found significant effects of age of BrdU injections on cell proliferation, survival, and neuronal differentiation. Collectively, our results suggest that the loss of vesicular zinc affects normal proliferation and survival of cells born at different age points during postnatal development and highlight prominent sex- and age-dependent differences. Our findings provide the foundation for future studies to further probe the role of vesicular zinc in the modulation of developmental neurogenesis.
... Both FGF-2 and EGF are essential for the proliferation and survival of neural precursor cells 44,45 , and hippocampal neurogenesis depends greatly on FGF-2 46 . An enriched environment, including progenitor cell proliferation and cell survival, improves cognitive performance 47,48 . Orally administered rice-memolin may alter the hippocampal expression of these genes, thereby affecting neurogenesis and improving cognitive function. ...
Many people eat polished rice, while rice bran, a by-product known to be rich in protein and expected to have potential functions for health benefits, has not been effectively utilized. In this study, we determined that orally administered Val-Tyr-Thr-Pro-Gly (VYTPG) derived from rice bran protein improved cognitive decline in mice fed a high-fat diet (HFD). It was demonstrated that VYTPG was released from model peptides corresponding to fragment sequences of original rice proteins (Os01g0941500, Os01g0872700, and allergenic protein) after treatment with thermolysin, a microorganism-derived enzyme often used in industrial scale processes. The thermolysin digest also improved cognitive decline after oral administration in mice. Because VYTPG (1.0 mg/kg) potently improved cognitive decline and is enzymatically produced from the rice bran, we named it rice-memolin. Next, we investigated the mechanisms underlying the cognitive decline improvement associated with rice-memolin. Methyllycaconitine, an antagonist for α7 nicotinic acetylcholine receptor, suppressed the rice-memolin-induced effect, suggesting that rice-memolin improved cognitive decline coupled to the acetylcholine system. Rice-memolin increased the number of 5-bromo-2’-deoxyuridine (BrdU)-positive cells and promoted the mRNA expression of EGF and FGF-2 in the hippocampus, implying that these neurotropic factors play a role in hippocampal neurogenesis after rice-memolin administration. Epidemiologic studies demonstrated that diabetes is a risk factor for dementia; therefore, we also examined the effect of rice-memolin on glucose metabolism. Rice-memolin improved glucose intolerance. In conclusion, we identified a novel rice-derived peptide that can improve cognitive decline. The mechanisms are associated with acetylcholine and hippocampal neurogenesis. Rice-memolin is the first rice-brain-derived peptide able to improve cognitive decline.
... For example, stress and sleep deprivation have been shown to reduce AHN (Gould et al., 1998;Hairston et al., 2005;Lucassen et al., 2010), while running increases neurogenesis (van Praag et al., 2005). Moreover, these environmental factors have been similarly correlated with spatial learning and memory (Nilsson et al., 1999;Oomen et al., 2010Oomen et al., , 2014, highlighting the possibility of leveraging behavioral interventions to target the neurogenic process and, consequently, cognitive ability. ...
... For example, the increase in AHN by EE can be induced by growth or brain-derived neurotrophic factor (BDNF), which are not specific regulators of AHN as they could also facilitate other neuroplastic processes-such as axonal branching, neurotransmission, and successful synapse formation-in the 'old' neurons. 72,73 Despite these limitations, this study supports that, in addition to pharmacological and cognitive therapies, positive and stimulating environmental conditions reduce the drug-induced cognitive decline and hence, could be key factors in the long-term treatment of addiction facilitating abstinence from drug use. 74,75 ...
Cocaine is a widely used psychostimulant drug whose repeated exposure induces persistent cognitive/emotional dysregulation, which could be a predictor of relapse in users. However, there is scarce evidence on effective treatments to alleviate these symptoms. Environmental enrichment (EE) has been shown to be associated with improved synaptic function and cellular plasticity changes related to adult hippocampal neurogenesis (AHN), resulting in cognitive enhancement. Therefore, EE could mitigate the negative impact of chronic administration of cocaine in mice and reduce the emotional and cognitive symptoms present during cocaine abstinence. In this study, mice were chronically administered with cocaine for 14 days, and control mice received saline. After the last cocaine or saline dose, mice were submitted to control or EE housing conditions, and they stayed undisturbed for 28 days. Subsequently, mice were evaluated with a battery of behavioural tests for exploratory activity, emotional behaviour, and cognitive performance. EE attenuated hyperlocomotion, induced anxiolytic-like behaviour and alleviated cognitive impairment in spatial memory in the cocaine-abstinent mice. The EE protocol notably upregulated AHN in both control and cocaine-treated mice, though cocaine slightly reduced the number of immature neurons. Altogether, these results demonstrate that EE could enhance hippocampal neuroplasticity ameliorating the behavioural and cognitive consequences of repeated administration of cocaine. Therefore, environmental stimulation may be a useful strategy in the treatment cocaine addiction.
... Vorhees & Williams, 2006) ve Hebb-Williams testinde (bknz. URL-3) zenginleştirilmiş ortam düzeneğinde bulunan sıçanların bilişsel yeteneklerinin ve beyin plastisitesinin daha fazla geliştiği gözlemlenmiştir (Andin, Hallbeck, Mohammed, & Marcusson, 2007;Nilsson, Perfilieva, Johansson, Orwar, & Eriksson, 1999). Tüm bu bilimsel çalışmaların sonuçlarından hareketle; farklı eğitim materyalleri ile zenginleştirilmiş öğrenme ortamlarının öğrenme ve bellek gelişimine doğrudan etki ederek bireylerin bilişsel ve duyuşsal gelişimlerini önemli ölçüde desteklediği belirtilmektedir(Akıllıoğulu, Kocahan, Babar Melik ve Melik, 2009; İzci ve Erbaş, 2015). ...
Epilepsy, one of the most common neurological disorders, often is not well controlled by current pharmacological and surgical treatments. Sensory neuromodulation, including multi-sensory stimulation, auditory stimulation, olfactory stimulation, is a kind of novel noninvasive mind-body intervention and receives continued attention as complementary safe treatment of epilepsy. In this review, we summarize the recent advances of sensory neuromodulation, including enriched environment therapy, music therapy, olfactory therapy, other mind-body interventions, for the treatment of epilepsy based on the evidence from both clinical and preclinical studies. We also discuss their possible anti-epileptic mechanisms on neural circuit level and propose perspectives on possible research directions for future studies.
Profound environmental, hormonal, and neurobiological changes mark the transition to motherhood as a major biosocial life event. Despite the ubiquity of motherhood, the enduring impact of caregiving on cognition and the brain across the lifespan is not well characterized and represents a unique window of opportunity to investigate human neural and cognitive development. By integrating insights from the human and animal maternal brain literatures with theories of cognitive ageing, we outline a framework for understanding maternal neural and cognitive changes across the lifespan. We suggest that the increased cognitive load of motherhood provides an initial challenge during the peripartum period, requiring continuous adaptation; yet when these demands are sustained across the lifespan, they result in increased late-life cognitive reserve.
A suitable enriched environment favors development but can also influence behavior and neuronal circuits throughout development. Studies have shown that environmental enrichment (EE) can be used as an essential tool or combined with conventional treatments to improve psychiatric and neurological symptoms, including major depressive disorder (MDD) and autism spectrum disorder (ASD). Both disorders affect a significant percentage of the world's population and have complex pathophysiology. Moreover, the available treatments for MDD and ASD are still inadequate for many affected individuals. Experimental models demonstrate that EE has significant positive effects on behavioral modulation. In addition, EE has effects on neurobiology, including improvement in synaptic connections and neuroplasticity, modulation of neurotransmissions, a decrease in inflammation and oxidative stress, and other neurobiology effects that can be involved in the pathophysiology of MDD and ASD. Thus, this review aims to describe the leading behavioral and neurobiological effects associated with EE in MDD and ASD.
In order to determine whether newly born cells in the dentate gyrus of the adult rat express the neuronal marker, neuron-specific enolase, or the glial marker, glial fibrillary acidic protein, we performed combined immunohistochemistry and autoradiography on brains from adult rats perfused at various times ranging from 1 h to four weeks following [3H]thymidine administration. Light-microscopic examination revealed a negligible number of [3H]thymidine-labeled cells showing neuron-specific enolase immunoreactivity during mitosis. However, by two weeks after [3H]thymidine administration, a significant increase in the density of [3H]thymidine-labeled neuron-specific enolase-immunoreactive cells was detected. Three weeks following [3H]thymidine injection the majority of [3H]thymidine-labeled cells (> 70%) were immunoreactive for the neuronal marker. At the four-week time-point, [3H]thymidine-labeled neuron-specific enolase-immunoreactive cells were indistinguishable from neighboring granule cells. In contrast, glial fibrillary acidic protein immunoreactivity was observed in a small but significant number of [3H]thymidine cells at the 1-h time-point and the proportion of labeled cells that were immunoreactive for this cell marker did not increase with time. [3H]Thymidine-labeled cells that were immunoreactive for glial fibrillary acidic protein typically showed morphologic characteristics of radial glia at all time-points. At the 1-h time-point, the majority of [3H]thymidine-labeled cells were observed in the hilus (> 60%) with the remainder being located in the granule cell layer. However, with a four-week survival-time most [3H]thymidine-labeled cells (> 85%) were located in the granule cell layer. The majority of newly born cells in the adult dentate gyrus differentiate into neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
Two neuronal calcium-binding proteins, calbindin-D28k (CaBP) and parvalbumin (PV), were localized in the normal rat hippocampus by using immunocytochemical methods to determine (1) their location and (2) whether a correlation exists between the presence of these two calcium-binding proteins and the selective vulnerability of different hippocampal neuronal populations to experimental seizure activity.
CaBP-like immunoreactivity (CaBP-LI) is present in all dentate granule cells and some, but not all, CA1 and CA2 pyramidal cells. Some CA1 pyramidal cells lack CaBP-LI, and those that do are lightly stained compared to the dentate granule cells. CA3 pyramidal cells appear to contain neither CaBP- nor PV-LI, and no granule or pyramidal cells exhibit PV-LI. CaBP-LI is present in distinct populations of dentate and hippocampal interneurons but absent from others. In area dentata, CaBP-LI is present in a small number of interneurons of the molecular and granule cell layers and in a small population of presumed basket cells in or below the granule cell layer. Conversely, more presumed dentate basket cells exhibit PV-LI than CaBP-LI. In the hilus of area dentata, few cells are CaBP- or PV-immunoreactive. The hilar somatostatin/neuropeptide Y (NPY)-immunoreactive cells and hilar mossy cells, two distinct and large populations, lack CaBP- and PV-LI. In the CA3 region, CaBP-LI is present in a relatively small number of interneurons in each stratum. PV-immunoreactive interneurons in area CA3 are more numerous. In area CA1, CaBP-LI is present in many interneurons in strata radiatum and lacunosum-moleculare. Some, but relatively fewer, CaBP-positive interneurons are present in strata pyramidale and oriens. Conversely, PV-immunoreactive interneurons are numerous in strata pyramidale and oriens but rare in strata radiatum and lacunosummoleculare.
Staining with the particulate chromagen benzidine hydrochloride revealed a previously undescribed dense band of CaBP-LI in the inner dentate molecular layer, a lamina enriched with kainate-displaceable glutamate-binding sites and innervated by the apparently excitatory ipsilateral associational/commissural (IAC) pathway that originates in the CaBP-negative hilar mossy cells. Bilateral electrical stimulation of the perforant path was performed in order to destroy the hilar mossy cells and to determine if this band of CaBP-LI is normally present within the mossy cell terminals. Perforant path stimulation that destroyed hilar mossy cells throughout the dorsal portions of both hippocampi did not abolish the dense CaBP-like immunoreactivity in the inner molecular layer.
In summary, the cell populations visualized by immunocytochemical staining for CaBP- or PV-LI are clearly distinct. All of the relatively seizure-resistant dentate granule cells and many basket cells and hippocampal CA2 pyramidal cells are darkly stained for either CABP- or PV-LI. The seizuresensitive dentate hilar somatostatin/NPY-positive cells, hilar mossy cells, and hippocampal CA3 pyramidal cells appear devoid of both CaBP- and PV-LI. The seizure sensitive CA1 pyramidal cells are devoid of PV-LI and exhibit less CaBP-LI than the seizure-resistant granule cells. Therefore, a positive correlation exists between the presence of at least one of these calcium-binding proteins in hippocampal neurons and their relative resistance to seizure-induced neuronal damage.
These data suggest that the relative vulnerability of different cell populations may be related to differences in the concentration of cytoplasmic proteins capable of sequestering free intracellular calcium.
Following the injection of pregnant mice on the tenth day of gestation with either 200 μCi/kg ³H-thymidine or 200 μCi/kg ³H-bromodeoxyuridine, the half-life of labelled nucleotides in the acid-soluble fraction was found to be of the order of 30 min in various maternal tissues and placentas, and approximately 60–80 min in the embryos. There appears to be no discrimination in turnover rate between thymidine (TdR) and bromodeoxyuridine (BrdU). The administration of a single injection containing 200 μCi/kg ³H-BrdU plus 500 mg/kg BrdU (a known teratogenic dose) resulted in increased labelled nucleotide half-lives in all of the tissues except the embryos. These increased half-lives ranged from 149 min in the maternal liver to 75 min in the kidneys. The turnover rate of labelled nucleotides in the embryos did not change significantly from those observed following a trace dose of ³H-BrdU.
The time course of incorporation of label into the DNA of the various tissues was determined following the injection of the trace doses of ³H-TdR or ³H-BrdU. Significant amounts of DNA label were found in all tissues studied except maternal liver and kidneys, the bulk of the incorporation occurring within one hour of administration. The DNA specific radioactivity had begun to decline by 8 h after injection but was still demonstrable at 48 h. When the teratogenic dose of BrdU was administered along with the ³H-BrdU, the time course of incorporation of label was very similar in all tissues, with the exception of the embryo and maternal intestine, to that observed following injection of the trace dose of ³H-BrdU. The fact that radioactivity found in the DNA fractions after the injection of ³H-BrdU was due to labelled bromouracil, was established by thin-layer chromatography of DNA bases.
At a time in mouse development when BrdU is capable of producing congenital defects in vivo, it is present at its presumed intracellular site of action, the DNA molecule. It is suggested that this demonstration supports the contention that, to study the role of teratogens in the interference with normal differentiation, it is essential to show their presence at their suspected site of action during morphogenesis.
The Morris water maze (MWM) offers several advantages over other methods of studying the neurochemical basis of learning and memory, particularly with respect to its ability to dissociate deficits in memory formation from deficits in sensory, motor, motivational and retrieval processes. The contributions of nearly all of the major neurotransmitter systems have been investigated and consistent patterns have emerged. Normal function in glutamatergic and cholinergic systems is necessary for spatial learning, as blockade of NMDA receptors and cholinergic hypofunction prevents spatial learning but does not impair recall. Peptides such as adrenal and sex hormones and somatostatin may also be necessary for spatial learning. In contrast, activity in either GABAergic or opioidergic systems impairs spatial learning, though by quite different means. GABAergic activity prevents memory formation, whereas opiodergic activity reduces motivation. Normal monoaminergic activity is necessary for normal performance in the MWM, but not for spatial learning per se. However, noradrenergic and serotonergic systems may enhance cholinergic-mediated mnemonic processes. Further research into the relative contributions of different receptor subtypes as well as interactions between neurochemical systems should provide significant advances in our understanding of the neural basis of learning and memory in mammals.
Bilateral aspiration of the dorsal hippocampus produced a disrupttion of blocking of the rabbit's nictitating membrane response in Kamin's two-stage paradigm (Experiment 1) but had no effect on the formation of a Pavlovian conditioned inhibitor (Experiment 2). The results of Experiment 1 indicated that normal animals and those with cortical lesions given conditioning to a light-plus-tone conditioned stimulus (CS) gave conditioned responses (CRs) to both the light and the tone during nonreinforced presentations of each (test phase). If, however, compound conditioning was preceded by tone acquisition, only the tone elicited a CR during testing; that is, blocking was observed. In rabbits with hippocampal lesions, however, CRs were given to both the light and the tone during testing whether or not compound conditioning was preceded by tone acquisition. The data from Experiment 2 showed that rabbits with hippocampal lesions could discriminate as well as normal rabbits and those with cortical lesions between a light (CS+) and light plus tone (CS-). In addition, when the inhibitory tone was subsequently paired with the unconditioned stimulus in retardation testing, animals in all three lesion conditions acquired the CR at the same rate. Thus, it appears that hippocampal lesions do not disrupt conditioned inhibition. The results of these experiments were taken as support for the view that the hippocampus is responsible for "tuning out" stimuli that have no adaptive value to the organism.