Biomedical subjects

Brian R Christie

Publications and source records attributed to Brian R Christie.

15 recordsLinked to original sources

PubMed2006

Temporally specific proliferation events are induced in the hippocampus following acute focal injury.

In models of global brain injury, such as stroke or epilepsy, a large increase in neurogenesis occurs in the dentate gyrus (DG) days after the damage is induced. In contrast, more focal damage in the DG produces an increase in neurogenesis within 24 hr. To determine how cell proliferation and differentiation differs in the DG after acute injury in the DG, focal electrolytic lesions were made and mitotic activity was assessed at early (1 day) and late (5 day) time points. At the early time point, bromodeoxyuridine (BrdU)-positive cells were diffusely spread throughout the extent of the hippocampus that was ipsilateral to the lesion. No significant increase in the subgranular zone (SGZ) of the DG was observed. When BrdU was administered at the later time point, the number of BrdU+ cells in the SGZ of the DG was significantly increased. This fourfold increase in BrdU+ cells also resulted in a significant increase in neurogenesis, as measured 6 weeks following BrdU administration. This increase in neurogenesis was not observed when BrdU was administered at the early time point. These results indicate that focal injury in the DG activates two temporally specific proliferation events and that enhanced neurogenesis is observed only following a latent period after the lesion is made.

Animals↗

PubMed2006

Neurogenesis in the adult hippocampus.

The dentate gyrus (DG) contains one of the few neuronal populations in the mammalian brain that are generated throughout life. Research into the regulation and function of adult neurogenesis continues its rapid growth in popularity. With the researcher new to the field in mind, we review the processes that together constitute adult neurogenesis and some of the methods most commonly used for studying these processes. (c) 2006 Wiley-Liss, Inc.

Animals↗

PubMed2006

Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways.

Environmental enrichment (EE) and voluntary exercise (VEx) have consistently been shown to increase adult hippocampal neurogenesis and improve spatial learning ability. Although it appears that these two manipulations are equivalent in this regard, evidence exists that EE and VEx affect different phases of the neurogenic process in distinct ways. We review the data suggesting that EE increases the likelihood of survival of new cells, whereas VEx increases the level of proliferation of progenitor cells. We then outline the factors that may mediate these relationships. Finally, we provide a model showing that VEx leads to the convergence of key somatic and cerebral factors in the dentate gyrus (DG) to induce cell proliferation. Although insufficient evidence exists to provide a similar model for EE, we suggest that EE-induced cell survival in the DG involves cortical restructuring as a means of promoting survival. We conclude that EE and VEx lead to an increase in overall hippocampal neurogenesis via dissociable pathways, and should therefore, be considered distinct interventions with regard to hippocampal plasticity and associated behaviors.

Animals↗

PubMed2006

Hippocampal cell proliferation is reduced following prenatal ethanol exposure but can be rescued with voluntary exercise.

The ingestion of ethanol during pregnancy has a number of deleterious consequences for the unborn offspring, producing structural and functional deficits that affect the brain and many other organs into adulthood. The hippocampus is a brain area that is particularly sensitive to ethanol's adverse effects. In a previous study we showed that voluntary exercise can ameliorate deficits in long-term potentiation and behavior that occur following prenatal ethanol exposure (Eur J Neurosci, 2005, 21, 1719-1726). In the present study, we investigated the effects of prenatal ethanol exposure on neurogenesis in adulthood, and tested the hypothesis that voluntary exercise would ameliorate any deficits observed. Sprague-Dawley females were administered one of three diets throughout gestation: (i) ethanol (E), a liquid diet containing 36.5% ethanol-derived calories; (ii) pair-fed (PF), a liquid control diet, with maltose-dextrin isocalorically substituted for ethanol, in the amount consumed by an E partner (g/kg body wt/day of gestation); and (iii) ad-libitum-fed control (C), normal laboratory chow and water, ad libitum. The offspring were housed individually at postnatal day (PND) 35, and at PND 50 were randomly assigned to cages either with or without an exercise wheel. BrdU (200 mg/kg, I.P.) was injected on PND 57, and animals terminated either 24 h (proliferation) or 4 weeks (neurogenesis) later. Our results demonstrate that prenatal ethanol exposure significantly decreases both cell proliferation and neurogenesis in the adult dentate gyrus. Animals in the PF condition also showed reduced neurogenesis. In contrast, all animals that engaged in voluntary exercise showed a significant increase in cell proliferation and neurogenesis. These results indicate that prenatal ethanol exposure can suppress both cell proliferation and neurogenesis, and that these effects may be, at least in part, nutritionally mediated. Importantly, voluntary exercise appears to have beneficial effects for these long-lasting deficits in hippocampal volume and cell number that have been observed in animals exposed to ethanol in utero.

Alcohol-Induced Disorders, Nervous System↗

PubMed2006

Contribution of NR2A and NR2B NMDA subunits to bidirectional synaptic plasticity in the hippocampus in vivo.

It has recently been proposed that activation of the NR2A subunit results in Long-term potentiation (LTP) induction, whereas activation of the NR2B subunit results in long-term depression (LTD) induction. The present study undertakes to replicate these findings in vivo to determine if a role for specific subunits in synaptic plasticity can be shown in the intact brain. Field recordings were made from the CA1 subfield of the hippocampus using Schaffer collateral stimulation in anesthetized male Sprague-Dawley rats. Antagonists of the N-methyl-D-aspartate receptors NR2A and NR2B subunits were administered by either intraperitoneal (i.p.) or intrahippocampal (i.h.) injections to assess their involvement in LTP (100 Hz stimuli) and LTD (200 Paired-burst stimuli). i.h. injection of Ro25-6981 (100 microM) significantly attenuated hippocampal LTP expression and completely blocked LTD expression. When administered i.p., Ro25-6981 (6 mg/kg) again blocked LTD, but did not significantly diminish the expression of LTP. When NVP-AAM077 was administered i.h. (80 microM) both LTP and LTD were completely abolished. The administration of this compound i.p. (1.2 mg/kg) also significantly attenuated LTP, but did not affect LTD. These data suggest that both NR2A and NR2B subunits can play roles in LTP and LTD in the hippocampus in vivo.

Analysis of Variance↗

PubMed2006

Antidepressant effects of exercise: evidence for an adult-neurogenesis hypothesis?

It has been hypothesized that a decrease in the synthesis of new neurons in the adult hippocampus might be linked to major depressive disorder (MDD). This hypothesis arose after it was discovered that antidepressant medications increased the synthesis of new neurons in the brain, and it was noted that the therapeutic effects of antidepressants occurred over a time span that approximates the time taken for the new neurons to become functional. Like antidepressants, exercise also increases the synthesis of new neurons in the adult brain: a 2-3-fold increase in hippocampal neurogenesis has been observed in rats with regular access to a running wheel when they are compared with control animals. We hypothesized, based on the adult-neurogenesis hypothesis of MDD, that exercise should alleviate the symptoms of MDD and that potential mechanisms should exist to explain this therapeutic effect. Accordingly, we evaluated studies that suggest that exercise is an effective treatment for MDD, and we explored potential mechanisms that could link adult neurogenesis, exercise and MDD. We conclude that there is evidence to support the hypothesis that exercise alleviates MDD and that several mechanisms exist that could mediate this effect through adult neurogenesis.

Adult↗

PubMed2005

Isolectin-IB 4 as a vascular stain for the study of adult neurogenesis.

It has been proposed that new neurons in the adult brain might preferentially develop in the immediate vicinity of existing vasculature, an area that has been referred to as a "vascular niche". The most common method for identifying neurons that arise as the result of mitotic activity is to label them with the thymidine analogue bromodeoxyuridine (BrdU), and a nuclear marker for mature neurons (NeuN). Unfortunately, commercially available forms of NeuN and the vasculature stain, RECA-1, are incompatible, as both antibodies are raised in the same species. This technical limitation has impeded the analysis of the relationship between new neurons and existing vasculature. In the present work we show that Isolectin-IB 4, a 114 k Da protein isolated from the seeds of the African legume, Griffonia simplicifolia, can be used to identify vasculature in conjunction with both NeuN and BrdU immunohistochemistry. Isolectin-IB 4 serves as an easy to use and robust marker for obtaining spatial information regarding the proximity of new neurons to vasculature in the mammalian brain.

Age Factors↗

PubMed2005

Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density.

Voluntary exercise produces a dramatic increase in the number of bromodeoxyuridine (BrdU)-positive cells in the adult dentate gyrus (DG); however, it has never been determined whether this increase reflects neurogenic activity or some exercise-induced change in the metabolic processing of systemically injected BrdU. In these experiments, we show that 1) 200 mg/kg is a saturating dose for single injections of BrdU in both control and voluntary exercise animals; 2) there is significantly more cell labeling in animals that exercise when saturating doses of BrdU are employed; 3) high doses of BrdU do not affect the number, appearance, or distribution of labeled cells; 4) voluntary exercise leads to similar increases in the number of cells expressing Ki67, an intrinsic marker of cellular proliferation; 5) both dendritic length and complexity are significantly increased in the DG of animals that exercise; and 6) spine density is significantly greater on dendrites in the DG following voluntary exercise. This study demonstrates that exercise up-regulates neurogenic activity in the DG of adult rats, independently of any putative changes in altered BrdU metabolism, and that it also substantially alters the morphology of dentate granule cell dendrites. The dramatic changes in the cytoarchitecture of the DG induced by voluntary exercise might underlie the enhancement of hippocampal long-term potentiation and hippocampal-dependent memory that our group has previously described. These results suggest that exercise may be an effective component of therapeutic regimes aimed at improving the functioning of individuals with neuropathologies that involve the degradation of cells in the hippocampus.

Age Factors↗

PubMed2005

Voluntary exercise rescues deficits in spatial memory and long-term potentiation in prenatal ethanol-exposed male rats.

Prenatal ethanol exposure can lead to long-lasting impairments in the ability to process spatial information in rats, as well as produce long-lasting deficits in the ability of animals to exhibit long-term potentiation, a biological model of learning and memory processing. Conversely, we have recently shown that both spatial memory and long-term potentiation can be enhanced in animals that are given access to a running wheel in their home cage. In the present study, Sprague-Dawley rat dams were given one of three diets throughout gestation: (i) a liquid diet containing ethanol (35.5% ethanol-derived calories); (ii) a liquid diet, isocaloric to the ethanol diet, but with maltose-dextrin substituting for the ethanol derived calories and (iii) an ad libitum diet of standard rat chow. At weaning (28 days) animals were housed individually in either a standard rat cage, or a cage that contained a running wheel. Adult offspring were tested on a two trial version of the Morris water maze beginning at postnatal day 60, for five consecutive days. Following this, the capacity of the perforant path to dentate gyrus pathway to sustain long-term potentiation was examined in these animals using theta-patterned conditioning stimuli. Our results demonstrate that prenatal ethanol exposure can produce pronounced deficits in both spatial memory and long-term potentiation, but that allowing animal's access to voluntary exercise can attenuate these deficits to the point that those exposed to ethanol prenatally can no longer be differentiated from control animals. These findings indicate that voluntary exercise may have therapeutic benefits for individuals that have undergone prenatal ethanol exposure.

Animals↗

PubMed2005

Nestin-expressing cells and their relationship to mitotically active cells in the subventricular zones of the adult rat.

Nestin is a protein that is thought to be expressed in neural stem cells; however, there is a paucity of data on nestin expression in vivo, and little is known of the relationship between nestin and mitotically active cell populations in the subventricular zones (SVZ). In this study, the subventricular zone of the third ventricle contained a high proportion of cells that expressed nestin, while there were significantly fewer cells that expressed nestin in the SVZ of the lateral ventricles. In contrast, bromodeoxyuridine (BrdU) immunoreactivity was the diametric opposite, being higher in the SVZ of the lateral ventricle than in the SVZ of the third ventricle. Morphological and anatomical evidence suggests that nestin-expressing cells in these two areas may be different cell types. In a separate set of experiments, an acute localized lesion was induced adjacent to one of the ventricles. While the number of BrdU cells and Ki-67 cells in the SVZs increased with this manipulation, the number of nestin-expressing cells did not change significantly. These data indicate that the expression of nestin does not correlate with mitotic activity in cells of the SVZs under either normal or inflammatory conditions. It is hypothesized that nestin-expressing cells in the SVZs may give way to transit amplifying cells that in turn give way to immature neurons or glia. These transit-amplifying cells may have a much higher rate of mitosis than nestin-positive cells and may react to neural damage by increasing their rate of proliferation.

Animals↗

PubMed2004

Prolonged cannabinoid treatment results in spatial working memory deficits and impaired long-term potentiation in the CA1 region of the hippocampus in vivo.

Adult male Long-Evans rats were administered the potent cannabinoid 1 receptor agonist HU-210 (100 microg/kg, i.p.) for 15 days continuously and their performance on a matching-to-place version of the Morris water maze was subsequently evaluated. Overall, experimental animals performed significantly worse initially on the reference memory component of this task, but their performance improved over 5 days until it was indistinguishable from that of control animals. Animals given HU-210 did not exhibit working memory impairments at short intertrial delays (30 s); however, significant impairments were observed in learning performance with longer intertrial delays (300 s). In vivo electrophysiological analyses revealed that long-term potentiation in the CA1 region of the hippocampus was significantly impaired following the administration of HU-210 for 15 days. These results indicate that long-term cannabinoid exposure can produce marked deficits in reference and working memory performance, and also impair hippocampal synaptic plasticity in vivo.

Animals↗

PubMed2003

Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function.

DNA methylation-mediated epigenetic regulation plays critical roles in regulating mammalian gene expression, but its role in normal brain function is not clear. Methyl-CpG binding protein 1 (MBD1), a member of the methylated DNA-binding protein family, has been shown to bind methylated gene promoters and facilitate transcriptional repression in vitro. Here we report the generation and analysis of MBD1-/- mice. MBD1-/- mice had no detectable developmental defects and appeared healthy throughout life. However, we found that MBD1-/- neural stem cells exhibited reduced neuronal differentiation and increased genomic instability. Furthermore, adult MBD1-/- mice had decreased neurogenesis, impaired spatial learning, and a significant reduction in long-term potentiation in the dentate gyrus of the hippocampus. Our findings indicate that DNA methylation is important in maintaining cellular genomic stability and is crucial for normal neural stem cell and brain functions.

Animals↗

PubMed2003

Active dendrites, potassium channels and synaptic plasticity.

The dendrites of CA1 pyramidal neurons in the hippocampus express numerous types of voltage-gated ion channel, but the distributions or densities of many of these channels are very non-uniform. Sodium channels in the dendrites are responsible for action potential (AP) propagation from the axon into the dendrites (back-propagation); calcium channels are responsible for local changes in dendritic calcium concentrations following back-propagating APs and synaptic potentials; and potassium channels help regulate overall dendritic excitability. Several lines of evidence are presented here to suggest that back-propagating APs, when coincident with excitatory synaptic input, can lead to the induction of either long-term depression (LTD) or long-term potentiation (LTP). The induction of LTD or LTP is correlated with the magnitude of the rise in intracellular calcium. When brief bursts of synaptic potentials are paired with postsynaptic APs in a theta-burst pairing paradigm, the induction of LTP is dependent on the invasion of the AP into the dendritic tree. The amplitude of the AP in the dendrites is dependent, in part, on the activity of a transient, A-type potassium channel that is expressed at high density in the dendrites and correlates with the induction of the LTP. Furthermore, during the expression phase of the LTP, there are local changes in dendritic excitability that may result from modulation of the functioning of this transient potassium channel. The results support the view that the active properties of dendrites play important roles in synaptic integration and synaptic plasticity of these neurons.

Animals↗

PubMed2003

Reduced synaptic plasticity in the lateral perforant path input to the dentate gyrus of aged C57BL/6 mice.

Hippocampal slices obtained from C57BL/6 mice (3-25 mo) were used to investigate the effects of aging on excitatory postsynaptic potentials (EPSPs) elicited in dentate gyrus with lateral perforant path stimulation. The maximal amplitude of the EPSP, as well as the degree of paired-pulse facilitation, was significantly reduced in animals aged 12 mo or more compared with younger animals (<12 mo). Although all animals showed equivalent short-term potentiation (STP) in response to high-frequency stimulation, this did not translate into a long-lasting increase in synaptic efficacy in the older animals. A significant degree of long-term potentiation (LTP) of synaptic efficacy was only observed in animals <12 mo of age when measured 30 min after induction. Blocking GABAA-mediated inhibition significantly enhanced STP in younger and older animals; however, a significant degree of LTP was again only observed in slices taken from younger animals. These data indicate that the lateral perforant path input to the dentate gyrus is altered by the aging process, and that this results in a reduction in the capacity of this input to exhibit long-lasting synaptic plasticity.

Aging↗

PubMed2002

Functional neurogenesis in the adult hippocampus.

There is extensive evidence indicating that new neurons are generated in the dentate gyrus of the adult mammalian hippocampus, a region of the brain that is important for learning and memory. However, it is not known whether these new neurons become functional, as the methods used to study adult neurogenesis are limited to fixed tissue. We use here a retroviral vector expressing green fluorescent protein that only labels dividing cells, and that can be visualized in live hippocampal slices. We report that newly generated cells in the adult mouse hippocampus have neuronal morphology and can display passive membrane properties, action potentials and functional synaptic inputs similar to those found in mature dentate granule cells. Our findings demonstrate that newly generated cells mature into functional neurons in the adult mammalian brain.

Aging↗