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H van Praag

Publications and source records attributed to H van Praag.

At least 19 recordsLinked to original sources
PubMed2004

Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo.

We have previously shown that voluntary exercise produces enhanced neurogenesis and long-term potentiation (LTP) in the dentate gyrus (DG) of mice in vitro. In the present experiments we show that rats given access to a running wheel (Runners) exhibit significantly more short-term potentiation and LTP with theta-patterned conditioning stimulation in vivo than do age-matched litter mates (Controls). This increase in LTP appears to reflect an alteration in the induction threshold for synaptic plasticity that accompanies voluntary exercise. Weak theta-patterned stimulation, which did not produce LTP in control subjects, produced a robust and long-lasting LTP in Runners. LTP induction in both groups was dependent upon the activation of N-methyl-D-aspartate (NMDA) receptors, and could be blocked by the competitive antagonist [+/-]-3-[2-carboxypiperazin-4-yl] propanephosphonic acid. Consistent with these findings, we found that mRNA levels for NR2B subtype of NMDA receptor were increased specifically in the DG of Runners. In addition to changes in NR2B mRNA levels, quantitative polymerase chain reaction analysis revealed that brain-derived neurotrophic factor (BDNF) and glutamate receptor 5 mRNA levels were also significantly elevated in the DG of Runners, but not in other areas of the hippocampus. Thus, alterations in the expression of BDNF, and specific glutamate receptor subtypes, may underlie the ability of exercise to enhance neurogenesis and reduce the threshold for LTP in the DG.

Age Factors↗
PubMed2001

Ataxia telangiectasia mutated is essential during adult neurogenesis.

Ataxia telangiectasia (A-T) is an autosomal recessive disease characterized by normal brain development followed by progressive neurodegeneration. The gene mutated in A-T (ATM) is a serine protein kinase implicated in cell cycle regulation and DNA repair. The role of ATM in the brain and the consequences of its loss on neuronal survival remain unclear. We studied the role of ATM in adult neural progenitor cells in vivo and in vitro to define the role of ATM in dividing and postmitotic neural cells from Atm-deficient (Atm(-/-)) mice in a physiologic context. We demonstrate that ATM is an abundant protein in dividing neural progenitor cells but is markedly down-regulated as cells differentiate. In the absence of ATM, neural progenitor cells of the dentate gyrus show abnormally high rates of proliferation and genomic instability. Atm(-/-) cells in vivo, and in cell culture, show a blunted response to environmental stimuli that promote neural progenitor cell proliferation, survival, and differentiation along a neuronal lineage. This study defines a role for ATM during the process of neurogenesis, demonstrates that ATM is required for normal cell fate determination and neuronal survival both in vitro and in vivo, and points to a mechanism for neuronal cell loss in progressive neurodegenerative diseases.

Animals↗
PubMed2000

Lentiviral vectors: regulated gene expression.

Lentiviral vectors can deliver and express genes in a wide variety of dividing and nondividing cells. These include terminally differentiated neurons, myotubes, hepatocytes, and hematopoietic stem cells. We now describe the generation of lentiviral vectors in which the expression of the transgene can be regulated. We have developed an inducible lentiviral vector system that contains the entire tetracycline (Tet)-regulated system developed by H. Bujard and colleagues. The novel vector expresses the GFP reporter gene and the tetracycline transactivator under the control of the tetracycline-inducible promoter and the human CMV promoter, respectively. In vitro transduction of human 293 cells resulted in a very low basal expression of GFP in the presence of the effector substance doxycyline. Withdrawal of doxycyline induced a more than 500-fold increase in transgene expression. Switching transgene expression "off and on" did not change either the kinetics or the magnitude of induction. Maximal suppression of GFP mRNA transcription was achieved within 24 h of addition of the drug; however, due to the slow turnover rate of GFP, green fluorescent cells could be detected up to 10 days following doxycyline treatment. Following transduction of rat brain with recombinant lentiviruses, doxycyline-regulated GFP expression could be observed in terminally differentiated neurons. Specifically, by adding or withdrawing doxycyline from the rats' drinking water, induction and suppression of GFP expression could be regulated in vivo. These studies show that an inducible lentiviral vector can deliver and regulate transgene expression in vivo. We believe that regulated gene expression is an essential tool for successful gene therapy approaches.

Animals↗
PubMed2000

Activity-dependent regulation of neuronal plasticity and self repair.

Plasticity is an essential characteristic of the brain: it is part of how the brain functions and is continuous while the brain interacts with the outer world. The state of activation and the level of activity of the entire organism affect the brain's plastic response. Brain plasticity has many substrates, ranging from synapses to neurites and entire cells. The production of new neurons is part of plasticity even in the adult and old brain, but under normal conditions neurogenesis only occurs in two privileged regions of the adult brain: hippocampus and olfactory system. At least in the hippocampus, physical activity stimulates neurogenesis by acting on the proliferation of neuronal stem cells. More specific functions such as learning may be able to recruit new neurons from the pool of cells with neurogenic potential. In a broader context neuronal stem cells can likely be found throughout the brain. Therefore, novel approaches to neuroregeneration will, when most effective, make use of the activity-related effects on neuronal stem cells in the adult brain to activate these stem cells in a targeted manner to enhance brain function.

Animals↗
PubMed2000

Neural consequences of environmental enrichment.

Neuronal plasticity is a central theme of modern neurobiology, from cellular and molecular mechanisms of synapse formation in Drosophila to behavioural recovery from strokes in elderly humans. Although the methods used to measure plastic responses differ, the stimuli required to elicit plasticity are thought to be activity-dependent. In this article, we focus on the neuronal changes that occur in response to complex stimulation by an enriched environment. We emphasize the behavioural and neurobiological consequences of specific elements of enrichment, especially exercise and learning.

Animals↗
PubMed2000

Adult brain neurogenesis and psychiatry: a novel theory of depression.

Neurogenesis (the birth of new neurons) continues postnatally and into adulthood in the brains of many animal species, including humans. This is particularly prominent in the dentate gyrus of the hippocampal formation. One of the factors that potently suppresses adult neurogenesis is stress, probably due to increased glucocorticoid release. Complementing this, we have recently found that increasing brain levels of serotonin enhance the basal rate of dentate gyrus neurogenesis. These and other data have led us to propose the following theory regarding clinical depression. Stress-induced decreases in dentate gyrus neurogenesis are an important causal factor in precipitating episodes of depression. Reciprocally, therapeutic interventions for depression that increase serotonergic neurotransmission act at least in part by augmenting dentate gyrus neurogenesis and thereby promoting recovery from depression. Thus, we hypothesize that the waning and waxing of neurogenesis in the hippocampal formation are important causal factors, respectively, in the precipitation of, and recovery from, episodes of clinical depression.

Adult↗
PubMed1999

Running enhances neurogenesis, learning, and long-term potentiation in mice.

Running increases neurogenesis in the dentate gyrus of the hippocampus, a brain structure that is important for memory function. Consequently, spatial learning and long-term potentiation (LTP) were tested in groups of mice housed either with a running wheel (runners) or under standard conditions (controls). Mice were injected with bromodeoxyuridine to label dividing cells and trained in the Morris water maze. LTP was studied in the dentate gyrus and area CA1 in hippocampal slices from these mice. Running improved water maze performance, increased bromodeoxyuridine-positive cell numbers, and selectively enhanced dentate gyrus LTP. Our results indicate that physical activity can regulate hippocampal neurogenesis, synaptic plasticity, and learning.

Animals↗
PubMed1999

Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus.

Exposure to an enriched environment increases neurogenesis in the dentate gyrus of adult rodents. Environmental enrichment, however, typically consists of many components, such as expanded learning opportunities, increased social interaction, more physical activity and larger housing. We attempted to separate components by assigning adult mice to various conditions: water-maze learning (learner), swim-time-yoked control (swimmer), voluntary wheel running (runner), and enriched (enriched) and standard housing (control) groups. Neither maze training nor yoked swimming had any effect on bromodeoxyuridine (BrdU)-positive cell number. However, running doubled the number of surviving newborn cells, in amounts similar to enrichment conditions. Our findings demonstrate that voluntary exercise is sufficient for enhanced neurogenesis in the adult mouse dentate gyrus.

Animals↗
PubMed1999

A packaging cell line for lentivirus vectors.

Lentivirus vectors can transduce dividing and nondividing cells. Using three-plasmid transient transfections, high-titer (>10(9) IU/ml) recombinant lentivirus vectors pseudotyped with vesicular stomatitis virus G (VSV-G) protein can be generated (T. Kafri et al., Nat. Genet. 17:314-317, 1997; H. Miyoshi et al., Proc. Natl. Acad. Sci. USA 94:10319-10323, 1997; L. Naldini et al., Science 272:263-267, 1996). The recombinant lentiviruses can efficiently infect brain, liver, muscle, and retinal tissue in vivo. Furthermore, the transduced tissues demonstrated long-term expression of reporter genes in immunocompetent rodents. We now report the generation of a tetracycline-inducible VSV-G pseudotyped lentivirus packaging cell line which can generate virus particles at titers greater than 10(6) IU/ml for at least 3 to 4 days. The vector produced by the inducible cell line can be concentrated to titers of 10(9) IU/ml and can efficiently transduce nondividing cells in vitro and in vivo. The availability of a lentivirus packaging cell line will significantly facilitate the production of high-titer lentivirus vectors for gene therapy and study of human immunodeficiency virus biology.

Animals↗
PubMed1998

Unilateral hippocampal ablation at birth causes a reduction in contralateral LTP.

Subcortical damage in neonates often has more severe consequences than in adults. Unilateral electrolytic hippocampal lesions in adult rats typically result in transient memory deficits, whereas neonatal lesions cause lasting memory impairments. We hypothesized that unilateral lesions made at birth may affect synaptic physiology in the contralateral hippocampus. Consequently, the ability to sustain long-term potentiation (LTP), a form of synaptic plasticity believed to underlie certain forms of memory, was compared between slices from the remaining hippocampus of rats lesioned as newborns and as adults. Initial studies showed that a train of 10 stimulation bursts patterned after the hippocampal theta rhythm produced robust and stable LTP both in slices from controls and rats lesioned at birth. However, a theta burst pattern of stimulation closer to intrinsic physiology (five burst pairs separated by 30 s each), induced significantly less LTP in slices from rats lesioned at birth compared to those from controls and rats lesioned as adults. To investigate possible mechanisms underlying the deficit, the degree of paired-pulse facilitation (PPF) as well as the amount of depolarization occurring between two successive theta bursts were analyzed. The lesion did not detectably change PPF characteristics, suggesting that presynaptic mechanisms are normal. However, the extent to which a burst response was increased by a prior burst was significantly diminished in slices from rats lesioned at birth compared to those from controls and rats lesioned as adults, indicating that postsynaptic factors involved in the initial triggering events of LTP are affected by the lesion. Reduced ability to sustain LTP in the remaining hippocampus may contribute to impaired memory function after unilateral neonatal hippocampal lesion.

Animals↗
PubMed1998

Unilateral hippocampal lesions in newborn and adult rats: effects on spatial memory and BDNF gene expression.

Subcortical damage at birth often produces more severe deficits than similar lesions in an adult. In the present study, effects of unilateral electrolytic hippocampal ablations made on postnatal day 1 or in 3-month-old adult rats, were compared. Exploratory behavior and spatial navigation in the Morris water maze (MWM) were assessed 8 and 20 weeks after hippocampal damage. Rats with neonatal damage did not respond to novelty in the environment and did not learn to find the hidden platform in the MWM. Rats lesioned as adults did learn the water maze task, but slower than controls. We hypothesized that behavioral deficits observed in rats lesioned at birth, may be due, in part, to neurochemical dysfunction of the contralateral hippocampus. Specifically, cholinergic and GABAergic neurotransmission were assessed by measuring choline-acetyltransferase (ChAT) and GABAdecarboxylase (GAD) activity. In addition, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) mRNA levels were assayed in the remaining (contralateral) hippocampus. Of these molecules, only BDNF gene expression was significantly reduced (by 30%) at 8 and 20 weeks after neonatal and adult unilateral ablation. The similar reduction in BDNF mRNA in both treatment groups does not correspond with the lesion's differential effect on memory function. However, the more severe learning impairment after neonatal lesion may reflect increased dependence on trophins during development.

Aging↗
PubMed1997

Neonatal vs. adult unilateral hippocampal lesions: differential alterations in contralateral hippocampal theta rhythm.

Subcortical damage often has more severe consequences in neonates than in adults. For example, unilateral hippocampal lesions in adult rats typically lead to transient memory deficits, whereas neonatal lesions cause lasting learning impairment. We hypothesized that the defects triggered by unilateral damage may include synaptic dysfunction in the contralateral hippocampus. Consequently, we examined the hippocampal theta rhythm, an EEG pattern thought to be associated with learning. Initial comparisons between intact and lesioned rats revealed no obvious differences in basal theta rhythm properties. However, manipulations of ascending brainstem projections to hippocampus with drugs specific for serotonergic, noradrenergic and cholinergic receptors uncovered differences. Antagonism of 5-HT3 receptors known to promote learning significantly increased theta frequency in controls and adult lesioned rats, but not after neonatal damage. In contrast, blockade of noradrenergic-alpha2 receptors had no effect. Antagonism of cholinergic receptors which typically impairs learning disrupted theta and caused irregular, high-amplitude activity that was significantly more pronounced in the lesioned groups. A final approach involved pharmacological facilitation of AMPA receptor-mediated currents, using a drug which enhances memory. This treatment significantly enhanced theta frequency in controls and animals lesioned as adults. In contrast, it failed to do so in rats lesioned at birth. These observations suggest that latent dysfunction in contralateral hippocampal physiology may contribute to the lasting memory deficits seen after unilateral hippocampal lesion in neonates.

Adrenergic alpha-Antagonists↗
PubMed1996

Unilateral neonatal hippocampal lesion alters septal innervation and trophism of the entorhinal cortex.

It is generally assumed that central nervous system injury sustained during development produces less severe behavioral deficits than damage in the adult, due to increased plasticity of the immature brain. However, developmental plasticity may also exacerbate deficits, presumably through formation of anomalous connections. Previous studies showed that after unilateral neonatal, but not adult, electrolytic hippocampal lesion spatial memory is severely impaired. To determine whether the memory deficit is correlated with anatomical changes in a major hippocampal afferent system, the septal input, the anterograde tracer Phaeseolus vulgaris leucoagglutinin was injected into the medial septum 2 months after unilateral neonatal hippocampal lesion. The density of septal fiber projections into the entorhinal cortex (EC) was found to be increased. Choline-acetyltransferase activity increased significantly in the EC 2 months postlesion, suggesting that septal cholinergic fibers are sprouting. Finally, nerve growth factor (NGF), which can mediate sprouting, was measured in the EC, NGF protein increased transiently 7 to 12 days postlesion in the ipsilateral EC, suggesting that increased trophic support is associated with growth of septal afferents into the EC. Thus, neonatal hippocampal lesion causes a reorganization of axonal connections associated with elevated NGF in the target region of the increased septal input. Moreover, since previous studies showed that the neonatal lesion is accompanied by a spatial memory deficit, this plasticity may compromise function of the remaining circuitry.

Animals↗
PubMed1995

Caffeine attenuates scopolamine-induced memory impairment in humans.

Caffeine consumption can be beneficial for cognitive functioning. Although caffeine is widely recognized as a mild CNS stimulant drug, the most important consequence of its adenosine antagonism is cholinergic stimulation, which might lead to improvement of higher cognitive functions, particularly memory. In this study, the scopolamine model of amnesia was used to test the cholinergic effects of caffeine, administered as three cups of coffee. Subjects were 16 healthy volunteers who received 250 mg caffeine and 2 mg nicotine separately, in a placebo-controlled double-blind cross-over design. Compared to placebo, nicotine attenuated the scopolamine-induced impairment of storage in short-term memory and attenuated the scopolamine-induced slowing of speed of short-term memory scanning. Nicotine also attenuated the scopolamine-induced slowing of reaction time in a response competition task. Caffeine attenuated the scopolamine-induced impairment of free recall from short- and long-term memory, quality and speed of retrieval from long-term memory in a word learning task, and other cognitive and non-cognitive measures, such as perceptual sensitivity in visual search, reading speed, and rate of finger-tapping. On the basis of these results it was concluded that caffeine possesses cholinergic cognition enhancing properties. Caffeine could be used as a control drug in studies using the scopolamine paradigm and possibly also in other experimental studies of cognitive enhancers, as the effects of a newly developed cognition enhancing drug should at least be superior to the effects of three cups of coffee.

Adult↗
PubMed1992

The effects of systemic morphine on behavior and EEG in newborn rats.

Early studies suggested that newborn animals are far more susceptible to the convulsant effect of systemic morphine than adult animals. The present study reassessed morphine's (0, 6, 12.5, 25, 50, 100 and 300 mg/kg) toxic effects, making use of electroencephalographic (EEG) recordings, behavioral observations and the specific opiate antagonist naloxone in immature rats (postnatal days 1, 3, 6, 12 and 24). Although morphine had opiate-specific effects (such as inhibition of activity at low doses), non-specific effects (such as hyperactivity) elicited by the highest doses, predominated in the 3 youngest age groups. At day 12 high doses of morphine first produced Straub tail and catatonia. At this age morphine produced EEG spikes that were not reversed by naloxone. Only at day 24 were electrographic spikes temporarily inhibited by naloxone. Behavioral convulsions were never observed, at any age. These findings indicate that morphine is less toxic in newborns than suggested previously.

Animals↗
PubMed1992

Effect of m-chlorophenylpiperazine on plasma arginine-vasopressin concentrations in healthy subjects.

It has been demonstrated convincingly that ACTH and prolactin release are under the stimulatory control of serotonin (5-hydroxytryptamine, 5HT). Recent animal studies suggest that stimulation of 5HT activity also induces the release of arginine-vasopressin (AVP). More specifically, m-chlorophenylpiperazine (MCPP), a 5HT agonist widely used to examine 5HT receptor responsivity in human subjects, has been found to induce AVP release in rodents. This study examined whether MCPP increased plasma AVP levels in healthy human subjects. MCPP was administered orally to 17 healthy subjects in a placebo-controlled design in doses of 0.25 and 0.5 mg/kg. AVP was measured twice hourly over a 210 min period after administration of capsules. MCPP did not significantly alter AVP levels as compared to placebo. However, female subjects had significantly lower plasma AVP levels than males. Since it has been suggested that MCPP-induced AVP release in animals is due to stimulation of 5HT1c receptors, the fact that MCPP did not induce the release of AVP in humans suggests that either MCPP is not a potent 5HT1c agonist or that AVP is not released by stimulation of 5HT(1c) receptors in human subjects. The observation of gender differences in plasma AVP levels suggests that this factor should be taken into account in future studies of AVP secretion in plasma.

Adult↗
PubMed1991

The development of stimulation-produced analgesia (SPA) in the rat.

The present study studied the development of stimulation produced analgesia (SPA) from the periaqueductal gray (PAG) in rats. A monopolar stimulating electrode was lowered into the dorsal or ventral PAG of animals aged 7, 14, 21, or 90-120 days. Constant current cathodal pulses (100 Hz, 100 microseconds) were delivered, starting 10 s before analgesia was tested by the tail-flick (TF) test and continuing throughout each TF trial or until cut-off (7 s). Current intensity was increased stepwise (3-200 microA). It was found that SPA can be elicited starting at 21 days, but not earlier. However, supraspinal modulation of nociception is still immature at 3 weeks after birth. First, stimulation intensities needed to produce SPA are higher in 21-day-old pups than in adult animals. Second, in 21-day-old pups, but not in adults effective current intensities in the dorsal PAG are higher than in the ventral PAG. Third, naltrexone decreases SPA from the ventral PAG in 21-day-old pups, but not in adult animals. These findings indicate that supraspinal modulation of nociception develops only 3 weeks after birth, with the ventral PAG maturing prior to the dorsal PAG, and that the contribution of endogenous opioids to SPA does not remain constant throughout the ontogeny of rats.

Aging↗