Effects of voluntary physical exercise on adult hippocampal neurogenesis and behavior of Ts65Dn mice, a model of Down syndrome.

Llorens-Martín MV, Rueda N, Tejeda GS, Flórez J, Trejo JL, Martínez-Cué C.

doi: 10.1016/j.neuroscience.2010.09.043.

The Ts65Dn (TS) mouse is the most widely used model of Down syndrome (DS). This mouse shares many phenotypic characteristics with the human condition including cognitive and neuromorphological alterations. In this study the effects of physical exercise on hippocampal neurogenesis and behavior in TS mice were assessed. 10-12 month-old male TS and control (CO) mice were submitted to voluntary physical exercise for 7 weeks and the effects of this protocol on hippocampal morphology, neurogenesis and apoptosis were evaluated. Physical exercise improved performance in the acquisition sessions of the Morris water maze in TS but not in CO mice. Conversely, it did not have any effect on anxiety or depressive behavior in TS mice but it did reduce the cognitive components of anxiety in CO mice. TS mice presented a reduced dentate gyrus (DG) volume, subgranular zone area and number of granule neurons. Hippocampal neurogenesis was reduced in TS mice as shown by the reduced number of 5-bromo-2-deoxyuridine (BrdU) positive cells. Voluntary physical exercise did not rescue these alterations in TS mice but it did increase the number of doublecortin (DCX)-and phospho histone 3 (PH3)-positive neurons in CO mice. It is concluded that physical exercise produced a modest anxiolytic effect in CO mice and that this was accompanied by an increased number of immature cells in the hippocampal DG. On the other hand, voluntary physical exercise exerted a positive effect on TS mice learning of the platform position in the Morris water maze that seems to be mediated by a neurogenesis-independent mechanism.

Differential regulation of the variations induced by environmental richness in adult neurogenesis as a function of time: a dual birthdating analysis.

Llorens-Martín M, Tejeda GS, Trejo JL.

PLoS One. 
doi: 10.1371/journal.pone.0012188.

Adult hippocampal neurogenesis (AHN) augments after environmental enrichment (EE) and it has been related to some of the anxiolytic, antidepressant and neuroprotective effects of EE. Indeed, it has been suggested that EE specifically modulates hippocampal neurogenic cell populations over the course of time. Here we have used dual-birthdating to study two subpopulations of newborn neuron in mice (Mus musculus): those born at the beginning and at the end of enrichment. In this way, we demonstrate that while short-term cell survival is upregulated after an initial 1 week period of enrichment in 2 month old female mice, after long-term enrichment (2 months) neither cell proliferation nor the survival of the younger newly born cell populations are distinguishable from that observed in non-enriched control mice. In addition, we show that the survival of older newborn neurons alone (i.e. those born at the beginning of the enrichment) is higher than in controls, due to the significantly lower levels of cell death. Indeed, these parameters are rapidly adjusted to the sudden cessation of the EE conditions. These findings suggest both an early selective, long-lasting effect of EE on the neurons born in the initial stages of enrichment, and a quick response when the environment again becomes impoverished. Therefore, EE induces differential effects on distinct subpopulations of newborn neurons depending on the age of the immature cells and on the duration of the EE itself. The interaction of these two parameters constitutes a new, specific regulation of these neurogenic populations that might account for the long-term enrichment's behavioral effects.

Memantine normalizes several phenotypic features in the Ts65Dn mouse model of Down syndrome.

Rueda N, Llorens-Martín M, Flórez J, Valdizán E, Banerjee P, Trejo JL, Martínez-Cué C.

Journal of Alzheimer's Disease.
doi: 10.3233/JAD-2010-100240.

Ts65Dn (TS) mice exhibit several phenotypic characteristics of human Down syndrome, including an increased brain expression of amyloid-beta protein precursor (AbetaPP) and cognitive disturbances. Aberrant N-methyl-D-aspartate (NMDA) receptor signaling has been suspected in TS mice, due to an impaired generation of hippocampal long-term potentiation (LTP). Memantine, an uncompetitive NMDA receptor antagonist approved for the treatment of moderate to severe Alzheimer's disease, is known to normalize LTP and improve cognition in transgenic mice with high brain levels of AbetaPP and amyloid-beta protein. It has recently been demonstrated that acute injections of memantine rescue performance deficits of TS mice on a fear conditioning test. Here we show that oral treatment of aged TS mice with a clinically relevant dose of memantine (30 mg/kg/day for 9 weeks) improved spatial learning in the water maze task and slightly reduced brain AbetaPP levels. We also found that TS mice exhibited a significantly reduced granule cell count and vesicular glutamate transporter-1 (VGLUT1) labeling compared to disomic control mice. After memantine treatment, the levels of hippocampal VGLUT1 were significantly increased, reaching the levels observed in vehicle treated-control animals. Memantine did not significantly affect granule cell density. These data indicate that memantine may normalize several phenotypic abnormalities in TS mice, many of which--such as impaired cognition--are also associated with Down syndrome and Alzheimer's disease.

Exercise modulates insulin-like growth factor 1-dependent and -independent effects on adult hippocampal neurogenesis and behaviour.

Llorens-Martín M, Torres-Alemán I, Trejo JL.

Molecular and Cellular Neuroscience. 
doi: 10.1016/j.mcn.2010.02.006.

While physical exercise clearly has beneficial effects on the brain, fomenting neuroprotection as well as promoting neural plasticity and behavioural modifications, the cellular and molecular mechanisms mediating these effects are not yet fully understood. We have analyzed sedentary and exercised animals to examine the effects of activity on behaviour (spatial memory and anxiety--as measured by a fear/exploration conflict test), as well as on adult hippocampal neurogenesis (a well-known form of neural plasticity). We have found that the difference in activity between sedentary and exercised animals induced a decrease in the fear/exploration conflict scores (a measure usually accepted as an anxiolytic effect), while no changes are evident in terms of spatial memory learning. The short-term anxiolytic-like effect of exercise was IGF1-dependent and indeed, the recall of hippocampus-dependent spatial memory is impaired by blocking serum IGF1 (as observed by measuring serum IGF levels in the same animals used to analyze the behaviour), irrespective of the activity undertaken by the animals. On the other hand, activity affected neurogenesis as reflected by counting the numbers of several cell populations, while the dependence of this effect on IGF1 varied according to the differentiation state of the new neurons. Hence, while proliferating precursors and postmitotic immature neurons (measured by means of doublecortin and calretinin) are influenced by serum IGF1 levels in both sedentary and exercised animals, premitotic immature neurons (an intermediate stage) respond to exercise independently of serum IGF1. Therefore, we conclude that physical exercise has both serum IGF1-independent and -dependent effects on neural plasticity. Furthermore, several effects mediated by serum IGF1 are induced by physical activity while others are not (both in terms of behaviour and neural plasticity). These findings help to delimit the role of serum IGF1 as a mediator of the effects of exercise, as well as to extend the role of serum IGF1 in the brain in basal conditions. Moreover, these data reveal the complexity of the interaction between neurogenesis, behaviour, and IGF1 under different levels of physical activity.

Blockade of insulin-like growth factor-I has complex effects on structural plasticity in the hippocampus.

Glasper ER, Llorens-Martin MV, Leuner B, Gould E, Trejo JL.

doi: 10.1002/hipo.20672.

Physical exercise enhances adult neurogenesis in the hippocampus. Running induces the uptake of blood insulin-like growth factor-I (IGF-I) into the brain. A causal link between these two phenomena has been reported; running-induced increases in adult neurogenesis can be blocked by peripheral infusion of anti-IGF-I. Running also alters other aspects of hippocampal structure, including dendritic spine density. It remains unclear, however, whether these effects are also mediated through an IGF-I mechanism. To examine this possibility, we blocked peripheral IGF-I and examined adult neurogenesis and dendritic spine density in treadmill running mice. Two weeks of running resulted in an increase in cell proliferation in the dentate gyrus (DG) as well as an increase in dendritic spine density on DG granule cells and basal dendrites of CA1 pyramidal neurons, while having no effect on apical or basal dendritic spine density of CA3 pyramidal neurons. IGF-I blockade reduced cell proliferation in both sedentary and running mice, but by contrast, this treatment had no effect on granule cell or CA3 pyramidal cell dendritic spine density in sedentary or running mice. However, IGF-I antibody treatment seemed to prevent the running-induced increase in spine density on basal dendrites of CA1 pyramidal cells. These results suggest that IGF-I exerts a complex influence over hippocampal structure and that its effects are not restricted to those induced by running.


Centro de Biología Molecular Severo Ochoa (CBMSO) Universidad Autónoma de Madrid (Campus de Cantoblanco)
C/ Nicolás Cabrera 1 - 28049 Madrid (Spain)

María Llorens-Martín (PI)
+34 911964632