Djoher Nora Abrous

Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis

Neurogenesis occurs within the adult dentate gyrus of the hippocampal formation and it has been proposed that the newly born neurons, recruited into the preexistent neuronal circuits, might be involved in hippocampal-dependent learning processes. Age-dependent spatial memory impairments have been related to an alteration in hippocampal plasticity. The aim of the current study was to examine whether cognitive functions in aged rats are quantitatively correlated with hippocampal neurogenesis. To this end, we took advantage of the existence of spontaneous individual differences observed in aged subjects in a hippocampal-dependent task, the water maze. We expected that the spatial memory capabilities of aged rats would be related to the levels of hippocampal neurogenesis. Old rats were trained in the water maze, and, 3 weeks after training, rats were injected with 5-bromo-2′-deoxyuridine (BrdUrd, 50 or 150 mg/kg) to label dividing cells. Cell proliferation was examined one day after the last BrdUrd injection, whereas cell survival and differentiation were determined 3 weeks later. It is shown that a quantitative relationship exists between learning and the number of newly generated neurons. Animals with preserved spatial memory, i.e., the aged-unimpaired rats, exhibited a higher level of cell proliferation and a higher number of new neurons in comparison with rats with spatial memory impairments, i.e., the aged-impaired rats. In conclusion, the extent of memory dysfunction in aged rats is quantitatively related to the hippocampal neurogenesis. These data reinforce the assumption that neurogenesis is involved in memory processes and aged-related cognitive alterations.

Spatial Relational Memory Requires Hippocampal Adult Neurogenesis

The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning.

Adult hippocampal neurogenesis is involved in anxiety-related behaviors

Adult hippocampal neurogenesis is a unique example of structural plasticity, the functional role of which has been a matter of intense debate. New transgenic models have recently shown that neurogenesis participates in hippocampus-mediated learning. Here, we show that transgenic animals, in which adult hippocampal neurogenesis has been specifically impaired, exhibit a striking increase in anxiety-related behaviors. Our results indicate that neurogenesis plays an important role in the regulation of affective states and could be the target of new treatments for anxiety disorders.

Acute Cannabinoids Impair Working Memory through Astroglial CB1 Receptor Modulation of Hippocampal LTD

Impairment of working memory is one of the most important deleterious effects of marijuana intoxication in humans, but its underlying mechanisms are presently unknown. Here, we demonstrate that the impairment of spatial working memory (SWM) and in vivo long-term depression (LTD) of synaptic strength at hippocampal CA3-CA1 synapses, induced by an acute exposure of exogenous cannabinoids, is fully abolished in conditional mutant mice lacking type-1 cannabinoid receptors (CB(1)R) in brain astroglial cells but is conserved in mice lacking CB(1)R in glutamatergic or GABAergic neurons. Blockade of neuronal glutamate N-methyl-D-aspartate receptors (NMDAR) and of synaptic trafficking of glutamate α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR) also abolishes cannabinoid effects on SWM and LTD induction and expression. We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB(1)R and is associated with astroglia-dependent hippocampal LTD in vivo.

The dopaminergic hyper-responsiveness of the shell of the nucleus accumbens is hormone-dependent.

The dopaminergic projection to the shell of the nucleus accumbens is the most reactive to stress, reward and drugs of abuse and this subregion of the nucleus accumbens is also considered a target of therapeutic effects of atypical antipsychotic drugs (APD). In this report we show, by means of in vivo microdialysis and Fos immunohistochemistry, that the hyper‐responsiveness which characterizes the dopaminergic transmission to the shell is dependent on glucocorticoid hormones. In Sprague‐Dawley rats, after suppression of endogenous glucocorticoids by adrenalectomy, extracellular dopamine levels selectively decreased in the shell, whilst they remained unchanged in the core. This effect was observed in basal conditions, after a mild stress (vehicle injection), as well as after subcutaneous administration of morphine (2 mg/kg, s.c.) or intraperitoneal injection of cocaine (15 mg/kg, i.p.). The decrease in dopamine observed in the shell had a postsynaptic impact, as shown by less induction of Fos‐like proteins selectively in the shell in response to cocaine. However, the induction of Fos‐like proteins by the full D1 agonist SKF82958 (1.5 mg/kg, i.p.) remained unchanged after adrenalectomy, suggesting that the changes in Fos expression after cocaine injection were likely to depend on changes in extracellular dopamine levels rather than on changes in postsynaptic sensitivity to dopamine. The effects of adrenalectomy were glucocorticoid‐specific given that they were prevented by corticosterone treatment. This anatomical specificity in the control of neuronal activity by a hormonal input highlights the role of steroid hormones in shaping the functional activity of the brain.

Postnatal Stimulation of the Pups Counteracts Prenatal Stress-Induced Deficits in Hippocampal Neurogenesis

BACKGROUND Prenatal stress constitutes a developmental risk factor for later psychopathology. The behavioral disorders are sustained by neurobiological alterations including long-term reduction of hippocampal neurogenesis; its deregulation has been involved in cognitive impairments, mood disorders and addiction. A major goal is to define periods in development and strategies for intervening to prevent the effects of early stressful events. We investigated the ability of a postnatal infantile stimulation to prevent prenatal stress-induced alteration in hippocampal neurogenesis. METHODS The influence of postnatal handling on prenatal stress-induced changes in hippocampal neurogenesis was examined in 4 and 26 month-old male rats. Three distinct phases of the neurogenesis were studied: proliferation, survival and neuronal differentiation. RESULTS Prenatal stress reduced hippocampal cell proliferation all throughout life. Furthermore, the survival rate of newborn cells, the number of immature neurons and the number of differentiated new neurons were reduced in young and old prenatally-stressed rats. All those deleterious effects were counteracted by neonatal handling. CONCLUSIONS These data show that finer aspects of brain shaping can be rewired by environmental influences occurring at sensitive phase of development. They also suggest that infantile stimulation may reverse the appearance of behavioral disorders induced by early life stress.

Adult-born neurons are necessary for extended contextual discrimination.

New neurons are continuously produced in the adult dentate gyrus of the hippocampus. It has been shown that one of the functions of adult neurogenesis is to support spatial pattern separation, a process that transforms similar memories into nonoverlapping representations. This prompted us to investigate whether adult‐born neurons are required for discriminating two contexts, i.e., for identifying a familiar environment and detect any changes introduced in it. We show that depleting adult‐born neurons impairs the animals ability to disambiguate two contexts after extensive training. These data suggest that the continuous production of new dentate neurons plays a crucial role in extracting and separating efficiently contextual representation in order to discriminate features within events.

Spatial learning sculpts the dendritic arbor of adult-born hippocampal neurons

Neurogenesis in the hippocampus is characterized by the birth of thousand of cells that generate neurons throughout life. The fate of these adult newborn neurons depends on life experiences. In particular, spatial learning promotes the survival and death of new neurons. Whether learning influences the development of the dendritic tree of the surviving neurons (a key parameter for synaptic integration and signal processing) is unknown. Here we show that learning accelerates the maturation of their dendritic trees and their integration into the hippocampal network. We demonstrate that these learning effects on dendritic arbors are homeostatically regulated, persist for several months, and are specific to neurons born during adulthood. Finally, we show that this dendritic shaping depends on the cognitive demand and relies on the activation of NMDA receptors. In the search for the structural changes underlying long-term memory, these findings lead to the conclusion that shaping neo-networks is important in forming spatial memories.

A new chapter in the field of memory: adult hippocampal neurogenesis

Understanding the cellular mechanisms underlying learning and memory is a major challenge in neurobiology. Structural and functional changes occurring in the hippocampus such as synaptic remodeling and long‐term potentiation are key signatures of long‐term memory processes. The discovery of a de novo hippocampal production of neurons in the adult brain has been a breakthrough in the field of plasticity and memory, introducing a new actor that could sustain memory processes. Here we will review our current knowledge on the role of these adult new neurons in memory. In particular we will provide evidence showing that they are required for learning and memory and that an alteration in their production rate or maturation leads to memory impairments. Through a thorough survey of the literature, we will also acknowledge that there are many controversies regarding the specific role played by newborn neurons. The emerging picture is that they are involved in the establishment of spatiotemporal relationships among multiple environmental cues for the flexible use of the acquired information. Indeed, newborn neurons have been found to be required for separating events based on their spatial and temporal characteristics, a process that preserves the uniqueness of a memory representation. Thus, adult‐born neurons are required for allocentric space representation, for long‐term memory retention and for flexible inferential memory expression. Finally, we will conclude by highlighting directions for future research, emphasizing that the exact participation of newborn neurons in memory processes will not be approached without considering the hippocampal network in general.

Cellular and behavioral effects of cranial irradiation of the subventricular zone in adult mice.

Background In mammals, new neurons are added to the olfactory bulb (OB) throughout life. Most of these new neurons, granule and periglomerular cells originate from the subventricular zone (SVZ) lining the lateral ventricles and migrate via the rostral migratory stream toward the OB. Thousands of new neurons appear each day, but the function of this ongoing neurogenesis remains unclear. Methodology/Principal Findings In this study, we irradiated adult mice to impair constitutive OB neurogenesis, and explored the functional impacts of this irradiation on the sense of smell. We found that focal irradiation of the SVZ greatly decreased the rate of production of new OB neurons, leaving other brain areas intact. This effect persisted for up to seven months after exposure to 15 Gray. Despite this robust impairment, the thresholds for detecting pure odorant molecules and short-term olfactory memory were not affected by irradiation. Similarly, the ability to distinguish between odorant molecules and the odorant-guided social behavior of irradiated mice were not affected by the decrease in the number of new neurons. Only long-term olfactory memory was found to be sensitive to SVZ irradiation. Conclusion/Significance These findings suggest that the continuous production of adult-generated neurons is involved in consolidating or restituting long-lasting olfactory traces.