Muriel Koehl

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.

Sleep Restriction Alters the Hypothalamic-Pituitary-Adrenal Response to Stress

Chronic sleep restriction is an increasing problem in many countries and may have many, as yet unknown, consequences for health and well being. Studies in both humans and rats suggest that sleep deprivation may activate the hypothalamic‐pituitary‐adrenal (HPA) axis, one of the main neuroendocrine stress systems. However, few attempts have been made to examine how sleep loss affects the HPA axis response to subsequent stressors. Furthermore, most studies applied short‐lasting total sleep deprivation and not restriction of sleep over a longer period of time, as often occurs in human society. Using the rat as our model species, we investigated: (i) the HPA axis activity during and after sleep deprivation and (ii) the effect of sleep loss on the subsequent HPA response to a novel stressor. In one experiment, rats were subjected to 48 h of sleep deprivation by placing them in slowly rotating wheels. Control rats were placed in nonrotating wheels. In a second experiment, rats were subjected to an 8‐day sleep restriction protocol allowing 4 h of sleep each day. To test the effects of sleep loss on subsequent stress reactivity, rats were subjected to a 30‐min restraint stress. Blood samples were taken at several time points and analysed for adrenocorticotropic hormone (ACTH) and corticosterone. The results show that ACTH and corticosterone concentrations were elevated during sleep deprivation but returned to baseline within 4 h of recovery. After 1 day of sleep restriction, the ACTH and corticosterone response to restraint stress did not differ between control and sleep deprived rats. However, after 48 h of total sleep deprivation and after 8 days of restricted sleep, the ACTH response to restraint was significantly reduced whereas the corticosterone response was unaffected. These results show that sleep loss not only is a mild activator of the HPA axis itself, but also affects the subsequent response to stress. Alterations in HPA axis regulation may gradually appear under conditions of long total sleep deprivation but also after repeated sleep curtailment.

Prenatal stress in rats predicts immobility behavior in the forced swim test. Effects of a chronic treatment with tianeptine

Prenatally-stressed (PS) rats are characterized by a general impairment of the hypothalamo-pituitary-adrenal (HPA) axis and sleep disturbances indicating that this model has face validity with some clinical features observed in a subpopulation of depressed patients. The prolonged corticosterone secretion shown by PS rats in response to stress was positively correlated with an increased immobility behavior in the forced swim test. To investigate the predictive validity of this model, a separate group of animals was chronically treated with the antidepressant tianeptine (10 mg/kg i.p. for 21 days). Such chronic treatment reduced in PS rats immobility time in the forced swim test. These findings suggest that the PS rat is an interesting animal model for the evaluation of antidepressant treatment.

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.

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.

Prenatal stress induces a phase advance of circadian corticosterone rhythm in adult rats which is prevented by postnatal stress.

Prenatal and postnatal stressors can have different long-term neuroendocrine effects including modifications of stress-induced corticosterone secretion. However, very little is known about the possible long-term effects of prenatal or postnatal stress on the rhythmicity of basal corticosterone secretion in adult offspring. Corticosterone levels were thus determined at six different time points over 24 h in adult rats whose mothers had undergone restraint stress manipulations. The results demonstrate that prenatal stress induces a phase advance in the evening increase of corticosterone levels, and that this change is prevented by postnatal stress. It thus appears that the circadian system governing the HPA axis is modifiable by a prenatal stress, and remains susceptible to compensatory changes during the postnatal period.

Exercise-induced promotion of hippocampal cell proliferation requires beta-endorphin

Adult hippocampal neurogenesis is influenced by a variety of stimuli, including exercise, but the mechanisms by which running affects neurogenesis are not yet fully understood. Because β‐endorphin, which is released in response to exercise, increases cell proliferation in vitro, we hypothesized that it could exert a similar effect in vivo and mediate the stimula tory effects of running on neurogenesis. We thus analyzed the effects of voluntary wheel‐running on adult neurogenesis (proliferation, differentiation, survival/death) in wild‐type and β‐endorphin‐deficient mice. In wild‐type mice, exercise promoted cell proliferation evaluated by sacrificing animals 24 h after the last 5‐bromo‐2′‐deoxyuridine (BrdU) pulse and by using endogenous cell cycle markers (Ki67 and pH3). This was accompanied by an increased survival of 4‐wk‐old BrdU‐labeled cells, leading to a net increase of neurogenesis. β‐Endorphin deficiency had no effect in sedentary mice, but it completely blocked the runninginduced increase in cell proliferation; this blockade was accompanied by an increased survival of 4‐wk‐old cells and a decreased cell death. Altogether, adult neurogenesis was increased in response to exercise in knockout mice. We conclude that β‐endorphin released during running is a key factor for exercise‐induced cell proliferation and that a homeostatic balance may regulate the final number of new neurons.—Koehl, M., Meerlo, P., Gonzales, D., Rontal, A., Turek, F. W., Abrous, D. N. Exercise‐induced promotion of hippocampal cell proliferation requires β‐endorphin. FASEB J. 22, 2253–2262 (2008)

Pregnenolone sulfate increases hippocampal acetylcholine release and spatial recognition.

The pregnenolone sulfate is a neurosteroid with promnesic properties. Recently, a correlation between endogenous levels of pregnenolone sulfate in the hippocampus and performance in a spatial memory task has been reported in aged rats. Cholinergic transmission is known to modulate memory processes and to be altered with age. In the present experiment we investigated the effect of increasing doses of pregnenolone sulfate on hippocampal acetylcholine release. Our results show that intracerebroventricular administrations of this neurosteroid induced a dose-dependent increase in acetylcholine release. Administration of 12 and 48 nmol of pregnenolone sulfate induced a short lasting (20 min) enhancement of acetylcholine output with a maximum around 120% over baseline and the administration of 96 and 192 nmol doses induced a long-lasting (80 min) increase that peaked around 300% over baseline. In a second experiment we have observed that the 12 nmol dose enhanced spatial memory performance, whereas the 192 nmol dose was inefficient. These results are consistent with previous work suggesting that, a modest increase in acetylcholine release facilitates memory processes, while elevation beyond an optimal level is ineffective. Nevertheless, neurosteroids may be of value for reinforcing depressed cholinergic transmission in certain age-related memory disorders.