Time-course of age-related temporal order memory decline in an object recognition paradigm in mice.

Temporal order memory refers to the ability to remember the order of occurrence of items across time. It is a critical feature of episodic memory that is often tested in rodents using spontaneous object recognition paradigms. However, impact of aging over performances of temporal order memory decline is barely known. Herein, we characterized here the effect of normal aging on the temporal order memory performances in NMRI mice between 3 and 19months of age, with an inter-session interval of 24h.We found that temporal order memory was impaired as soon as7 months of age. These results provide strong evidence that temporal order memory is particularly vulnerable to the deleterious effect of normal aging.

Characterizing age-related decline of recognition memory and brain activation profile in mice.

Episodic memory decline is one of the earlier deficits occurring during normal aging in humans. The question of spatial versus non-spatial sensitivity to age-related memory decline is of importance for a full understanding of these changes. Here, we characterized the effect of normal aging on both non-spatial (object) and spatial (object location) memory performances as well as on associated neuronal activation in mice. Novel-object (NOR) and object-location (OLR) recognition tests, respectively assessing the identity and spatial features of object memory, were examined at different ages. We show that memory performances in both tests were altered by aging as early as 15 months of age: NOR memory was partially impaired whereas OLR memory was found to be fully disrupted at 15 months of age. Brain activation profiles were assessed for both tests using immunohistochemical detection of c-Fos (neuronal activation marker) in 3and 15 month-old mice. Normal performances in NOR task by 3 month-old mice were associated to an activation of the hippocampus and a trend towards an activation in the perirhinal cortex, in a way that did significantly differ with 15 month-old mice. During OLR task, brain activation took place in the hippocampus in 3 month-old but not significantly in 15 month-old mice, which were fully impaired at this task. These differential alterations of the object- and object-location recognition memory may be linked to differential alteration of the neuronal networks supporting these tasks.

Time decay of object, place and temporal order memory in a paradigm assessing simultaneously episodic-like memory components in mice.

A common trait of numerous memory disorders is the impairment of episodic memory. Episodic memory is a delay-dependant memory, especially associating three components, the "what", "where" and "when" of a unique event. To investigate underlying mechanisms of such memory, several tests, mainly based on object exploration behaviour, have been set up in rodents. Recently, a three-trial object recognition task has been proposed to evaluate simultaneously the different components of episodic-like memory in rodents. However, to date, the time course of each memory component in this paradigm is not known. We characterised here the time course of memory decay in adult mice during the three-trial object recognition task, with inter-trial interval (ITI) ranging from 1h to 4h. We found that, with 1h and 2h, but not 4h ITI, mice spent more time to explore the displaced "old object" relative to the displaced "recent object", reflecting memory for "what and when". Concomitantly, animals exhibited more exploration time for the displaced "old object" relative to the stationary "old object", reflecting memory for "what and where". These results provide strong evidence that mice establish an integrated memory for unique experience consisting of the "what", "where" and "when" that can persist until 2h ITI.

Pharmacological blockade of 5-HT7 receptors as a putative fast acting antidepressant strategy.

Current antidepressants still display unsatisfactory efficacy and a delayed onset of therapeutic action. Here we show that the pharmacological blockade of serotonin 7 (5-HT(7)) receptors produced a faster antidepressant-like response than the commonly prescribed antidepressant fluoxetine. In the rat, the selective 5-HT(7) receptor antagonist SB-269970 counteracted the anxiogenic-like effect of fluoxetine in the open field and exerted an antidepressant-like effect in the forced swim test. In vivo, 5-HT(7) receptors negatively regulate the firing activity of dorsal raphe 5-HT neurons and become desensitized after long-term administration of fluoxetine. In contrast with fluoxetine, a 1-week treatment with SB-269970 did not alter 5-HT firing activity but desensitized cell body 5-HT autoreceptors, enhanced the hippocampal cell proliferation, and counteracted the depressive-like behavior in olfactory bulbectomized rats. Finally, unlike fluoxetine, early-life administration of SB-269970, did not induce anxious/depressive-like behaviors in adulthood. Together, these findings indicate that the 5-HT(7) receptor antagonists may represent a new class of antidepressants with faster therapeutic action.