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J L Guillou

Publications and source records attributed to J L Guillou.

11 recordsLinked to original sources
PubMed2003

Spatial learning induces differential changes in calcium/calmodulin-stimulated (ACI) and calcium-insensitive (ACII) adenylyl cyclases in the mouse hippocampus.

Several lines of evidence indicate that Ca2+/calmodulin-stimulated isoforms of adenylyl cyclase (AC) are involved in long-term potentiation and in certain forms of learning. Recently, we found that training in different types of learning task differentially activates Ca2+-sensitive versus Ca2+-insensitive AC activities in certain brain regions, indicating that AC species other than those stimulated by Ca2+/calmodulin may play an important role in learning processes (Guillou, Rose, & Cooper, 1999). Here, we report the effects of spatial reference memory training in a radial arm maze on the levels of AC1 and AC2 mRNA in the dorsal hippocampus of C57BL/6 mice. Acquisition of the task was associated with a learning-specific and time-dependent increase of AC1 mRNA expression selectively in subfields CA1-CA2. In contrast, AC2 mRNA levels were either reduced or not reliably affected depending on the stage of acquisition. Moreover, no significant changes in AC expression were observed either in the dorsal hippocampus of mice trained in a non-spatial (procedural) version of the task or in cortical regions of mice learning the spatial or procedural task. The regional specificity of these effects indicates that the formation of spatial and non-spatial memory requires distinct contributions from Ca2+-sensitive and Ca2+-insensitive AC in the hippocampus. It is suggested that downregulation of AC2 throughout all hippocampal subfields may play a permissive role during the acquisition of spatial learning whereas an upregulation of AC1 specifically in subfield CA1, may be critical to accurately encode, store or use spatial information.

Adenylyl Cyclases↗
PubMed2001

Intrahippocampal injections of somatostatin dissociate acquisition from the flexible use of place responses.

Previous studies showed that injections of somatostatin (SS-14) into the hippocampus facilitate the acquisition of spatial tasks in mice. The present study was aimed at better understanding the learning and memory processes that could be affected by hippocampal SS-14 stimulation. Balb/c mice were submitted to a two-stage learning paradigm. In stage 1, they were trained for acquisition of a spatial discrimination task in a radial maze and, in stage 2, were submitted to a probe test aiming at evaluating their ability to use flexibly their previously acquired knowledge. Injections of vehicle or SS-14 were given during the acquisition phase and/or before the probe test using a 2 x 2 factorial design. Mice receiving SS-14 during acquisition failed to succeed in the probe test despite showing a trend to faster acquisition of the initial spatial discrimination task. By contrast, when given only prior to probe trials, SS-14 did not yield any behavioural effects. Thus, SS-14 interfered with the establishment of a flexible form of memory, not with its expression per se, and therefore dissociated the acquisition of place responses from their flexible use. The theoretical issues raised by the present findings are discussed.

Animals↗
PubMed1999

Inhibition by calcium of mammalian adenylyl cyclases.

Ca(2+) regulates mammalian adenylyl cyclases in a type-specific manner. Stimulatory regulation is moderately well understood. By contrast, even the concentration range over which Ca(2+) inhibits adenylyl cyclases AC5 and AC6 is not unambiguously defined; even less so is the mechanism of inhibition. In the present study, we compared the regulation of Ca(2+)-stimulable and Ca(2+)-inhibitable adenylyl cyclases expressed in Sf9 cells with tissues that predominantly express these activities in the mouse brain. Soluble forms of AC5 containing either intact or truncated major cytosolic domains were also examined. All adenylyl cyclases, except AC2 and the soluble forms of AC5, displayed biphasic Ca(2+) responses, suggesting the presence of two Ca(2+) sites of high ( approximately 0.2 microM) and low affinity ( approximately 0.1 mM). With a high affinity, Ca(2+) (i) stimulated AC1 and cerebellar adenylyl cyclases, (ii) inhibited AC6 and striatal adenylyl cyclase, and (iii) was without effect on AC2. With a low affinity, Ca(2+) inhibited all adenylyl cyclases, including AC1, AC2, AC6, and both soluble forms of AC5. The mechanism of both high and low affinity inhibition was revealed to be competition for a stimulatory Mg(2+) site(s). A remarkable selectivity for Ca(2+) was displayed by the high affinity site, with a K(i) value of approximately 0.2 microM, in the face of a 5000-fold excess of Mg(2+). The present results show that high and low affinity inhibition by Ca(2+) can be clearly distinguished and that the inhibition occurs type-specifically in discrete adenylyl cyclases. Distinction between these sites is essential, or quite spurious inferences may be drawn on the nature or location of high affinity binding sites in the Ca(2+)-inhibitable adenylyl cyclases.

Adenosine Triphosphate↗
PubMed1999

5-HT1B receptor knock-out mice exhibit increased exploratory activity and enhanced spatial memory performance in the Morris water maze.

In an attempt to characterize the contribution of the 5-HT1B receptor to behavior, 5-HT1B knock-out (KO) mice were subjected to a battery of behavioral paradigms aimed at differentiating various components of cognitive and emotional behaviors. In an object exploration task, wild-type (WT) and 5-HT1B KO mice did not differ in locomotor activity. 5-HT1B KO mice, however, displayed lower thigmotaxis (an index of anxiety) associated with a higher level of object exploratory activity, but no genotype differences were observed in the elevated plus maze. 5-HT1B KO mice also displayed a lack of exploratory habituation. In the spatial version of the Morris water maze, 5-HT1B KO mice showed higher performances in acquisition and transfer test, which was not observed in the visual version of the task. No genotype differences were found in contextual fear conditioning, because both WT and 5-HT1B KO mice were able to remember the context where they had received the aversive stimulus. The deletion of the 5-HT1B receptor, associated with appropriate behavioral paradigms, thus allowed us to dissociate anxiety from response to novelty, and perseverative behavior (lack of habituation) from adaptive behavioral inhibition underlying cognitive flexibility (transfer stage in the water maze). The deletion of the 5-HT1B receptor did not result in significant developmental plasticities for other major 5-HT receptor types but may have influenced other neurotransmission systems. The 5-HT1B receptor may be a key target for serotonin in the modulation of cognitive behavior, particularly in situations involving a high cognitive demand.

Analysis of Variance↗
PubMed1999

Differential activation of adenylyl cyclases by spatial and procedural learning.

Adenylyl cyclases (ACs) are involved in a variety of advanced CNS functions, including some types of learning and memory. At least nine AC isoforms are expressed in the brain, which are divisible into three broad classes based on the ability of Ca(2+) to modulate their activity. This study examined the hypothesis that different learning tasks would differentially activate ACs in selected brain regions. The ability of forskolin or Ca(2+) to enhance AC activity in the hippocampus, parietal cortex, striatum, and cerebellum was examined after mice had been trained in either a spatial or procedural learning task using a Morris water maze. Sensitivity of ACs to forskolin was enhanced to a greater degree in most brain regions after procedural learning, but Ca(2+)-sensitive ACs in the hippocampus were more sensitive to spatial learning. Because nonspecific behavioral elements, such as stress or motor activity, were similar in both experimental tasks, these results provide the first evidence that acquisition of different kinds of learning is associated with selective changes in particular AC species in a mammalian brain and support the idea that different biochemical processing, involving particular isoforms of ACs, subserves different memory systems.

Adenylyl Cyclases↗
PubMed1999

The role of Ca2+/calmodulin-stimulable adenylyl cyclases as molecular coincidence detectors in memory formation.

Evidence from systems as diverse as mollusks, insects and mammals has revealed that adenylyl cyclase, cyclic adenosine 3',5'-monophosphate (cAMP) cascade, cAMP-dependent protein kinases and their substrates are required for the cellular events underlying the short-term and long-term forms of memory. In Aplysia and Drosophila models, the coincident activation of independent paths converge to produce a synergistic activation of Ca2+/calmodulin-stimulable adenylyl cyclase, thereby enhancing the cAMP level that appears as the primary mediator of downstream events that strengthen enduring memory. In mammals, in which long-term memories require hippocampal function, our understanding of the role of adenylyl cyclases is still fragmentary. Of the differently regulated isoforms present in the hippocampus, the susceptibility of type 1 and type 8 to stimulation by the complex Ca2+/calmodulin and their expression in the hippocampus suggest a role for these two isoforms as a molecular coincidence device for hippocampus-related memory function. Here, we review the key features of Ca2+/calmodulin stimulable adenylyl cyclases, as well as the involvement of cAMP-regulated signaling pathway in the processes of learning and memory.

Adenylyl Cyclases↗
PubMed1999

Intrahippocampal injections of cysteamine improve the retention of a bar-pressing task in mice.

Cysteamine was used as a tool aimed at investigating the role of central somatostatin (SS-14) and was shown to modulate learning in a task-dependent manner. However, direct arguments have not yet been provided to support the hypothesis that impairments and facilitation of learning produced by cysteamine are both mediated by the hippocampus. Mice were given daily intrahippocampal injections of artificial cerebrospinal fluid (CSF) or cysteamine at doses of either 2.5 microg/0.2 microl or 25 microg/0.2 microl 1 h prior to each learning session of a bar-pressing task, for which the acquisition was previously shown to be improved by systemic injections. The results showed that, with respect to CSF, the mice injected with cysteamine learned the bar pressing task faster whereas no evidence of changes in locomotor activity was provided. Moreover, the results showed that retention was specifically increased in the two groups injected with cysteamine. It is argued that the action of cysteamine on the hippocampus is sufficient to modulate specifically learning-memory processes in a task-dependent manner. In conclusion, the blockade of some hippocampal information processing function by cysteamine is discussed to understand the bidirectional effects of drugs on learning and memory.

Animals↗
PubMed1998

The opposite effects of cysteamine on the acquisition of two different tasks in mice are associated with bidirectional testing-induced changes in hippocampal adenylyl cyclase activity.

The hypothesis of a role for hippocampal somatostatin (SS-14) in learning and memory processes was further examined by means of 2 selective learning tasks that were previously shown to be either impaired (spatial discrimination task) or facilitated (barpressing task) by hippocampal lesions. Results showed that subcutaneous injections of cysteamine (160 mg/kg) (a) impaired acquisition of the spatial task while producing an opposite (i.e., facilitative) effect on acquisition of the barpressing task and (b) produced an up regulation of hippocampal adenylyl cyclase (AC) activity, which was antagonized by spatial discrimination training but enhanced by training in the barpressing task. Moreover, opposite task-dependent training-induced changes in hippocampal AC activity was observed in saline-treated mice. These results suggest that bidirectional regulatory mechanisms of hippocampal function involving both SS-14 and ACs may occur as a function of the type of learning.

Adenylyl Cyclases↗
PubMed1997

Construction of a full-length Ca2+-sensitive adenylyl cyclase/aequorin chimera.

Ca2+-sensitive adenylyl cyclases are key integrators of Ca2+ and cAMP signaling. To selectively probe dynamic changes in [Ca2+]i at the plasma membrane where adenylyl cyclases reside, a full-length, Ca2+-inhibitable type VI adenylyl cyclase/aequorin chimera has been constructed by a two-stage polymerase chain reaction method. The expressed adenylyl cyclase/aequorin chimera was appropriately localized to the plasma membrane, as judged by biochemical fractionation and functional analysis. The chimera retained full adenylyl cyclase activity and sensitivity to inhibition by physiological [Ca2+]i elevation. The aequorin portion of the chimeric construct was also capable of measuring changes in [Ca2+] both in vitro and in vivo. When the plasma membrane-tagged aequorin and cytosolic aequorin were compared in their measurement of [Ca2+]i, they showed contrasting sensitivities depending on whether the [Ca2+]i originated from internal stores or capacitative entry. This is the first full-length enzyme-aequorin chimera that retains the full biological properties of both aequorin and a Ca2+-sensitive adenylyl cyclase. This novel chimeric Ca2+ sensor provides the unique ability to directly report the dynamics of [Ca2+]i that regulates this Ca2+-sensitive enzyme under a variety of physiological conditions. Since this chimera is localized to the plasma membrane, it can also be used to assess local changes in [Ca2+]i at the plasma membrane as distinct from global changes in [Ca2+]i within the cytosol.

Adenylyl Cyclases↗
PubMed1994

[Hippocampus as interaction sites between cerebral memory systems].

Most of the current theories assume that there are multiple forms of memory that are supported by separate brain systems and have different characteristics. Animals studies on the various dual-memory theories have been carried out mainly on the basis of hippocampal system function. Specifically, they have focused on aspects of learning and memory that are impaired (vs. spared) by lesions of the hippocampal formation. However, there are several instances in the animal literature showing that hippocampal lesions actually produced enhanced learning and memory function. Moreover, the acquisition of tasks that are facilitated by hippocampal lesions (or dysfunction) is nevertheless associated, in intact subjects, with specific neurobiological alterations in the hippocampus. This problem has been analysed using two different tasks in mice: a bar-press conditioning and a spatial discrimination task. Results showed that, depending on the task considered, the same pharmacological treatment produced either a facilitation or an impairment of acquisition. Moreover, each task induced significant alterations in hippocampal adenylate cyclase activity but in opposite directions. Together with previous findings, these results suggest that the hippocampus is involved in both the so-called "hippocampal-dependent" and "hippocampal-independent" forms of memory. It is postulated that some of the observed training-induced neurobiological alterations might reflect the interaction between two (or more) competing memory systems at the hippocampal level. Thus, in addition to its proposed specific information processing functions (i.e., relational), the hippocampus would play a role in addressing information to the brain memory system that, in a given situation, has the best adaptive value.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗