Papers by Guillaume Martel
Frontiers in Endocrinology
The neuropeptide somatostatin (SOM) is widely expressed in rodent brain and somatostatin-IRES-Cre... more The neuropeptide somatostatin (SOM) is widely expressed in rodent brain and somatostatin-IRES-Cre (SOM-cre) mouse strains are increasingly used to unravel the physiology of SOM-containing neurons. However, while knock-in targeting strategy greatly improves Cre-Lox system accuracy, recent reports have shown that genomic insertion of Cre construct per se can markedly affect physiological function. We show that Cre transgene insertion into the 3′UTR of the somatostatin gene leads to the selective and massive depletion of endogenous SOM in all tested brain regions. It also strongly impacts SOM-related neuroendocrine responses in a similar manner to what has been reported for SST KO mice: increased corticosterone levels after 30-min restraint stress, decreased amplitude and regularity of ultradian growth hormone secretory patterns accompanied by changes in sexually dimorphic liver gene expression (serpina1, Cyp2b9, Cyp2a4, Cyp2d9, and Cyp7b1). In addition to demonstrating the need for examination of the consequences of Cre transgenesis, these results also reveal how this SOM-cre strain may be a useful tool in studying the functional consequences of moderate to low SOM levels as reported in neurological and psychiatric disorders.
Neuropsychopharmacology, 2016
Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of st... more Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of stress-related neuropsychiatric disorders. The hippocampus exerts an inhibitory feedback on stress but the mechanisms involved remain unclear. We investigated herein the role of hippocampal somatostatin receptor subtypes in both stress response and behavioral emotionality using C57BL/6, wild type and sst 2 or sst 4 knockout mice. Inhibitory effects of hippocampal infusions of somatostatin agonists on stress-induced hypothalamo-pituitary-adrenal axis (HPA) activity were tested by monitoring peripheral blood and local hippocampus corticosterone levels, the latter by using microdialysis. Anxiolytic and antidepressant-like effects were determined in the elevated-plus maze, open field, forced swimming, and stress-sensitive beam walking tests. Hippocampal injections of somatostatin analogs and sst 2 or sst 4, but not sst 1 or sst 3 receptor agonists produced rapid and sustained inhibition of HPA axis. sst 2 agonists selectively produced anxiolytic-like behaviors whereas both sst 2 and sst 4 agonists had antidepressant-like effects. Consistent with these findings, high corticosterone levels and anxiety were found in sst 2 KO mice and depressive-like behaviors observed in both sst 2 KO and sst 4 KO strains. Both hippocampal sst 2 and sst 4 receptors selectively inhibit stressinduced HPA axis activation but mediate anxiolytic and antidepressive effects through distinct mechanisms. Such results are to be accounted for in development of pathway-specific somatostatin receptor agents in the treatment of hypercortisolism (Cushing's disease) and stress-related neuropsychiatric disorders.
Journal of Neuroscience, 2016
Neurogenesis and memory formation are essential features of the dentate gyrus (DG) area of the hi... more Neurogenesis and memory formation are essential features of the dentate gyrus (DG) area of the hippocampus, but to what extent the mechanisms responsible for both processes overlap remains poorly understood. Stathmin protein, whose tubulin-binding and microtubule-destabilizing activity is negatively regulated by its phosphorylation, is prominently expressed in the DG. We show here that stathmin is involved in neurogenesis, spinogenesis, and memory formation in the DG. tTA/tetO-regulated bitransgenic mice, expressing the unphosphorylatable constitutively active Stathmin4A mutant (Stat4A), exhibit impaired adult hippocampal neurogenesis and reduced spine density in the DG granule neurons. Although Stat4A mice display deficient NMDA receptor-dependent memory in contextual discrimination learning, which is dependent on hippocampal neurogenesis, their NMDA receptor-independent memory is normal. Confirming NMDA receptor involvement in the memory deficits, Stat4A mutant mice have a decrease in the level of synaptic NMDA receptors and a reduction in learning-dependent CREB-mediated gene transcription. The deficits in neurogenesis, spinogenesis, and memory in Stat4A mice are not present in mice in which tTA/tetO-dependent transgene transcription is blocked by doxycycline through their life. The memory deficits are also rescued within 3 d by intrahippocampal infusion of doxycycline, further indicating a role for stathmin expressed in the DG in contextual memory. Our findings therefore point to stathmin and microtubules as a mechanistic link between neurogenesis, spinogenesis, and NMDA receptor-dependent memory formation in the DG.
Mémoire déclarative et mémoire procédurale : quand et comment s'opère la sélection du système de mémoire adapté ?
Http Www Theses Fr, 2006
Les phenomenes de consolidation permettant le maintien d'informations ont pour support des ca... more Les phenomenes de consolidation permettant le maintien d'informations ont pour support des cascades moleculaires ayant un role specifique dans les processus mnesiques. Ainsi, bien que la voie AMPc/PKA/CREB semble necessaire a la consolidation d'informations, une augmentation de l'activite de cette voie est observee dans des structures mnesiques non necessaires au stockage d'un type d'information donne. Ce travail de these a consiste a preciser le role de cette augmentation d'activite lors des processus de consolidation. L'etude de la cinetique de phosphorylation de CREB dans l'hippocampe (Hpc) et le striatum (Str) a revele que l'Hpc developpe une activite biphasique avec un pic precoce et un pic tardif. Les etudes pharmocologiques ont revele que seule la phase tardive d'activite est critique pour la selection du systeme de memoire adapte. Le Str presente une activite monophasique avec un pic precoce et transitoire, les effets des modifications de la voie AMPc/PKA/CREB etant differents en fonction de la partie du Str consideree, au moment de l'intervention et du type d'information traite. L'implication differentielle de 2 isoformes d'adenylyl-cyclase dans l'Hpc lors de la consolisation d'informations procedurales et relationnelles a ete revelee, caracterisant ainsi l'augmentation de l'activite de la voie AMPc/PKA/CREB lors de la consolidation de ces deux types d'informations. Ce travail suggere que les phenomenes de consolisation permettent la selection du systeme de memoire adapte et qu'un fonctionnement particulier de l'Hpc oriente la strategie comportementale vers une modalite relationnelle ou procedurale. De plus, la realisation de l'epreuve modifie en direct ces processus de consolisation, permettant d'adapter la strategie comportementale. Il faut donc considerer les phenomenes de Consolidation comme des mecanismes flexibles intervenant dans la configuration du reseau cerebral mnesique, permettant une adaptation appropriee a l'environnement.
Frontiers in endocrinology, 2012
Somatostatin is highly expressed in mammalian brain and is involved in many brain functions such ... more Somatostatin is highly expressed in mammalian brain and is involved in many brain functions such as motor activity, sleep, sensory, and cognitive processes. Five somatostatin receptors have been described: sst(1), sst(2) (A and B), sst(3), sst(4), and sst(5), all belonging to the G-protein-coupled receptor family. During the recent years, numerous studies contributed to clarify the role of somatostatin systems, especially long-range somatostatinergic interneurons, in several functions they have been previously involved in. New advances have also been made on the alterations of somatostatinergic systems in several brain diseases and on the potential therapeutic target they represent in these pathologies.
Nature Communications, 2014
Changes in the stability of microtubules regulate many biological processes, but their role in me... more Changes in the stability of microtubules regulate many biological processes, but their role in memory remains unclear. Here we show that learning causes biphasic changes in the microtubule-associated network in the hippocampus. In the early phase, stathmin is dephosphorylated, enhancing its microtubule-destabilizing activity by promoting stathmintubulin binding, whereas in the late phase these processes are reversed leading to an increase in microtubule/KIF5-mediated localization of the GluA2 subunit of AMPA receptors at synaptic sites. A microtubule stabilizer paclitaxel decreases or increases memory when applied at the early or late phases, respectively. Stathmin mutations disrupt changes in microtubule stability, GluA2 localization, synaptic plasticity and memory. Aged wild-type mice show impairments in stathmin levels, changes in microtubule stability and GluA2 localization. Blocking GluA2 endocytosis rescues memory deficits in stathmin mutant and aged wild-type mice. These findings demonstrate a role for microtubules in memory in young adult and aged individuals.
Neurobiology of aging, Jan 31, 2014
Somatostatin (SOM) cortical levels decline in Alzheimer's disease (AD) in correlation with co... more Somatostatin (SOM) cortical levels decline in Alzheimer's disease (AD) in correlation with cognitive impairment severity, the latter being closely related to the presence of neurofibrillary tangles. Impaired olfaction is another hallmark of AD tightly related to tau pathology in the olfactory pathways. Recent studies showed that SOM modulates olfactory processing, suggesting that alterations in SOM levels participate to olfactory deficits in AD. Herein, we first observed that human olfactory peduncle and cortex are enriched in SOM cells and fibers, in aged postmortem brains. Then, the possible link between SOM alterations and olfactory deficits was evaluated by exploring the impact of age and tau hyperphosphorylation on olfactory SOM networks and behavioral performances in THY-Tau22 mice, a tauopathy transgenic model. Distinct molecular repertoires of SOM peptide and receptors were associated to sensory or cortical olfactory processing structures. Aging mainly affected SOM neuro...
Frontiers in Aging Neuroscience, 2014
Mild Cognitive Impairment (MCI) is a heterogeneous cognitive status that can be a prodromal 2 sta... more Mild Cognitive Impairment (MCI) is a heterogeneous cognitive status that can be a prodromal 2 stage of Alzheimer's disease (AD). It is particularly relevant to focus on prodromal stages of 3 AD such as MCI, because pathophysiological abnormalities of AD start years before the 4 dementia stage. Medial temporal lobe atrophy (MTL) resulting from AD lesions and 5 cerebrovascular lesions (i.e. white matter lesions (WML), lacunar strokes and strokes) are 6 often revealed concurrently on Magnetic Resonance Imaging (MRI) in MCI subjects. Personality changes have been reported to be associated with MCI status and early AD. More specifically, an increase in neuroticism and a decrease in conscientiousness have been 9 reported, suggesting that higher and lower scores, respectively in neuroticism and 10 conscientiousness are associated with an increased risk of developing the disease. However, personality changes have not been studied concomitantly with pathological 12 structural brain alterations detected on MRI in patients suffering from MCI. Therefore, the 13 objective of the present study was to assess the relationship between MTL atrophy, WML, 14 lacunar strokes and personality traits in such patients. The severity of WML was strongly 15 associated with lower levels of conscientiousness and higher levels of neuroticism. Conversely, no association was detected between personality traits and the presence of 17 lacunar strokes or MTL atrophy. Altogether, these results strongly suggest that personality 18 changes occurring in a MCI population, at high risk of AD, are associated with WML, which 19 can induce executive dysfunctions, rather than with MTL atrophy. 20 21 22
Proceedings of the National Academy of Sciences, 2008
Innate parental behaviors and adult social interactions are essential for survival of the individ... more Innate parental behaviors and adult social interactions are essential for survival of the individual along with the species as a whole. Because these behaviors require threat assessment of the environment, it is plausible that they are regulated by the amygdalaassociated neural circuitry of fear. However, the amygdala is not a single anatomic and functional unit, and nuclei of the amygdala have multiple inter-and intra-connections. This poses a question as to the exact role of different amygdala nuclei in these behaviors and the mechanisms involved. The basolateral complex of the amygdala nuclei (BLA) is particularly interesting in this regard: although the BLA role in forming memories for learned fear is established, the BLA role in innate behaviors is not well understood. We recently demonstrated that mice without an inhibitor of microtubules, stathmin, a gene enriched in BLA-associated circuitry, have deficiency in innate and learned fear. Here we show that the deficiency in fear processing in stathmin ؊/؊ females leads to improper threat assessment, which in turn affects innate parental care and adult social interactions. Profound deficiency is observed in maternal behavior of stathmin ؊/؊ females: they lack motivation for retrieving pups and are unable to choose a safe location for nest-building. Remarkably, stathmin ؊/؊ females have an enhancement in social interactions. BLA lesions in WT mice produce similar effects in maternal and social behaviors, confirming vital BLA participation. The findings implicate stathmin as the critical molecular component linking the BLA-associated neural circuitry with innate parental behaviors and adult social interactions. amygdala-enriched genes ͉ maternal behavior ͉ fear ͉ threat ͉ pup retrieval
PLoS ONE, 2012
Extinction is an integral part of normal healthy fear responses, while it is compromised in sever... more Extinction is an integral part of normal healthy fear responses, while it is compromised in several fear-related mental conditions in humans, such as post-traumatic stress disorder (PTSD). Although much research has recently been focused on fear extinction, its molecular and cellular underpinnings are still unclear. The development of animal models for extinction will greatly enhance our approaches to studying its neural circuits and the mechanisms involved. Here, we describe two gene-knockout mouse lines, one with impaired and another with enhanced extinction of learned fear. These mutant mice are based on fear memory-related genes, stathmin and gastrin-releasing peptide receptor (GRPR). Remarkably, both mutant lines showed changes in fear extinction to the cue but not to the context. We performed indirect imaging of neuronal activity on the second day of cued extinction, using immediate-early gene c-Fos. GRPR knockout mice extinguished slower (impaired extinction) than wildtype mice, which was accompanied by an increase in c-Fos activity in the basolateral amygdala and a decrease in the prefrontal cortex. By contrast, stathmin knockout mice extinguished faster (enhanced extinction) and showed a decrease in c-Fos activity in the basolateral amygdala and an increase in the prefrontal cortex. At the same time, c-Fos activity in the dentate gyrus was increased in both mutant lines. These experiments provide genetic evidence that the balance between neuronal activities of the amygdala and prefrontal cortex defines an impairment or facilitation of extinction to the cue while the hippocampus is involved in the contextspecificity of extinction.
Neurobiology of Aging, 2008
APP 751SL mice of 5-6-and 7-8-month-old and their wild-type littermates were submitted to one-ses... more APP 751SL mice of 5-6-and 7-8-month-old and their wild-type littermates were submitted to one-session learning in a water-maze with three levels of training (4, 12 or 22 trials). Training consisted in finding a submerged platform with a fixed location and marked by a cue. During testing two platforms were presented: one consistent with the spatial location allowing place-response (PR) and the other signaled by the cue enabling cued-response (CR). When testing occurred 24 h after training, wild-type and 5-6-month-old APP 751SL mice exhibited a shift in response strategy as a function of training level, by executing CR when trained with 4 trials and PR when trained with 12 trials, but 7-8-monthold APP 751SL mice executed only CR. However, they displayed PR when tested 1 h after 12-and 22-trial, suggesting a consolidation deficit. Zif268 imaging showed plasticity impairment of the hippocampal-dependent memory system but not of the dorsolateral caudate nucleus. Moreover, in these APP 751SL mice, the deficit selectively affecting hippocampal function cannot be directly related to the onset of -amyloid deposits.
Learning & Memory, 2006
Procedural and declarative memory systems are postulated to interact in either a synergistic or a... more Procedural and declarative memory systems are postulated to interact in either a synergistic or a competitive manner, and memory consolidation appears to be a highly critical stage for this process. However, the precise cellular mechanisms subserving these interactions remain unknown. To investigate this issue, 24-h retention performances were examined in mice given post-training intrahippocampal injections of forskolin (FK) aiming at stimulating hippocampal adenylyl cyclases (ACs). The injection was given at different time points over a period of 9 h following acquisition in either an appetitive bar-pressing task or water-maze tasks challenging respectively “response memory” and “place memory.” Retention testing (24 h) showed that FK injection altered memory formation only when given within a 3- to 6-h time window after acquisition but yielded opposite memory effects as a function of task demands. Retention of the spatial task was impaired, whereas retention of both the cued-respon...
Learning & Memory, 2010
Synaptically released Zn2+ is a potential modulator of neurotransmission and synaptic plasticity ... more Synaptically released Zn2+ is a potential modulator of neurotransmission and synaptic plasticity in fear-conditioning pathways. Zinc transporter 3 (ZnT3) knock-out (KO) mice are well suited to test the role of zinc in learned fear, because ZnT3 is colocalized with synaptic zinc, responsible for its transport to synaptic vesicles, highly enriched in the amygdala-associated neural circuitry, and ZnT3 KO mice lack Zn2+ in synaptic vesicles. However, earlier work reported no deficiency in fear memory in ZnT3 KO mice, which is surprising based on the effects of Zn2+ on amygdala synaptic plasticity. We therefore reexamined ZnT3 KO mice in various tasks for learned and innate fear. The mutants were deficient in a weak fear-conditioning protocol using single tone–shock pairing but showed normal memory when a stronger, five-pairing protocol was used. ZnT3 KO mice were deficient in memory when a tone was presented as complex auditory information in a discontinuous fashion. Moreover, ZnT3 KO m...
Journal of Neuroscience - J NEUROSCI, 2010
Reference memory characterizes the long-term storage of information acquired through numerous tri... more Reference memory characterizes the long-term storage of information acquired through numerous trials. In contrast, working memory represents the short-term acquisition of trial-unique information. A number of studies in the rodent hippocampus have focused on the contribution of long-term synaptic potentiation (LTP) to long-term reference memory. In contrast, little is known about the synaptic plasticity correlates of hippocampal-based components of working memory. Here, we described a mouse with selective expression of a dominant-negative mutant of the regulatory subunit of protein kinase A (PKA) only in two regions of the hippocampus, the dentate gyrus and area CA1. This mouse showed a deficit in several forms of LTP in both hippocampal subregions and a lowered threshold for the consolidation of long-term synaptic depression (LTD). When trained with one trial per day in a water maze task, mutant mice displayed a deficit in consolidation of long-term memory. In contrast, these mice proved to be more flexible after a transfer test and also showed a delay-dependent increased performance in working memory, when repetitive information (proactive interference) was presented. We suggest that through its bidirectional control over synaptic plasticity PKA can regulate opposing forms of memory. The defect in L-LTP disrupts long-term memory consolidation. The persistence of LTD may allow acquisition of new information by restricting the body of previously stored information and suppressing interference.
PloS one, 2012
Extinction is an integral part of normal healthy fear responses, while it is compromised in sever... more Extinction is an integral part of normal healthy fear responses, while it is compromised in several fear-related mental conditions in humans, such as post-traumatic stress disorder (PTSD). Although much research has recently been focused on fear extinction, its molecular and cellular underpinnings are still unclear. The development of animal models for extinction will greatly enhance our approaches to studying its neural circuits and the mechanisms involved. Here, we describe two gene-knockout mouse lines, one with impaired and another with enhanced extinction of learned fear. These mutant mice are based on fear memory-related genes, stathmin and gastrin-releasing peptide receptor (GRPR). Remarkably, both mutant lines showed changes in fear extinction to the cue but not to the context. We performed indirect imaging of neuronal activity on the second day of cued extinction, using immediate-early gene c-Fos. GRPR knockout mice extinguished slower (impaired extinction) than wildtype mice, which was accompanied by an increase in c-Fos activity in the basolateral amygdala and a decrease in the prefrontal cortex. By contrast, stathmin knockout mice extinguished faster (enhanced extinction) and showed a decrease in c-Fos activity in the basolateral amygdala and an increase in the prefrontal cortex. At the same time, c-Fos activity in the dentate gyrus was increased in both mutant lines. These experiments provide genetic evidence that the balance between neuronal activities of the amygdala and prefrontal cortex defines an impairment or facilitation of extinction to the cue while the hippocampus is involved in the contextspecificity of extinction.
Learning & …, 2010
Synaptically released Zn 2+ is a potential modulator of neurotransmission and synaptic plasticity... more Synaptically released Zn 2+ is a potential modulator of neurotransmission and synaptic plasticity in fear-conditioning pathways. Zinc transporter 3 (ZnT3) knockout (KO) mice are well suited to test the role of zinc in learned fear, because ZnT3 is colocalized with synaptic zinc, responsible for its transport to synaptic vesicles, highly enriched in the amygdala-associated neural circuitry, and ZnT3 KO mice lack Zn 2+ in synaptic vesicles. However, earlier work reported no deficiency in fear memory in ZnT3 KO mice, which is surprising based on the effects of Zn 2+ on amygdala synaptic plasticity. We therefore reexamined ZnT3 KO mice in various tasks for learned and innate fear. The mutants were deficient in a weak fear-conditioning protocol using single tone-shock pairing but showed normal memory when a stronger, five-pairing protocol was used. ZnT3 KO mice were deficient in memory when a tone was presented as complex auditory information in a discontinuous fashion. Moreover, ZnT3 KO mice showed abnormality in trace fear conditioning and in fear extinction. By contrast, ZnT3 KO mice had normal anxiety. Thus, ZnT3 is involved in associative fear memory and extinction, but not in innate fear, consistent with the role of synaptic zinc in amygdala synaptic plasticity.
Behavioural Brain Research, 2011
Despite huge advances on Alzheimer's disease (AD) etiology, the clinical diagnosis remains the un... more Despite huge advances on Alzheimer's disease (AD) etiology, the clinical diagnosis remains the unique commonly used tool to detect the onset of the disease. For instance, epidemiological studies report that the combination of episodic and working memory disorders represents the most consistent sign of progression from mild cognitive impairment to AD. However, such working memory disorders failed to be observed early in transgenic mouse models of AD because the behavioral procedures used do not tackle properly crucial components of working memory. The aim of the present work was to assess early occurrence of working memory impairments in APP 751SL mice. Therefore, we designed a new behavioral task in the water-maze, based on the principle of a delayed matching to place task, where spatial recognition was assessed for four different platform locations within a single session. First, we showed that dorsal hippocampal but not medial prefrontal cortex lesions in C57Bl6 mice induced a time-dependent impairment of spatial recognition. Then, the hippocampal-like memory alterations were reproduced in 7-8-month-old APP 751SL mice but not in younger animals (5-6-month-old). We also demonstrated that these working memory deficits are related to progressive A accumulation in the hippocampus, but not in the other selected brain structures.
Behavioural Brain Research, 2011
Since zinc transporter ZnT3 is localized to the hippocampus and perirhinal cortex, we used ZnT3 k... more Since zinc transporter ZnT3 is localized to the hippocampus and perirhinal cortex, we used ZnT3 knockout mice (KO) to analyze the role of ZnT3 in memory and behavior dependent on these brain regions. ZnT3KO mice were normal in initial learning in the standard water maze but had difficulty finding a second platform location. The mutants showed increased social interaction but were deficient in social and object recognition memory. These data suggest that ZnT3 is involved in certain types of spatial memory and behavior dependent on the hippocampus and perirhinal cortex.
Dynamic interplays between memory systems depend on practice: The hippocampus is not always the first to provide solution
Neuroscience, 2007
Previous studies showed that the optimization of behavioral performance through extended training... more Previous studies showed that the optimization of behavioral performance through extended training depends on a switch from hippocampus-based memory to striatum-based habit. Here we investigate whether the amount of training within one learning session influences the retention of memory for hippocampal versus striatal strategies. Mice were trained to search for a submerged cue-marked platform which remained in the same spatial location in the water-maze for each of three training regimens (4, 12 or 22 trials). Subsequently, they were either tested for retention of memory 1 h or 24 h later on a probe test or killed at different time points over a 7-h period to determine the kinetic of cAMP response element binding protein (CREB) phosphorylation in both memory systems. During the probe test mice had to choose between a submerged platform located in the same position as during the acquisition phase (spatial solution) and a platform marked by the cue but located in the opposite quadrant of the pool (cue-guided solution). Results showed that the animals first preferred the cue-marked platform, which represents a strategy that was selectively impaired by lesions of the dorsolateral caudate-putamen. With further practice, or context pre-exposure, animals transiently favored the hippocampus-dependent place solution but finally, both strategies became interchangeable and insensitive to either lesion. CREB phosphorylation increased in both memory systems following acquisition but training-dependent changes selectively occurred in the hippocampus wherein biphasic activation was initiated by the four-trial training and blocked by training for 22 trials. These findings indicate that learning in one session consists of three acquisition stages with parallel engagement of multiple memory systems at the beginning of learning. They suggest, however, that, in a later phase, dynamic interplays promote the use of the most adapted brain system depending on practice and this is accompanied by specific patterns of CREB phosphorylation in the hippocampus.
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Papers by Guillaume Martel