Neurocentre Magendie

Xavier DE-JAEGER





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Cursus:
PhD Federal University of Minas Gerais, Brazil (2010)
Post-Doc University of Western Ontario, Canada (2011-2012)
Post-Doc CEA, Grenoble (2012-2013)

Expertise: Neuroscience, Memory, Behavior





17 publication(s) depuis Janvier 2007:


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Les IF indiqués ont été collectés par le Web of Sciences en


22/08/2014 | Neuroscience   IF 3.2
Indirect application of near infrared light induces neuroprotection in a mouse model of parkinsonism - an abscopal neuroprotective effect.
Johnstone DM, el Massri N, Moro C, Spana S, Wang XS, Torres N, Chabrol C, De Jaeger X, Reinhart F, Purushothuman S, Benabid AL, Stone J, Mitrofanis J

Abstract:
We have previously shown near infrared light (NIr), directed transcranially, mitigates the loss of dopaminergic cells in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mice, a model of parkinsonism. These findings complement others suggesting NIr treatment protects against damage from various insults. However one puzzling feature of NIr treatment is that unilateral exposure can lead to a bilateral healing response, suggesting NIr may have 'indirect' protective effects. We investigated whether remote NIr treatment is neuroprotective by administering different MPTP doses (50-, 75-, 100-mg/kg) to mice and treating with 670-nm light directed specifically at either the head or body. Our results show that, despite no direct irradiation of the damaged tissue, remote NIr treatment produces a significant rescue of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta at the milder MPTP dose of 50-mg/kg ( approximately 30% increase vs sham-treated MPTP mice, p<0.05). However this protection did not appear as robust as that achieved by direct irradiation of the head ( approximately 50% increase vs sham-treated MPTP mice, p<0.001). There was no quantifiable protective effect of NIr at higher MPTP doses, irrespective of the delivery mode. Astrocyte and microglia cell numbers in substantia nigra pars compacta were not influenced by either mode of NIr treatment. In summary, the findings suggest that treatment of a remote tissue with NIr is sufficient to induce protection of the brain, reminiscent of the 'abscopal effect' sometimes observed in radiation treatment of metastatic cancer. This discovery has implications for the clinical translation of light-based therapies, providing an improved mode of delivery over transcranial irradiation.




03/2014 | J Neurosurg   IF 3.4
Photobiomodulation inside the brain: a novel method of applying near-infrared light intracranially and its impact on dopaminergic cell survival in MPTP-treated mice.
Moro C, Massri NE, Torres N, Ratel D, De Jaeger X, Chabrol C, Perraut F, Bourgerette A, Berger M, Purushothuman S, Johnstone D, Stone J, Mitrofanis J, Benabid AL

Abstract:
OBJECT: Previous experimental studies have documented the neuroprotection of damaged or diseased cells after applying, from outside the brain, near-infrared light (NIr) to the brain by using external light-emitting diodes (LEDs) or laser devices. In the present study, the authors describe an effective and reliable surgical method of applying to the brain, from inside the brain, NIr to the brain. They developed a novel internal surgical device that delivers the NIr to brain regions very close to target damaged or diseased cells. They suggest that this device will be useful in applying NIr within the large human brain, particularly if the target cells have a very deep location. METHODS: An optical fiber linked to an LED or laser device was surgically implanted into the lateral ventricle of BALB/c mice or Sprague-Dawley rats. The authors explored the feasibility of the internal device, measured the NIr signal through living tissue, looked for evidence of toxicity at doses higher than those required for neuroprotection, and confirmed the neuroprotective effect of NIr on dopaminergic cells in the substantia nigra pars compacta (SNc) in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson disease in mice. RESULTS: The device was stable in freely moving animals, and the NIr filled the cranial cavity. Measurements showed that the NIr intensity declined as distance from the source increased across the brain (65% per mm) but was detectable up to 10 mm away. At neuroprotective (0.16 mW) and much higher (67 mW) intensities, the NIr caused no observable behavioral deficits, nor was there evidence of tissue necrosis at the fiber tip, where radiation was most intense. Finally, the intracranially delivered NIr protected SNc cells against MPTP insult; there were consistently more dopaminergic cells in MPTP-treated mice irradiated with NIr than in those that were not irradiated. CONCLUSIONS: In summary, the authors showed that NIr can be applied intracranially, does not have toxic side effects, and is neuroprotective.




2014 | Learn Mem   IF 4.1
Characterization of spatial memory reconsolidation.
De Jaeger X, Courtey J, Brus M, Artinian J, Villain H, Bacquie E, Roullet P

Abstract:
Reconsolidation is necessary for the restabilization of reactivated memory traces. However, experimental parameters have been suggested as boundary conditions for this process. Here we investigated the role of a spatial memory trace's age, strength, and update on the reconsolidation process in mice. We first found that protein synthesis is necessary for reconsolidation to occur in the hippocampal CA3 region after reactivation of partially acquired and old memories but not for strongly acquired and recent memories. We also demonstrated that the update of a previously stable memory required, again, a memory reconsolidation in the hippocampal CA3. Finally, we found that the reactivation of a strongly acquired memory requires an activation of the anterior cingulate cortex as soon as 24 h after acquisition. This study demonstrates the importance of the knowledge of the task on the dynamic nature of memory reconsolidation processing.




Abstract:
Cannabinoid, dopamine (DA), and opiate receptor pathways play integrative roles in emotional learning, associative memory, and sensory perception. Modulation of cannabinoid CB1 receptor transmission within the medial prefrontal cortex (mPFC) regulates the emotional valence of both rewarding and aversive experiences. Furthermore, CB1 receptor substrates functionally interact with opiate-related motivational processing circuits, particularly in the context of reward-related learning and memory. Considerable evidence demonstrates functional interactions between CB1 and DA signaling pathways during the processing of motivationally salient information. However, the role of mPFC CB1 receptor transmission in the modulation of behavioral opiate-reward processing is not currently known. Using an unbiased conditioned place preference paradigm with rats, we examined the role of intra-mPFC CB1 transmission during opiate reward learning. We report that activation or inhibition of CB1 transmission within the prelimbic cortical (PLC) division of the mPFC bidirectionally regulates the motivational valence of opiates; whereas CB1 activation switched morphine reward signaling into an aversive stimulus, blockade of CB1 transmission potentiated the rewarding properties of normally sub-reward threshold conditioning doses of morphine. Both of these effects were dependent upon DA transmission as systemic blockade of DAergic transmission prevented CB1-dependent modulation of morphine reward and aversion behaviors. We further report that CB1-mediated intra-PLC opiate motivational signaling is mediated through a mu-opiate receptor-dependent reward pathway, or a kappa-opiate receptor-dependent aversion pathway, directly within the ventral tegmental area. Our results provide evidence for a novel CB1-mediated motivational valence switching mechanism within the PLC, controlling dissociable subcortical reward and aversion pathways.




11/09/2013 | J Neurosci   IF 5.9
Opiate exposure and withdrawal induces a molecular memory switch in the basolateral amygdala between ERK1/2 and CaMKIIalpha-dependent signaling substrates.
Lyons D, de Jaeger X, Rosen LG, Ahmad T, Lauzon NM, Zunder J, Coolen LM, Rushlow W, Laviolette SR

Abstract:
Opiate reward memories are powerful triggers for compulsive opiate-seeking behaviors. The basolateral amygdala (BLA) is an important structure for the processing of opiate-related associative memories and is functionally linked to the mesolimbic dopamine (DA) pathway. Transmission through intra-BLA DA D1-like and D2-like receptors independently modulates the formation of opiate reward memories as a function of opiate-exposure state. Thus, in the opiate-naive state, intra-BLA D1 transmission is required for opiate-related memory formation. Once opiate dependence and withdrawal has developed, a functional switch to a DA D2-mediated memory mechanism takes place. However, the downstream molecular signaling events that control this functional switch between intra-BLA DA D1 versus D2 receptor transmission are not currently understood. Using an unbiased place conditioning procedure in rats combined with molecular analyses, we report that opiate reward memory acquisition requires intra-BLA ERK1/2 signaling only in the previously opiate-naive state. However, following chronic opiate exposure and withdrawal, intra-BLA reward memory processing switches to a CaMKIIalpha-dependent memory substrate. Furthermore, the ability of intra-BLA DA D1 or D2 receptor transmission to modulate the motivational salience of opiates similarly operates through a D1-mediated ERK-dependent mechanism in the opiate-naive state, but switches to a D2-mediated CaMKIIalpha-dependent mechanism in the dependent/withdrawn state. Protein analysis of BLA tissue revealed a downregulation of ERK1/2 phosphorylation and a dramatic reduction in both total and phosphorylated CaMKIIalpha signaling, specifically in the opiate-dependent/withdrawn state, demonstrating functional control of ERK1/2-dependent versus CaMKIIalpha-dependent memory mechanisms within the BLA, controlled by opiate-exposure state.




03/2013 | J Neurochem   IF 3.8
Mice with selective elimination of striatal acetylcholine release are lean, show altered energy homeostasis and changed sleep/wake cycle.
Guzman MS, De Jaeger X, Drangova M, Prado MA, Gros R, Prado VF

Abstract:
Cholinergic neurons are known to regulate striatal circuits; however, striatal-dependent physiological outcomes influenced by acetylcholine (ACh) are still poorly under;?>stood. Here, we used vesicular acetylcholine transporter (VAChT)(D2-Cre-flox/flox) mice, in which we selectively ablated the vesicular acetylcholine transporter in the striatum to dissect the specific roles of striatal ACh in metabolic homeostasis. We report that VAChT(D) (2-Cre-flox/flox) mice are lean at a young age and maintain this lean phenotype with time. The reduced body weight observed in these mutant mice is not attributable to reduced food intake or to a decrease in growth rate. In addition, changed activity could not completely explain the lean phenotype, as only young VAChT(D) (2-Cre-flox/flox) mice showed increased physical activity. Interestingly, VAChT(D) (2-Cre-flox/flox) mice show several metabolic changes, including increased plasma levels of insulin and leptin. They also show increased periods of wakefulness when compared with littermate controls. Taken together, our data suggest that striatal ACh has an important role in the modulation of metabolism and highlight the importance of striatum cholinergic tone in the regulation of energy expenditure. These new insights on how cholinergic neurons influence homeostasis open new avenues for the search of drug targets to treat obesity.




01/02/2013 | Behav Brain Res   IF 3
Decreased acetylcholine release delays the consolidation of object recognition memory.
De Jaeger X, Cammarota M, Prado MA, Izquierdo I, Prado VF, Pereira GS

Abstract:
Acetylcholine (ACh) is important for different cognitive functions such as learning, memory and attention. The release of ACh depends on its vesicular loading by the vesicular acetylcholine transporter (VAChT). It has been demonstrated that VAChT expression can modulate object recognition memory. However, the role of VAChT expression on object recognition memory persistence still remains to be understood. To address this question we used distinct mouse lines with reduced expression of VAChT, as well as pharmacological manipulations of the cholinergic system. We showed that reduction of cholinergic tone impairs object recognition memory measured at 24h. Surprisingly, object recognition memory, measured at 4 days after training, was impaired by substantial, but not moderate, reduction in VAChT expression. Our results suggest that levels of acetylcholine release strongly modulate object recognition memory consolidation and appear to be of particular importance for memory persistence 4 days after training.




02/2013 | Psychopharmacology (Berl)   IF 4.1
The effects of AMPA receptor blockade in the prelimbic cortex on systemic and ventral tegmental area opiate reward sensitivity.
De Jaeger X, Bishop SF, Ahmad T, Lyons D, Ng GA, Laviolette SR

Abstract:
RATIONALE: The medial prefrontal cortex (mPFC) is a key neural region involved in opiate-related reward memory processing. AMPA receptor transmission in the mPFC modulates opiate-related reward memory processing, and chronic opiate exposure is associated with alterations in intra-mPFC AMPA receptor function. OBJECTIVE: The objectives of this study were to examine how pharmacological blockade of AMPA receptor transmission in the prelimbic (PLC) division of the mPFC may modulate opiate reward memory acquisition and whether opiate exposure state may modulate the functional role of intra-PLC AMPA receptor transmission during opiate reward learning. METHODS: Using an unbiased conditioned place preference (CPP) procedure in rats, we performed discrete, bilateral intra-PLC microinfusions of the AMPA receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione, prior to behavioral morphine CPP conditioning, using sub-reward threshold conditioning doses of either systemic (0.05 mg/kg; i.p.) or intra-ventral tegmental area (VTA) morphine (250 ng/0.5 mul). RESULTS: We show that, in both opiate-naive and opiate-dependent states, intra-PLC blockade of AMPA receptor transmission, but not the infralimbic cortex, increases the behavioral reward magnitude of systemic or intra-VTA morphine. This effect is dependent on dopamine (DA)ergic signaling because pre-administration of cis-(Z)-flupenthixol-dihydrochloride (alpha-flu), a broad-spectrum dopamine receptor antagonist, blocked the morphine-reward potentiating effects of AMPA receptor blockade. CONCLUSIONS: These findings suggest a critical role for intra-PLC AMPA receptor transmission in the processing of opiate reward signaling. Furthermore, blockade of AMPA transmission specifically within the PLC is capable of switching opiate reward processing to a DA-dependent reward system, independently of previous opiate exposure history.




Abstract:
The consolidation of newly acquired memories involves the temporal transition from a recent, less stable trace to a more permanent consolidated form. Opiates possess potent rewarding effects and produce powerful associative memories. The activation of these memories is associated with opiate abuse relapse phenomena and the persistence of compulsive opiate dependence. However, the neuronal, molecular and temporal mechanisms by which associative opiate reward memories are consolidated are not currently understood. We report that the consolidation of associative opiate reward memories involves a temporal and molecular switch between the basolateral nucleus of the amygdala (BLA) (early consolidation phase) to the medial prefrontal cortex (mPFC) (late consolidation phase). We demonstrate at the molecular, behavioral and neuronal levels that the consolidation of a recently acquired opiate reward memory involves an extracellular signal-related kinase (ERK)-dependent phosphorylation process within the BLA. In contrast, later-stage consolidation of a newly acquired memory is dependent upon a calcium-calmodulin-dependent (CaMKII), ERK-independent, mechanism in the mPFC, over a 12 hr temporal gradient. In addition, using in vivo multi-unit neuronal recordings in the mPFC, we report that protein synthesis within the BLA modulates the consolidation of opiate-reward memory in neuronal mPFC sub-populations, via the same temporal dynamic.




23/10/2012 | Proc Natl Acad Sci U S A   IF 9.6
Elimination of the vesicular acetylcholine transporter in the forebrain causes hyperactivity and deficits in spatial memory and long-term potentiation.
Martyn AC, De Jaeger X, Magalhaes AC, Kesarwani R, Goncalves DF, Raulic S, Guzman MS, Jackson MF, Izquierdo I, Macdonald JF, Prado MA, Prado VF

Abstract:
Basal forebrain cholinergic neurons, which innervate the hippocampus and cortex, have been implicated in many forms of cognitive function. Immunolesion-based methods in animal models have been widely used to study the role of acetylcholine (ACh) neurotransmission in these processes, with variable results. Cholinergic neurons have been shown to release both glutamate and ACh, making it difficult to deduce the specific contribution of each neurotransmitter on cognition when neurons are eliminated. Understanding the precise roles of ACh in learning and memory is critical because drugs that preserve ACh are used as treatment for cognitive deficits. It is therefore important to define which cholinergic-dependent behaviors could be improved pharmacologically. Here we investigate the contributions of forebrain ACh on hippocampal synaptic plasticity and cognitive behavior by selective elimination of the vesicular ACh transporter, which interferes with synaptic storage and release of ACh. We show that elimination of vesicular ACh transporter in the hippocampus results in deficits in long-term potentiation and causes selective deficits in spatial memory. Moreover, decreased cholinergic tone in the forebrain is linked to hyperactivity, without changes in anxiety or depression-related behavior. These data uncover the specific contribution of forebrain cholinergic tone for synaptic plasticity and behavior. Moreover, these experiments define specific cognitive functions that could be targeted by cholinergic replacement therapy.