Skip to main content

Joëlle Lopez

Followers

4

Following

3

Co-authors

3

Public Views

C. Michael Hall

University of Canterbury/Te Whare Wānanga o Waitaha

Universidade Estadual de Campinas

Jennifer Gidley

University of Technology Sydney

Kansas State University

University of the Basque Country, Euskal Herriko Unibertsitatea

Macquarie University

Yannis Hamilakis

Brown University

Stephen J. Cowley

University of Southern Denmark

Rigas Arvanitis

Institut de Recherche pour le Développement (IRD - France)

Friederike Moltmann

Centre National de la Recherche Scientifique / French National Centre for Scientific Research

Interests

Uploads

Papers by Joëlle Lopez

P212. Sidekick-1, a Novel Regulator of Stress Resilience in the Prefrontal Cortex

Biological Psychiatry, May 1, 2022

The susceptibility to chronic social defeat stress is related to low hippocampal extrasynaptic NMDA receptor function

Neuropsychopharmacology, 2019

N-methyl-D-aspartate receptors (NMDARs) have been highly implicated in the pathogenesis and treat... more N-methyl-D-aspartate receptors (NMDARs) have been highly implicated in the pathogenesis and treatment of depression. While NMDARs can be found inside and outside glutamate synapses, it remains unclear if NMDARs at synaptic (sNMDAR) and extrasynaptic locations (exNMDAR) play different roles in the formation of depression-related behaviors. Using chronic social defeat stress (CSDS), an animal model for anxiety-and depression-related behaviors, we found that mice susceptible to CSDS exhibited low hippocampal exNMDAR function. Raising exNMDAR function by enhancing the release of glutamate from astrocytic cystineglutamate antiporters or targeting extrasynaptic receptors with agonist-coated gold nanoparticles that cannot enter the synaptic cleft prevented social avoidance behavior in stressed mice. Interestingly, ketamine, which is a fast-acting antidepressant, exhibited stronger blockade to sNMDARs than to exNMDARs. These findings suggest that the susceptibility and resilience of mice toward CSDS is related to low and high exNMDAR function in the hippocampus, respectively. Enhancing exNMDAR function could be a novel treatment approach for mood and anxiety disorders.

Wiring the depressed brain: optogenetic and chemogenetic circuit interrogation in animal models of depression

Neuropsychopharmacology, 2018

Differential role of the anterior and intralaminar/lateral thalamic nuclei in systems consolidation and reconsolidation

Brain Structure and Function, 2017

The anterior thalamic nuclei (ATN) and the intralaminar/lateral thalamic nuclei (ILN/LT) play dif... more The anterior thalamic nuclei (ATN) and the intralaminar/lateral thalamic nuclei (ILN/LT) play different roles in memory processes. The ATN are believed to be part of an extended hippocampal system, and the ILN/LT have strong connections with the medial prefrontal cortex. It was shown that the ILN/LT are involved in systems consolidation. However, whether they are necessary for memory retrieval as well remains unclear. We, therefore, used c-Fos immunohistochemistry and reversible inactivations to investigate the role of the ATN and ILN/LT in recent and remote contextual fear memory retrieval in rats. The results confirm a differential role of the ATN and ILN/ LT in systems consolidation, showing the involvement of the ATN in recent but not remote memory retrieval. This study also pinpoints which specific nuclei are involved in retrieval: the anterodorsal nucleus for recent memories, and the lateral mediodorsal nucleus for remote memories. Lastly, we also show that the ATN are not involved in reconsolidation. Together, the results suggest that these nuclei provide critical feedback for successful memory retrieval and systems consolidation.

Lopez JN2009 SupplementalData

Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression

Nature Communications, 2015

Enhanced glutamatergic transmission in the nucleus accumbens (NAc), a region critical for reward ... more Enhanced glutamatergic transmission in the nucleus accumbens (NAc), a region critical for reward and motivation, has been implicated in the pathophysiology of depression; however, the afferent source of this increased glutamate tone is not known. The NAc receives glutamatergic inputs from the medial prefrontal cortex (mPFC), ventral hippocampus (vHIP) and basolateral amygdala (AMY). Here, we demonstrate that glutamatergic vHIP afferents to NAc regulate susceptibility to chronic social defeat stress (CSDS). We observe reduced activity in vHIP in mice resilient to CSDS. Furthermore, attenuation of vHIP-NAc transmission by optogenetic induction of long-term depression is pro-resilient, whereas acute enhancement of this input is pro-susceptible. This effect is specific to vHIP afferents to the NAc, as optogenetic stimulation of either mPFC or AMY afferents to the NAc is pro-resilient. These data indicate that vHIP afferents to NAc uniquely regulate susceptibility to CSDS, highlighting a...

Memory retrieval requires ongoing protein synthesis and NMDA receptor activity-mediated AMPA receptor trafficking

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 11, 2015

Whereas consolidation and reconsolidation are considered dynamic processes requiring protein synt... more Whereas consolidation and reconsolidation are considered dynamic processes requiring protein synthesis, memory retrieval has long been considered a passive readout of previously established plasticity. However, previous findings suggest that memory retrieval may be more dynamic than previously thought. This study therefore aimed at investigating the molecular mechanisms underlying memory retrieval in the rat. Infusion of protein synthesis inhibitors (rapamycin or anisomycin) in the amygdala 10 min before memory retrieval transiently impaired auditory fear memory expression, suggesting ongoing protein synthesis is required to enable memory retrieval. We then investigated the role of protein synthesis in NMDA receptor activity-mediated AMPA receptor trafficking. Coinfusion of an NMDA receptor antagonist (ifenprodil) or infusion of an AMPA receptor endocytosis inhibitor (GluA23Y) before rapamycin prevented this memory impairment. Furthermore, rapamycin transiently decreased GluA1 level...

Reversible inactivation of the dorsal hippocampus by tetrodotoxin or lidocaine: A comparative study on cerebral functional activity and motor coordination in the rat

Neuroscience, 2006

Reversible inactivation of the hippocampus by lidocaine or tetrodotoxin is used to investigate im... more Reversible inactivation of the hippocampus by lidocaine or tetrodotoxin is used to investigate implications of this structure in memory processes. Crucial points related to such inactivation are the temporal and spatial extents of the blockade. We compared effects of intrahippocampal infusions of commonly-used doses of lidocaine (5 or 10 mug) or tetrodotoxin (5 or 10 ng) in rats at two post-infusion delays (5 or 30 min), using 2-deoxyglucose autoradiography to visualize local cerebral glucose metabolism, and beam-walking performance to assess motor coordination. In addition, memory retrieval was evaluated in a water maze after bilateral infusions of 10 mug lidocaine. A unilateral tetrodotoxin infusion induced dose- and time-dependent reductions of 2-deoxyglucose uptake in the vicinity of the infusion site (dorsal hippocampus: -29% to -67%) and in other ipsi- and contralateral brain regions (ventral hippocampus, lateral thalamus, cortical regions). The maximal effect was at 10 ng, at the delay of 30 min between the tetrodotoxin infusion and the 2-deoxyglucose injection. Uni- and bilateral infusions of tetrodotoxin induced dramatic motor coordination deficits. Conversely, lidocaine reduced 2-deoxyglucose uptake (-19%) in the dorsal hippocampus only at 10 mug, with weak extrahippocampal effects. Whether infused uni- or bilaterally and regardless of the dose, lidocaine did not alter motor coordination. When infused bilaterally, however, 10 microg of lidocaine impaired short-term retrieval of spatial information in a water maze. Because lidocaine i) induced a weak though significant functional blockade mainly restricted to the infusion site, ii) had no consequences on motor coordination and, nevertheless iii) altered short-term spatial memory retrieval, we conclude that acute intrahippocampal infusions of lidocaine may offer some advantages over tetrodotoxin at the doses used herein.

Cerebellar deep nuclei involvement in cognitive adaptation and automaticity

Learning & Memory, 2013

To determine the role of the interpositus nuclei of cerebellum in rule-based learning and optimiz... more To determine the role of the interpositus nuclei of cerebellum in rule-based learning and optimization processes, we studied (1) successive transfers of an initially acquired response rule in a cross maze and (2) behavioral strategies in learning a simple response rule in a T maze in interpositus lesioned rats (neurotoxic or electrolytic lesions). Even though lesioned animals showed no impairment in learning the initial stimulus–response association, they had difficulties in transferring the acquired adapted response rule, and in optimizing their response strategy. These results add information on the role of interpositus nuclei in adaptation to environmental changes.

Differential c-fos expression in the brain of male Japanese quail following exposure to stimuli that predict or do not predict the arrival of a female

European Journal of Neuroscience, 2007

We investigated the effects of presenting a sexual conditioned stimulus on the expression of c-fo... more We investigated the effects of presenting a sexual conditioned stimulus on the expression of c-fos in male Japanese quail. Eight brain sites were selected for analysis based on previous reports of c-fos expression in these areas correlated with sexual behaviour or learning. Males received either paired or explicitly unpaired presentations of an arbitrary stimulus and visual access to a female. Nine conditioning trials were conducted, one per day, for each subject. On the day following the ninth trial, subjects were exposed to the conditional stimulus (CS) for 5 min. Conditioning was confirmed by analysis of rhythmic cloacal sphincter movements (RCSM), an appetitive sexual behaviour, made in response to the CS presentation. Subjects in the paired condition performed significantly more RCSM than subjects in the unpaired group. Brains were collected 90 min following the stimulus exposure and stained by immunohistochemistry for the FOS protein. Significant group differences in the number of FOS-immunoreactive (FOS-ir) cells were found in two brain regions, the nucleus taeniae of the amygdala (TnA) and the hippocampus (Hp). Subjects in the paired condition had fewer FOS-ir cells in both areas than subjects in the unpaired condition. These data provide additional support to the hypothesis that TnA is implicated in the expression of appetitive sexual behaviours in male quail and corroborate numerous previous reports of the involvement of the hippocampus in conditioning. Further, these data suggest that conditioned and unconditioned sexual stimuli activate different brain regions but have similar behavioural consequences.

Lesions of the anterior thalamic nuclei and intralaminar thalamic nuclei: place and visual discrimination learning in the water maze

Brain Structure and Function, 2012

Medial thalamic damage produces memory deficits in humans (e.g., Korsakoff's syndrome) and experi... more Medial thalamic damage produces memory deficits in humans (e.g., Korsakoff's syndrome) and experimental animals. Both the anterior thalamic nuclei (ATN) and rostral intralaminar plus adjacent lateral thalamic nuclei (ILN/LT) have been implicated. Based on the differences in their main connections with other neural structures, we tested the prediction that ATN lesions would selectively impair acquisition of spatial location discrimination, reflecting a hippocampal system deficit, whereas ILN/LT lesions would impair acquisition of visual pattern discrimination, reflecting a striatal system deficit. Half the rats were first trained in a spatial task in a water maze before switching to a visual task in the same maze, while the remainder were tested with the reverse order of tasks. Compared with shamoperated controls, (1) rats with ATN lesions showed impaired place learning, but normal visual discrimination learning, (2) rats with ILN/LT lesions showed no deficit on either task. Rats with ATN lesions were also hyperactive when their home cage was placed in a novel room and remained more active than ILN/LT or SHAM rats for the subsequent 21 h, especially during the nocturnal phase. These findings confirmed the influence of ATN lesions on spatial learning, but failed to support the view that ILN/LT lesions disrupt striatal-dependent memory. Keywords Anterior thalamic nuclei Á Hippocampus Á Intralaminar thalamic nuclei Á Spatial memory Á Striatum Á Visual pattern memory Á Water maze P.-H. Moreau and Y. Tsenkina contributed equally to the work.

Defining Valid Chronic Stress Models for Depression With Female Rodents

Biological Psychiatry, 2021

Women are twice as likely to experience depression than men, yet until recently, preclinical stud... more Women are twice as likely to experience depression than men, yet until recently, preclinical studies in rodents have focused almost exclusively on males. As interest in sex differences and sex-specific mechanisms of stress susceptibility increases, chronic stress models for inducing depression-relevant behavioral and physiological changes in male rodents are being applied to females, and several new models have emerged to include both males and females, yet not all models have been systematically validated in females. An increasing number of researchers seek to include female rodents in their experimental designs, asking the question "what is the ideal chronic stress model for depression in females?" We review criteria for assessing female model validity in light of key research questions and the fundamental distinction between studying sex differences and studying both sexes. In overviewing current models, we explore challenges inherent to establishing an ideal female chronic stress model, with particular emphasis on the need for standardization and adoption of validated behavioral tests sensitive to stress effects in females. Taken together, these considerations will empower female chronic stress models to provide a better understanding of stress susceptibility and allow the development of efficient sex-specific treatments.

The Intralaminar Thalamic Nuclei Contribute to Remote Spatial Memory

by Joëlle Lopez and Mathieu Wolff

Recent studies have shown that the anterior (ATN) and lateral thalamic nuclei (including the intr... more Recent studies have shown that the anterior (ATN) and lateral thalamic nuclei (including the intralaminar nuclei; ILN/LT) play different roles in memory processes. These nuclei have prominent direct and indirect connections with the hippocampal system and/or the prefrontal cortex and may thus participate in the time-dependent reorganization of memory traces during systems-level consolidation. We investigated whether ATN or ILN/LT lesions in rats influenced acquisition and subsequent retrieval of spatial memory in a Morris water maze. Retrieval was assessed with a probe trial after a short (5 d, recent memory) or a long (25 d, remote memory) postacquisition delay. The ATN group showed impaired acquisition compared with the Sham controls and ILN/LT groups, which did not differ during acquisition, and exhibited no preference for the target quadrant during the recent or remote memory probe trials. In contrast, probe trial performance in rats with ILN/LT lesions differed according to the age of the memory, with accurate spatial retrieval for the recent memory probe trial but impaired retrieval during the remote memory one. These findings confirm that ATN but not ILN/LT lesions disrupt the acquisition of spatial memory and provide new evidence that the ILN/LT region contributes to remote memory processing. Thus, the lateral thalamus may modulate some aspects of remote memory formation and/or retrieval during the course of systems-level consolidation.

The Ventral Midline Thalamus (Reuniens and Rhomboid Nuclei) Contributes to the Persistence of Spatial Memory in Rats

Journal of Neuroscience, 2012

The formation of enduring declarative-like memories engages a dialog between the hippocampus and ... more The formation of enduring declarative-like memories engages a dialog between the hippocampus and the prefrontal cortex (PFC). Electrophysiological and neuroanatomical evidence for reciprocal connections with both of these structures makes the reuniens and rhomboid nuclei (ReRh) of the thalamus a major functional link between the PFC and hippocampus. Using immediate early gene imaging (c-Fos), fiber-sparing excitotoxic lesion, and reversible inactivation in rats, we provide evidence demonstrating a contribution of the ReRh to the persistence of a spatial memory. Intact rats trained in a Morris water maze showed increased c-Fos expression (vs home cage and visible platform groups: &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;500%) in the ReRh when tested in a probe trial at a 25 d delay, against no change at a 5 d delay; behavioral performance was comparable at both delays. In rats subjected to excitotoxic fiber-sparing NMDA lesions circumscribed to the ReRh, we found normal acquisition of the water-maze task (vs sham-operated controls) and normal probe trial performance at the 5 d delay, but there was no evidence for memory retrieval at the 25 d delay. In rats having learned the water-maze task, lidocaine-induced inactivation of the ReRh right before the probe trial did not alter memory retrieval tested at the 5 d or 25 d delay. Together, these data suggest an implication of the ReRh in the long-term consolidation of a spatial memory at the system level. These nuclei could then be a key structure contributing to the transformation of a new hippocampal-dependent spatial memory into a remote one also depending on cortical networks.

The Intralaminar Thalamic Nuclei Contribute to Remote Spatial Memory

Journal of Neuroscience, 2009

Recent studies have shown that the anterior (ATN) and lateral thalamic nuclei (including the intr... more Recent studies have shown that the anterior (ATN) and lateral thalamic nuclei (including the intralaminar nuclei; ILN/LT) play different roles in memory processes. These nuclei have prominent direct and indirect connections with the hippocampal system and/or the prefrontal cortex and may thus participate in the time-dependent reorganization of memory traces during systems-level consolidation. We investigated whether ATN or ILN/LT lesions in rats influenced acquisition and subsequent retrieval of spatial memory in a Morris water maze. Retrieval was assessed with a probe trial after a short (5 d, recent memory) or a long (25 d, remote memory) postacquisition delay. The ATN group showed impaired acquisition compared with the Sham controls and ILN/LT groups, which did not differ during acquisition, and exhibited no preference for the target quadrant during the recent or remote memory probe trials. In contrast, probe trial performance in rats with ILN/LT lesions differed according to the age of the memory, with accurate spatial retrieval for the recent memory probe trial but impaired retrieval during the remote memory one. These findings confirm that ATN but not ILN/LT lesions disrupt the acquisition of spatial memory and provide new evidence that the ILN/LT region contributes to remote memory processing. Thus, the lateral thalamus may modulate some aspects of remote memory formation and/or retrieval during the course of systems-level consolidation.

Hippocampal-dependent spatial memory functions might be lateralized in rats: An approach combining gene expression profiling and reversible inactivation

Hippocampus, 2009

The hippocampus is involved in spatial memory processes, as established in a variety of species s... more The hippocampus is involved in spatial memory processes, as established in a variety of species such as birds and mammals including humans. In humans, some hippocampal-dependent memory functions may be lateralized, the right hippocampus being predominantly involved in spatial navigation. In rodents, the question of possible lateralization remains open. Therefore, we first microdissected the CA1 subregion of the left and right dorsal hippocampi for analysis of mRNA expression using microarrays in rats having learnt a reference memory task in the Morris water-maze. Relative to untrained controls, 623 genes were differentially expressed in the right hippocampus, against only 74 in the left hippocampus, in the rats that had learnt the hidden platform location. Thus, in the right hippocampus, 299 genes were induced, 324 were repressed, and about half of them participate in signaling and transport, metabolism, and nervous system functions. In addition, most differentially expressed genes associated with spatial learning have been previously related to synaptic plasticity and memory. We then subjected rats to unilateral (left or right) or bilateral reversible functional inactivations in the dorsal hippocampus; lidocaine was infused either before each acquisition session or before retrieval of a reference spatial memory in the Morris water maze. We found that after drug-free acquisition, right or bilateral lidocaine inactivation (vs. left, or bilateral phosphate buffered saline (PBS) infusions) of the dorsal hippocampus just before a delayed (24 h) probe trial impaired performance. Conversely, left or bilateral hippocampus inactivation (vs. right, or bilateral PBS infusions) before each acquisition session weakened performance during a delayed, drug-free probe trial. Our data confirm a functional association between transcriptional activity within the dorsal hippocampus and spatial memory in the rat. Further, they suggest that there could be a leftward bias of hippocampal functions in engram formation or information transfer, and a rightward bias in spatial memory storage/retrieval processes. V V C 2009 Wiley-Liss, Inc.

Context-dependent modulation of hippocampal and cortical recruitment during remote spatial memory retrieval

Hippocampus, 2012

According to systems consolidation, as hippocampal-dependent memories mature over time, they beco... more According to systems consolidation, as hippocampal-dependent memories mature over time, they become additionally (or exclusively) dependent on extra-hippocampal structures. We assessed the recruitment of hippocampal and cortical structures on remote memory retrieval in a performance-degradation resistant (PDR; no performance degradation with time) versus performance-degradation prone (PDP; performance degraded with time) context. Using a water-maze task in two contexts with a hidden platform and three control conditions (home cage, visible platform with or without access to distal cues), we compared neuronal activation (c-Fos imaging) patterns in the dorsal hippocampus and the medial prefrontal cortex (mPFC) after the retrieval of recent (5 days) versus remote (25 days) spatial memory. In the PDR context, the hippocampus exhibited greater c-Fos protein expression on remote than recent memory retrieval, be it in the visible or hidden platform group. In the PDP context, hippocampal activation increased at the remote time point and only in the hidden platform group. In the anterior cingulate cortex, c-Fos expression was greater for remote than for recent memory retrieval and only in the PDR context. The necessity of the mPFC for remote memory retrieval in the PDR context was confirmed using region-specific lidocaine inactivation, which had no impact on recent memory. Conversely, inactivation of the dorsal hippocampus impaired both recent and remote memory in the PDR context, and only recent memory in the PDP context, in which remote memory performance was degraded. While confirming that neuronal circuits supporting spatial memory consolidation are reorganized in a time-dependent manner, our findings further indicate that mPFC and hippocampus recruitment (i) depends on the content and perhaps the strength of the memory and (ii) may be influenced by the environmental conditions (e.g., cue saliency, complexity) in which memories are initially formed and subsequently recalled.

Differential sensitivity of recent vs. remote memory traces to extinction in a water-maze task in rats

Neurobiology of Learning and Memory, 2008

Extinction has mostly been studied in conditioning paradigms, more sparsely in spatial tasks, and... more Extinction has mostly been studied in conditioning paradigms, more sparsely in spatial tasks, and never as a function of the age of a spatial memory. Using rats, we compared the time-course of extinction of a recent (5 days) vs. remote (25 days) spatial memory in a water maze, over three probe trials. When the trials were set 24 h apart, performance in the remote memory group was significantly worse on the first probe trial and significantly better on the third probe trial, as compared to the recent memory group, thereby showing differences between cognitive operations underlying recent vs. remote memory extinction. In contrast, when trials were given consecutively, both groups showed a similar profile of extinction. Furthermore, in a room with overly-salient cues providing a strong remote memory trace, no difference between groups was observed when the spaced extinction paradigm was used. These results might be related to a balance between reconsolidation and extinction processes occurring after a first retrieval experience, of which the outcome may depend on the extinction protocol, and on the age and strength of a memory.

Environmental cue saliency influences the vividness of a remote spatial memory in rats

Neurobiology of Learning and Memory, 2008

The Morris water maze is frequently used to evaluate the acquisition and retrieval of spatial mem... more The Morris water maze is frequently used to evaluate the acquisition and retrieval of spatial memories. Few experiments, however, have investigated the effects of environmental cue saliency on the strength or persistence of such memories after a short vs. long postacquisition interval. Using a Morris water maze, we therefore tested in rats the effect of the saliency of distal cues on the vividness of a recent (5 days) vs. remote (25 days) memory. Rats trained in a cue-enriched vs. a cue-impoverished context showed a better overall level of performance during acquisition. Furthermore, the probe trials revealed that the rats trained and tested in the cue-impoverished context (1) spent less time in the target quadrant at the 25-day delay, and (2) swam shorter distances in the target area, with fewer crossings at both 5-and 25-day delays, as compared to their counterparts trained and tested in the cue-enriched context. Thus, the memory trace formed in the cue-enriched context shows better resistance to time, suggesting an implication of cue saliency in the vividness of a spatial memory.

The ventral hippocampus is necessary for expressing a spatial memory

Brain Structure and Function, 2012

Current views posit the dorsal hippocampus (DHipp) as contributing to spatial memory processes. C... more Current views posit the dorsal hippocampus (DHipp) as contributing to spatial memory processes. Conversely, the ventral hippocampus (VHipp) modulates stress, emotions and affects. Arguments supporting this segregation include differences in (i) connectivity: the DHipp is connected with the entorhinal cortex which receives visuospatial neocortical inputs; the VHipp is connected with both the amygdala and hypothalamus, (ii) electrophysiological characteristics: there is a larger proportion of place cells in the DHipp than in the VHipp, and an increasing dorsoventral gradient in the size of place fields, suggesting less refined spatial coding in the VHipp, and (iii) consequences of lesions: spatial memory is altered after DHipp lesions, less dramatically, sometimes not, after VHipp lesions. Using reversible inactivation, we report in rats, that lidocaine infusions into the DHipp or VHipp right before a probe trial impair retrieval performance in a water-maze task. This impairment was found at two postacquisition delays compatible with recent memory (1 and 5 days). Pre-training blockade of the VHipp did not prevent task acquisition and drug-free retrieval, on the contrary to pre-training blockade of DHipp, which altered performance in a subsequent drug-free probe trial. Complementary experiments excluded possible locomotor, sensorimotor, motivational or anxiety-related biases from data interpretation. Our conclusion is that a spatial memory can be acquired with the DHipp, less efficiently with the VHipp, and that the retrieval of such a memory and/or the expression of its representation engages the dorsoventral axis of the hippocampus when the task has been learnt with an entirely functional hippocampus.

P212. Sidekick-1, a Novel Regulator of Stress Resilience in the Prefrontal Cortex

Biological Psychiatry, May 1, 2022

The susceptibility to chronic social defeat stress is related to low hippocampal extrasynaptic NMDA receptor function

Neuropsychopharmacology, 2019

N-methyl-D-aspartate receptors (NMDARs) have been highly implicated in the pathogenesis and treat... more N-methyl-D-aspartate receptors (NMDARs) have been highly implicated in the pathogenesis and treatment of depression. While NMDARs can be found inside and outside glutamate synapses, it remains unclear if NMDARs at synaptic (sNMDAR) and extrasynaptic locations (exNMDAR) play different roles in the formation of depression-related behaviors. Using chronic social defeat stress (CSDS), an animal model for anxiety-and depression-related behaviors, we found that mice susceptible to CSDS exhibited low hippocampal exNMDAR function. Raising exNMDAR function by enhancing the release of glutamate from astrocytic cystineglutamate antiporters or targeting extrasynaptic receptors with agonist-coated gold nanoparticles that cannot enter the synaptic cleft prevented social avoidance behavior in stressed mice. Interestingly, ketamine, which is a fast-acting antidepressant, exhibited stronger blockade to sNMDARs than to exNMDARs. These findings suggest that the susceptibility and resilience of mice toward CSDS is related to low and high exNMDAR function in the hippocampus, respectively. Enhancing exNMDAR function could be a novel treatment approach for mood and anxiety disorders.

Wiring the depressed brain: optogenetic and chemogenetic circuit interrogation in animal models of depression

Neuropsychopharmacology, 2018

Differential role of the anterior and intralaminar/lateral thalamic nuclei in systems consolidation and reconsolidation

Brain Structure and Function, 2017

The anterior thalamic nuclei (ATN) and the intralaminar/lateral thalamic nuclei (ILN/LT) play dif... more The anterior thalamic nuclei (ATN) and the intralaminar/lateral thalamic nuclei (ILN/LT) play different roles in memory processes. The ATN are believed to be part of an extended hippocampal system, and the ILN/LT have strong connections with the medial prefrontal cortex. It was shown that the ILN/LT are involved in systems consolidation. However, whether they are necessary for memory retrieval as well remains unclear. We, therefore, used c-Fos immunohistochemistry and reversible inactivations to investigate the role of the ATN and ILN/LT in recent and remote contextual fear memory retrieval in rats. The results confirm a differential role of the ATN and ILN/ LT in systems consolidation, showing the involvement of the ATN in recent but not remote memory retrieval. This study also pinpoints which specific nuclei are involved in retrieval: the anterodorsal nucleus for recent memories, and the lateral mediodorsal nucleus for remote memories. Lastly, we also show that the ATN are not involved in reconsolidation. Together, the results suggest that these nuclei provide critical feedback for successful memory retrieval and systems consolidation.

Lopez JN2009 SupplementalData

Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression

Nature Communications, 2015

Enhanced glutamatergic transmission in the nucleus accumbens (NAc), a region critical for reward ... more Enhanced glutamatergic transmission in the nucleus accumbens (NAc), a region critical for reward and motivation, has been implicated in the pathophysiology of depression; however, the afferent source of this increased glutamate tone is not known. The NAc receives glutamatergic inputs from the medial prefrontal cortex (mPFC), ventral hippocampus (vHIP) and basolateral amygdala (AMY). Here, we demonstrate that glutamatergic vHIP afferents to NAc regulate susceptibility to chronic social defeat stress (CSDS). We observe reduced activity in vHIP in mice resilient to CSDS. Furthermore, attenuation of vHIP-NAc transmission by optogenetic induction of long-term depression is pro-resilient, whereas acute enhancement of this input is pro-susceptible. This effect is specific to vHIP afferents to the NAc, as optogenetic stimulation of either mPFC or AMY afferents to the NAc is pro-resilient. These data indicate that vHIP afferents to NAc uniquely regulate susceptibility to CSDS, highlighting a...

Memory retrieval requires ongoing protein synthesis and NMDA receptor activity-mediated AMPA receptor trafficking

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 11, 2015

Whereas consolidation and reconsolidation are considered dynamic processes requiring protein synt... more Whereas consolidation and reconsolidation are considered dynamic processes requiring protein synthesis, memory retrieval has long been considered a passive readout of previously established plasticity. However, previous findings suggest that memory retrieval may be more dynamic than previously thought. This study therefore aimed at investigating the molecular mechanisms underlying memory retrieval in the rat. Infusion of protein synthesis inhibitors (rapamycin or anisomycin) in the amygdala 10 min before memory retrieval transiently impaired auditory fear memory expression, suggesting ongoing protein synthesis is required to enable memory retrieval. We then investigated the role of protein synthesis in NMDA receptor activity-mediated AMPA receptor trafficking. Coinfusion of an NMDA receptor antagonist (ifenprodil) or infusion of an AMPA receptor endocytosis inhibitor (GluA23Y) before rapamycin prevented this memory impairment. Furthermore, rapamycin transiently decreased GluA1 level...

Reversible inactivation of the dorsal hippocampus by tetrodotoxin or lidocaine: A comparative study on cerebral functional activity and motor coordination in the rat

Neuroscience, 2006

Reversible inactivation of the hippocampus by lidocaine or tetrodotoxin is used to investigate im... more Reversible inactivation of the hippocampus by lidocaine or tetrodotoxin is used to investigate implications of this structure in memory processes. Crucial points related to such inactivation are the temporal and spatial extents of the blockade. We compared effects of intrahippocampal infusions of commonly-used doses of lidocaine (5 or 10 mug) or tetrodotoxin (5 or 10 ng) in rats at two post-infusion delays (5 or 30 min), using 2-deoxyglucose autoradiography to visualize local cerebral glucose metabolism, and beam-walking performance to assess motor coordination. In addition, memory retrieval was evaluated in a water maze after bilateral infusions of 10 mug lidocaine. A unilateral tetrodotoxin infusion induced dose- and time-dependent reductions of 2-deoxyglucose uptake in the vicinity of the infusion site (dorsal hippocampus: -29% to -67%) and in other ipsi- and contralateral brain regions (ventral hippocampus, lateral thalamus, cortical regions). The maximal effect was at 10 ng, at the delay of 30 min between the tetrodotoxin infusion and the 2-deoxyglucose injection. Uni- and bilateral infusions of tetrodotoxin induced dramatic motor coordination deficits. Conversely, lidocaine reduced 2-deoxyglucose uptake (-19%) in the dorsal hippocampus only at 10 mug, with weak extrahippocampal effects. Whether infused uni- or bilaterally and regardless of the dose, lidocaine did not alter motor coordination. When infused bilaterally, however, 10 microg of lidocaine impaired short-term retrieval of spatial information in a water maze. Because lidocaine i) induced a weak though significant functional blockade mainly restricted to the infusion site, ii) had no consequences on motor coordination and, nevertheless iii) altered short-term spatial memory retrieval, we conclude that acute intrahippocampal infusions of lidocaine may offer some advantages over tetrodotoxin at the doses used herein.

Cerebellar deep nuclei involvement in cognitive adaptation and automaticity

Learning & Memory, 2013

To determine the role of the interpositus nuclei of cerebellum in rule-based learning and optimiz... more To determine the role of the interpositus nuclei of cerebellum in rule-based learning and optimization processes, we studied (1) successive transfers of an initially acquired response rule in a cross maze and (2) behavioral strategies in learning a simple response rule in a T maze in interpositus lesioned rats (neurotoxic or electrolytic lesions). Even though lesioned animals showed no impairment in learning the initial stimulus–response association, they had difficulties in transferring the acquired adapted response rule, and in optimizing their response strategy. These results add information on the role of interpositus nuclei in adaptation to environmental changes.

Differential c-fos expression in the brain of male Japanese quail following exposure to stimuli that predict or do not predict the arrival of a female

European Journal of Neuroscience, 2007

We investigated the effects of presenting a sexual conditioned stimulus on the expression of c-fo... more We investigated the effects of presenting a sexual conditioned stimulus on the expression of c-fos in male Japanese quail. Eight brain sites were selected for analysis based on previous reports of c-fos expression in these areas correlated with sexual behaviour or learning. Males received either paired or explicitly unpaired presentations of an arbitrary stimulus and visual access to a female. Nine conditioning trials were conducted, one per day, for each subject. On the day following the ninth trial, subjects were exposed to the conditional stimulus (CS) for 5 min. Conditioning was confirmed by analysis of rhythmic cloacal sphincter movements (RCSM), an appetitive sexual behaviour, made in response to the CS presentation. Subjects in the paired condition performed significantly more RCSM than subjects in the unpaired group. Brains were collected 90 min following the stimulus exposure and stained by immunohistochemistry for the FOS protein. Significant group differences in the number of FOS-immunoreactive (FOS-ir) cells were found in two brain regions, the nucleus taeniae of the amygdala (TnA) and the hippocampus (Hp). Subjects in the paired condition had fewer FOS-ir cells in both areas than subjects in the unpaired condition. These data provide additional support to the hypothesis that TnA is implicated in the expression of appetitive sexual behaviours in male quail and corroborate numerous previous reports of the involvement of the hippocampus in conditioning. Further, these data suggest that conditioned and unconditioned sexual stimuli activate different brain regions but have similar behavioural consequences.

Lesions of the anterior thalamic nuclei and intralaminar thalamic nuclei: place and visual discrimination learning in the water maze

Brain Structure and Function, 2012

Medial thalamic damage produces memory deficits in humans (e.g., Korsakoff's syndrome) and experi... more Medial thalamic damage produces memory deficits in humans (e.g., Korsakoff's syndrome) and experimental animals. Both the anterior thalamic nuclei (ATN) and rostral intralaminar plus adjacent lateral thalamic nuclei (ILN/LT) have been implicated. Based on the differences in their main connections with other neural structures, we tested the prediction that ATN lesions would selectively impair acquisition of spatial location discrimination, reflecting a hippocampal system deficit, whereas ILN/LT lesions would impair acquisition of visual pattern discrimination, reflecting a striatal system deficit. Half the rats were first trained in a spatial task in a water maze before switching to a visual task in the same maze, while the remainder were tested with the reverse order of tasks. Compared with shamoperated controls, (1) rats with ATN lesions showed impaired place learning, but normal visual discrimination learning, (2) rats with ILN/LT lesions showed no deficit on either task. Rats with ATN lesions were also hyperactive when their home cage was placed in a novel room and remained more active than ILN/LT or SHAM rats for the subsequent 21 h, especially during the nocturnal phase. These findings confirmed the influence of ATN lesions on spatial learning, but failed to support the view that ILN/LT lesions disrupt striatal-dependent memory. Keywords Anterior thalamic nuclei Á Hippocampus Á Intralaminar thalamic nuclei Á Spatial memory Á Striatum Á Visual pattern memory Á Water maze P.-H. Moreau and Y. Tsenkina contributed equally to the work.

Defining Valid Chronic Stress Models for Depression With Female Rodents

Biological Psychiatry, 2021

Women are twice as likely to experience depression than men, yet until recently, preclinical stud... more Women are twice as likely to experience depression than men, yet until recently, preclinical studies in rodents have focused almost exclusively on males. As interest in sex differences and sex-specific mechanisms of stress susceptibility increases, chronic stress models for inducing depression-relevant behavioral and physiological changes in male rodents are being applied to females, and several new models have emerged to include both males and females, yet not all models have been systematically validated in females. An increasing number of researchers seek to include female rodents in their experimental designs, asking the question "what is the ideal chronic stress model for depression in females?" We review criteria for assessing female model validity in light of key research questions and the fundamental distinction between studying sex differences and studying both sexes. In overviewing current models, we explore challenges inherent to establishing an ideal female chronic stress model, with particular emphasis on the need for standardization and adoption of validated behavioral tests sensitive to stress effects in females. Taken together, these considerations will empower female chronic stress models to provide a better understanding of stress susceptibility and allow the development of efficient sex-specific treatments.

The Intralaminar Thalamic Nuclei Contribute to Remote Spatial Memory

by Joëlle Lopez and Mathieu Wolff

Recent studies have shown that the anterior (ATN) and lateral thalamic nuclei (including the intr... more Recent studies have shown that the anterior (ATN) and lateral thalamic nuclei (including the intralaminar nuclei; ILN/LT) play different roles in memory processes. These nuclei have prominent direct and indirect connections with the hippocampal system and/or the prefrontal cortex and may thus participate in the time-dependent reorganization of memory traces during systems-level consolidation. We investigated whether ATN or ILN/LT lesions in rats influenced acquisition and subsequent retrieval of spatial memory in a Morris water maze. Retrieval was assessed with a probe trial after a short (5 d, recent memory) or a long (25 d, remote memory) postacquisition delay. The ATN group showed impaired acquisition compared with the Sham controls and ILN/LT groups, which did not differ during acquisition, and exhibited no preference for the target quadrant during the recent or remote memory probe trials. In contrast, probe trial performance in rats with ILN/LT lesions differed according to the age of the memory, with accurate spatial retrieval for the recent memory probe trial but impaired retrieval during the remote memory one. These findings confirm that ATN but not ILN/LT lesions disrupt the acquisition of spatial memory and provide new evidence that the ILN/LT region contributes to remote memory processing. Thus, the lateral thalamus may modulate some aspects of remote memory formation and/or retrieval during the course of systems-level consolidation.

The Ventral Midline Thalamus (Reuniens and Rhomboid Nuclei) Contributes to the Persistence of Spatial Memory in Rats

Journal of Neuroscience, 2012

The formation of enduring declarative-like memories engages a dialog between the hippocampus and ... more The formation of enduring declarative-like memories engages a dialog between the hippocampus and the prefrontal cortex (PFC). Electrophysiological and neuroanatomical evidence for reciprocal connections with both of these structures makes the reuniens and rhomboid nuclei (ReRh) of the thalamus a major functional link between the PFC and hippocampus. Using immediate early gene imaging (c-Fos), fiber-sparing excitotoxic lesion, and reversible inactivation in rats, we provide evidence demonstrating a contribution of the ReRh to the persistence of a spatial memory. Intact rats trained in a Morris water maze showed increased c-Fos expression (vs home cage and visible platform groups: &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;500%) in the ReRh when tested in a probe trial at a 25 d delay, against no change at a 5 d delay; behavioral performance was comparable at both delays. In rats subjected to excitotoxic fiber-sparing NMDA lesions circumscribed to the ReRh, we found normal acquisition of the water-maze task (vs sham-operated controls) and normal probe trial performance at the 5 d delay, but there was no evidence for memory retrieval at the 25 d delay. In rats having learned the water-maze task, lidocaine-induced inactivation of the ReRh right before the probe trial did not alter memory retrieval tested at the 5 d or 25 d delay. Together, these data suggest an implication of the ReRh in the long-term consolidation of a spatial memory at the system level. These nuclei could then be a key structure contributing to the transformation of a new hippocampal-dependent spatial memory into a remote one also depending on cortical networks.

The Intralaminar Thalamic Nuclei Contribute to Remote Spatial Memory

Journal of Neuroscience, 2009

Recent studies have shown that the anterior (ATN) and lateral thalamic nuclei (including the intr... more Recent studies have shown that the anterior (ATN) and lateral thalamic nuclei (including the intralaminar nuclei; ILN/LT) play different roles in memory processes. These nuclei have prominent direct and indirect connections with the hippocampal system and/or the prefrontal cortex and may thus participate in the time-dependent reorganization of memory traces during systems-level consolidation. We investigated whether ATN or ILN/LT lesions in rats influenced acquisition and subsequent retrieval of spatial memory in a Morris water maze. Retrieval was assessed with a probe trial after a short (5 d, recent memory) or a long (25 d, remote memory) postacquisition delay. The ATN group showed impaired acquisition compared with the Sham controls and ILN/LT groups, which did not differ during acquisition, and exhibited no preference for the target quadrant during the recent or remote memory probe trials. In contrast, probe trial performance in rats with ILN/LT lesions differed according to the age of the memory, with accurate spatial retrieval for the recent memory probe trial but impaired retrieval during the remote memory one. These findings confirm that ATN but not ILN/LT lesions disrupt the acquisition of spatial memory and provide new evidence that the ILN/LT region contributes to remote memory processing. Thus, the lateral thalamus may modulate some aspects of remote memory formation and/or retrieval during the course of systems-level consolidation.

Hippocampal-dependent spatial memory functions might be lateralized in rats: An approach combining gene expression profiling and reversible inactivation

Hippocampus, 2009

The hippocampus is involved in spatial memory processes, as established in a variety of species s... more The hippocampus is involved in spatial memory processes, as established in a variety of species such as birds and mammals including humans. In humans, some hippocampal-dependent memory functions may be lateralized, the right hippocampus being predominantly involved in spatial navigation. In rodents, the question of possible lateralization remains open. Therefore, we first microdissected the CA1 subregion of the left and right dorsal hippocampi for analysis of mRNA expression using microarrays in rats having learnt a reference memory task in the Morris water-maze. Relative to untrained controls, 623 genes were differentially expressed in the right hippocampus, against only 74 in the left hippocampus, in the rats that had learnt the hidden platform location. Thus, in the right hippocampus, 299 genes were induced, 324 were repressed, and about half of them participate in signaling and transport, metabolism, and nervous system functions. In addition, most differentially expressed genes associated with spatial learning have been previously related to synaptic plasticity and memory. We then subjected rats to unilateral (left or right) or bilateral reversible functional inactivations in the dorsal hippocampus; lidocaine was infused either before each acquisition session or before retrieval of a reference spatial memory in the Morris water maze. We found that after drug-free acquisition, right or bilateral lidocaine inactivation (vs. left, or bilateral phosphate buffered saline (PBS) infusions) of the dorsal hippocampus just before a delayed (24 h) probe trial impaired performance. Conversely, left or bilateral hippocampus inactivation (vs. right, or bilateral PBS infusions) before each acquisition session weakened performance during a delayed, drug-free probe trial. Our data confirm a functional association between transcriptional activity within the dorsal hippocampus and spatial memory in the rat. Further, they suggest that there could be a leftward bias of hippocampal functions in engram formation or information transfer, and a rightward bias in spatial memory storage/retrieval processes. V V C 2009 Wiley-Liss, Inc.

Context-dependent modulation of hippocampal and cortical recruitment during remote spatial memory retrieval

Hippocampus, 2012

According to systems consolidation, as hippocampal-dependent memories mature over time, they beco... more According to systems consolidation, as hippocampal-dependent memories mature over time, they become additionally (or exclusively) dependent on extra-hippocampal structures. We assessed the recruitment of hippocampal and cortical structures on remote memory retrieval in a performance-degradation resistant (PDR; no performance degradation with time) versus performance-degradation prone (PDP; performance degraded with time) context. Using a water-maze task in two contexts with a hidden platform and three control conditions (home cage, visible platform with or without access to distal cues), we compared neuronal activation (c-Fos imaging) patterns in the dorsal hippocampus and the medial prefrontal cortex (mPFC) after the retrieval of recent (5 days) versus remote (25 days) spatial memory. In the PDR context, the hippocampus exhibited greater c-Fos protein expression on remote than recent memory retrieval, be it in the visible or hidden platform group. In the PDP context, hippocampal activation increased at the remote time point and only in the hidden platform group. In the anterior cingulate cortex, c-Fos expression was greater for remote than for recent memory retrieval and only in the PDR context. The necessity of the mPFC for remote memory retrieval in the PDR context was confirmed using region-specific lidocaine inactivation, which had no impact on recent memory. Conversely, inactivation of the dorsal hippocampus impaired both recent and remote memory in the PDR context, and only recent memory in the PDP context, in which remote memory performance was degraded. While confirming that neuronal circuits supporting spatial memory consolidation are reorganized in a time-dependent manner, our findings further indicate that mPFC and hippocampus recruitment (i) depends on the content and perhaps the strength of the memory and (ii) may be influenced by the environmental conditions (e.g., cue saliency, complexity) in which memories are initially formed and subsequently recalled.

Differential sensitivity of recent vs. remote memory traces to extinction in a water-maze task in rats

Neurobiology of Learning and Memory, 2008

Extinction has mostly been studied in conditioning paradigms, more sparsely in spatial tasks, and... more Extinction has mostly been studied in conditioning paradigms, more sparsely in spatial tasks, and never as a function of the age of a spatial memory. Using rats, we compared the time-course of extinction of a recent (5 days) vs. remote (25 days) spatial memory in a water maze, over three probe trials. When the trials were set 24 h apart, performance in the remote memory group was significantly worse on the first probe trial and significantly better on the third probe trial, as compared to the recent memory group, thereby showing differences between cognitive operations underlying recent vs. remote memory extinction. In contrast, when trials were given consecutively, both groups showed a similar profile of extinction. Furthermore, in a room with overly-salient cues providing a strong remote memory trace, no difference between groups was observed when the spaced extinction paradigm was used. These results might be related to a balance between reconsolidation and extinction processes occurring after a first retrieval experience, of which the outcome may depend on the extinction protocol, and on the age and strength of a memory.

Environmental cue saliency influences the vividness of a remote spatial memory in rats

Neurobiology of Learning and Memory, 2008

The Morris water maze is frequently used to evaluate the acquisition and retrieval of spatial mem... more The Morris water maze is frequently used to evaluate the acquisition and retrieval of spatial memories. Few experiments, however, have investigated the effects of environmental cue saliency on the strength or persistence of such memories after a short vs. long postacquisition interval. Using a Morris water maze, we therefore tested in rats the effect of the saliency of distal cues on the vividness of a recent (5 days) vs. remote (25 days) memory. Rats trained in a cue-enriched vs. a cue-impoverished context showed a better overall level of performance during acquisition. Furthermore, the probe trials revealed that the rats trained and tested in the cue-impoverished context (1) spent less time in the target quadrant at the 25-day delay, and (2) swam shorter distances in the target area, with fewer crossings at both 5-and 25-day delays, as compared to their counterparts trained and tested in the cue-enriched context. Thus, the memory trace formed in the cue-enriched context shows better resistance to time, suggesting an implication of cue saliency in the vividness of a spatial memory.

The ventral hippocampus is necessary for expressing a spatial memory

Brain Structure and Function, 2012

Current views posit the dorsal hippocampus (DHipp) as contributing to spatial memory processes. C... more Current views posit the dorsal hippocampus (DHipp) as contributing to spatial memory processes. Conversely, the ventral hippocampus (VHipp) modulates stress, emotions and affects. Arguments supporting this segregation include differences in (i) connectivity: the DHipp is connected with the entorhinal cortex which receives visuospatial neocortical inputs; the VHipp is connected with both the amygdala and hypothalamus, (ii) electrophysiological characteristics: there is a larger proportion of place cells in the DHipp than in the VHipp, and an increasing dorsoventral gradient in the size of place fields, suggesting less refined spatial coding in the VHipp, and (iii) consequences of lesions: spatial memory is altered after DHipp lesions, less dramatically, sometimes not, after VHipp lesions. Using reversible inactivation, we report in rats, that lidocaine infusions into the DHipp or VHipp right before a probe trial impair retrieval performance in a water-maze task. This impairment was found at two postacquisition delays compatible with recent memory (1 and 5 days). Pre-training blockade of the VHipp did not prevent task acquisition and drug-free retrieval, on the contrary to pre-training blockade of DHipp, which altered performance in a subsequent drug-free probe trial. Complementary experiments excluded possible locomotor, sensorimotor, motivational or anxiety-related biases from data interpretation. Our conclusion is that a spatial memory can be acquired with the DHipp, less efficiently with the VHipp, and that the retrieval of such a memory and/or the expression of its representation engages the dorsoventral axis of the hippocampus when the task has been learnt with an entirely functional hippocampus.

Lopez JN2009 SupplementalData

by Mathieu Wolff and Joëlle Lopez