Papers by Stephanie Trouche
Neuron, Nov 1, 2013
A more complete understanding of how fear extinction alters neuronal activity and connectivity wi... more A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos-based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit.
Nature Neuroscience, Feb 22, 2016
The hippocampus provides the brain's memory system with a subset of neurons holding a maplike rep... more The hippocampus provides the brain's memory system with a subset of neurons holding a maplike representation of each environment experienced. We found in mice that optogenetic-silencing those neurons active in an environment unmasked a subset of quiet neurons, enabling the emergence of an alternative map. This intervention applied in a cocaine-paired environment neutralized an otherwise long-lasting drug-place preference, showing that recoding a spatial memory engram can alleviate associated maladaptive behavior. Memory is central to behavior, enabling individuals to respond to their environment using past experiences 1 . The spatially-tuned and temporally-coordinated activity of hippocampal CA1 principal cells contributes to adaptive memories by providing the brain with neuronal engrams that represent the spatial context of life events 2-5 . Nonetheless, the recall of certain representations, such as those associating an environment with a drug of abuse, can impair the individual's ability to make adaptive choices, including an uncontrolled drive to revisit drug-paired locations 6 . Manipulating hippocampal neuronal representations could redress undesirable spatio-contextual behaviors. However, a given hippocampal 'place cell' can contribute not to one but to multiple representations 4,7-12 . Therefore, it remains unknown how the hippocampal neuronal representation of a particular place could be selectively edited. In a given environment the hippocampus exhibits, alongside the active place cells, a subset of quiet neurons without clear spatial selectivity . Here, we used a c-fos-based optogenetic approach to silence hippocampal neurons active in a particular environment and examined whether quiet neurons could implement an alternative representation that neutralizes a drug-place memory. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: Correspondence should be addressed to D.D.
Current Opinion in Physiology, Jun 1, 2020
Sleep is essential for the regulation of neural dynamics and animal behavior. In particular, slee... more Sleep is essential for the regulation of neural dynamics and animal behavior. In particular, sleep is crucial for memory consolidation and emotional regulation. In turn, emotions are key to the modulation of learning processes in which sleep also plays a crucial role. Emotional processing triggers coordinated activity between neuronal populations embedded in a network including the hippocampus, amygdala and prefrontal cortex. The optogenetic modulation of these distributed engrams' activity interferes with emotional memory. During non-REM sleep, cross-structure coordinated replay may underpin the consolidation of brain-wide emotional associative engrams. Fear conditioning induces neural synchronization between the amygdala, hippocampus, and medial prefrontal cortex during subsequent REM sleep, the perturbation of which interferes with fear memory consolidation. Future work may focus on the differential mechanisms during REM vs non-REM sleep that underpin emotional regulation and memory consolidation, as well as on distinguishing between these two tightly linked cognitive processes. of memories over time. The second is emotional regulation, allowing for the maintenance of an appropriate level of reactivity to emotional situations (let he who has never experienced irritability or even outbursts of rage/tears when sleep-deprived cast the first pillow). The intensity and vividness of emotions during dreams has also been a constant subject of great fascination in art (Fig. ) and conversation in everyday life, driving early studies on the link between dreams, sleep, and emotions in neuroscience.
Cell, Mar 1, 2019
Highlights d Neuronal and behavioral reinstatement of a memory trace are dissociable processes d ... more Highlights d Neuronal and behavioral reinstatement of a memory trace are dissociable processes d Spatial appetitive memory requires direct dCA1 inputs to two types of NAc neurons d dCA1 exerts feedforward inhibition onto its postsynaptic NAc medium spiny neurons d dCA1 organizes assemblies of co-active medium spiny neurons during memory retrieval
Hippocampus, 2014
Hippocampal adult neurogenesis contributes to key functions of the dentate gyrus (DG), including ... more Hippocampal adult neurogenesis contributes to key functions of the dentate gyrus (DG), including contextual discrimination. This is due, at least in part, to the unique form of plasticity that new neurons display at a specific stage of their development when compared with the surrounding principal neurons. In addition, the contribution that newborn neurons make to dentate function can be enhanced by an increase in their numbers induced by a stimulating environment. However, signaling mechanisms that regulate these properties of newborn neurons are poorly understood. Here, we show that Ras-GRF2 (GRF2), a calcium-regulated exchange factor that can activate Ras and Rac GTPases, contributes to both of these properties of newborn neurons. Using Ras-GRF2 knockout mice and wild-type mice stereotactically injected with retrovirus containing shRNA against the exchange factor, we demonstrate that GRF2 promotes the survival of newborn neurons of the DG at approximately 1-2 weeks after their bi...
Hippocampus, 2013
The dentate gyrus of the hippocampus plays a pivotal role in pattern separation, a process requir... more The dentate gyrus of the hippocampus plays a pivotal role in pattern separation, a process required for the behavioral task of contextual discrimination. One unique feature of the dentate gyrus that contributes to pattern separation is adult neurogenesis, where newly born neurons play a distinct role in neuronal circuitry. Moreover, the function of neurogenesis in this brain region differs in adolescent and adult mice. The signaling mechanisms that differentially regulate the distinct steps of adult neurogenesis in adolescence and adulthood remain poorly understood. We used mice lacking RAS-GRF1 (GRF1), a calcium-dependent exchange factor that regulates synaptic plasticity and participates in contextual discrimination performed by mice, to test whether GRF1 plays a role in adult neurogenesis. We show Grf1 knockout mice begin to display a defect in neurogenesis at the onset of adulthood (~2 months of age), when wild-type mice first acquire the ability to distinguish between closely related contexts. At this age, young hippocampal neurons in Grf1 knockout mice display severely reduced dendritic arborization. By 3 months of age, new neuron survival is also impaired. BrdU labeling of new neurons in 2 month-old Grf1 knockout mice shows they begin to display reduced survival between 2 and 3 weeks after birth, just as new neurons begin to develop complex dendritic morphology and transition into using glutamatergic excitatory input. Interestingly, GRF1 expression appears in new neurons at the developmental stage when GRF1 loss begins to effect neuronal function. In addition, we induced a similar loss of new hippocampal neurons by knocking down expression of GRF1 solely in new neurons by injecting retrovirus that express shRNA against GRF1 into the dentate gyrus. Together, these findings show that GRF1 expressed in new neurons promotes late stages of adult neurogenesis. Overall our findings show GRF1 to be an age-dependent regulator of adult hippocampal neurogenesis, which contributes to ability of mice to distinguish closely related contexts.
Nature Neuroscience, 2021
investigating the topology of neuronal coactivity, we found that mnemonic information spans multi... more investigating the topology of neuronal coactivity, we found that mnemonic information spans multiple operational axes in the mouse hippocampus network. High activity principal cells form the core of each memory along a first axis, segregating spatial contexts and novelty. Low activity cells join coactivity motifs across behavioural events and enable their crosstalk along two other axes. This reveals an organizational principle for continuous integration and interaction of hippocampal memories.
SSRN Electronic Journal, 2018
Retrieving and acting upon memories of food-predicting environments are essential for survival. P... more Retrieving and acting upon memories of food-predicting environments are essential for survival. Pyramidal cells (PYRs) in dorsal CA1 hippocampus (dCA1) of the mammalian brain provide mnemonic representations of space. While dCA1 PYRs cannot directly access motor centers, the brain substrates by which these internal representations guide appetitive behavior are unknown. Here, we uncover a circuit motif embedded in the nucleus accumbens (NAc) that enables the behavioral readout of reward-place memories. By monitoring neuronal ensemble activity in mouse dCA1-NAc pathway, combined with cell-type-selective optogenetic manipulations of dCA1-input-defined postsynaptic neurons, we show that PYRs innervate and engage NAc parvalbumin-expressing fast-spiking interneurons (PV+ FSIs) to influence medium spiny neuron (MSN) firing and thus, NAc output. This motif is specialized for memory-guided appetitive behavior, being dispensable for spatial novelty detection and hedonic motivation. Our findings demonstrate that this PYR-PV+ FSI-MSN circuit motif instantiates a limbic-motor interface for hippocampal representations of space to promote behaviorally-effective appetitive memory.
Cell, 2019
Highlights d Neuronal and behavioral reinstatement of a memory trace are dissociable processes d ... more Highlights d Neuronal and behavioral reinstatement of a memory trace are dissociable processes d Spatial appetitive memory requires direct dCA1 inputs to two types of NAc neurons d dCA1 exerts feedforward inhibition onto its postsynaptic NAc medium spiny neurons d dCA1 organizes assemblies of co-active medium spiny neurons during memory retrieval
Neuron, Jan 9, 2018
Theta oscillations reflect rhythmic inputs that continuously converge to the hippocampus during e... more Theta oscillations reflect rhythmic inputs that continuously converge to the hippocampus during exploratory and memory-guided behavior. The theta-nested operations that organize hippocampal spiking could either occur regularly from one cycle to the next or be tuned on a cycle-by-cycle basis. To resolve this, we identified spectral components nested in individual theta cycles recorded from the mouse CA1 hippocampus. Our single-cycle profiling revealed theta spectral components associated with different firing modulations and distinguishable ensembles of principal cells. Moreover, novel co-firing patterns of principal cells in theta cycles nesting mid-gamma oscillations were the most strongly reactivated in subsequent offline sharp-wave/ripple events. Finally, theta-nested spectral components were differentially altered by behavioral stages of a memory task; the 80-Hz mid-gamma component was strengthened during learning, whereas the 22-Hz beta, 35-Hz slow gamma, and 54-Hz mid-gamma co...
Neuron, Jan 7, 2016
The ability to reinstate neuronal assemblies representing mnemonic information is thought to requ... more The ability to reinstate neuronal assemblies representing mnemonic information is thought to require their consolidation through offline reactivation during sleep/rest. To test this, we detected cell assembly patterns formed by repeated neuronal co-activations in the mouse hippocampus during exploration of spatial environments. We found that the reinstatement of assembly patterns representing a novel, but not a familiar, environment correlated with their offline reactivation and was impaired by closed-loop optogenetic disruption of sharp wave-ripple oscillations. Moreover, we discovered that reactivation was only required for the reinstatement of assembly patterns whose expression was gradually strengthened during encoding of a novel place. The context-dependent reinstatement of assembly patterns whose expression did not gain in strength beyond the first few minutes of spatial encoding was not dependent on reactivation. This demonstrates that the hippocampus can hold concurrent repr...
Nature Neuroscience, 2016
The hippocampus provides the brain's memory system with a subset of neurons holding a maplike rep... more The hippocampus provides the brain's memory system with a subset of neurons holding a maplike representation of each environment experienced. We found in mice that optogenetic-silencing those neurons active in an environment unmasked a subset of quiet neurons, enabling the emergence of an alternative map. This intervention applied in a cocaine-paired environment neutralized an otherwise long-lasting drug-place preference, showing that recoding a spatial memory engram can alleviate associated maladaptive behavior. Memory is central to behavior, enabling individuals to respond to their environment using past experiences 1. The spatially-tuned and temporally-coordinated activity of hippocampal CA1 principal cells contributes to adaptive memories by providing the brain with neuronal engrams that represent the spatial context of life events 2-5. Nonetheless, the recall of certain representations, such as those associating an environment with a drug of abuse, can impair the individual's ability to make adaptive choices, including an uncontrolled drive to revisit drug-paired locations 6. Manipulating hippocampal neuronal representations could redress undesirable spatio-contextual behaviors. However, a given hippocampal 'place cell' can contribute not to one but to multiple representations 4,7-12. Therefore, it remains unknown how the hippocampal neuronal representation of a particular place could be selectively edited. In a given environment the hippocampus exhibits, alongside the active place cells, a subset of quiet neurons without clear spatial selectivity 3,9,12-17. Here, we used a c-fos-based optogenetic approach to silence hippocampal neurons active in a particular environment and examined whether quiet neurons could implement an alternative representation that neutralizes a drug-place memory. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Frontiers in Behavioral Neuroscience, 2009
ABSTRACT In the adult brain, the dentate gyrus continuously produces new neurons that become func... more ABSTRACT In the adult brain, the dentate gyrus continuously produces new neurons that become functionally integrated into existing neural circuits. Supporting the idea that this form of plasticity contributes to memory functions, we recently found that new neurons are recruited into neuronal networks involved in retrieval of remote spatial memory and that their activation is situation-specific [1]. Moreover, our data revealed that the recruitment of new neurons into hippocampal networks contributes predominantly to the updating and strengthening of a previously encoded memory. Here, we examined the extent to which the population of surviving new neurons is recruited into memory networks depending on the strength of initial learning. First we evaluated whether the strength of initial spatial learning differentially affects the survival of new neurons. Two groups of mice were initially trained to find the position of the hidden platform in the water maze. Fully trained mice were submitted to a massed training procedure consisting in 24 trials over one single day. In contrast, partially trained mice underwent only 12 trials. Remote memory in these two groups was assessed 30 days later during 9 trials in the presence of the hidden platform. Mice from the partially trained group performed more poorly during remote testing than fully trained mice and exhibited no improvement over the additional trials. Then, using the birthdating marker BrdU, we examined whether memory strength influences the survival of cells born 9 days before spatial training. The extent to which the population of surviving new cells is recruited into memory networks depending on the strength of initial learning was further determined using triple BrdU/NeuN/Zif268 labeling. Structural equation modeling analyses are currently underway to help decipher the contribution of new neurons emerging from the hippocampal-cortical activation.
Brain Structure and Function, 2015
The neural cell adhesion molecule NCAM and its association with the polysialic acid (PSA) are bel... more The neural cell adhesion molecule NCAM and its association with the polysialic acid (PSA) are believed to contribute to brain structural plasticity that underlies memory formation. Indeed, the attachment of long chains of PSA to the glycoprotein NCAM down-regulates its adhesive properties by altering cell-cell interactions. In the brain, the biosynthesis of PSA is catalyzed by two polysialyltransferases, which are differentially regulated during lifespan. One of them, ST8SiaIV (PST), is predominantly expressed during adulthood whereas the other one, ST8SiaII (STX), dominates during embryonic and post-natal development. To understand the role played by ST8SiaIV during learning and memory and its underlying hippocampal plasticity, we used knockout mice deleted for the enzyme ST8SiaIV (PST-ko mice). At adult age, PST-ko mice show a drastic reduction of PSA-NCAM expression in the hippocampus and intact hippocampal adult neurogenesis. We found that these mice display impaired long-term but not short-term memory in both, spatial and non-spatial behavioral tasks. Remarkably, memory deficits of PST-ko mice were abolished by exposure to environmental enrichment that was also associated with an increased number of PSA-NCAM expressing new neurons in the dentate gyrus of these mice. Whether the presence of a larger pool of immature, likely plastic, new neurons favored the rescue of long-term memory in PST-ko mice remains to be determined. Our findings add new evidence to the role played by PSA in memory consolidation. They also suggest that PSA synthesized by PST critically controls the tempo of new neurons maturation in the adult hippocampus.
Nature Neuroscience, 2014
Here we found that optogenetic burst stimulation of hippocampal dopaminergic fibers from midbrain... more Here we found that optogenetic burst stimulation of hippocampal dopaminergic fibers from midbrain neurons in mice exploring novel environments enhanced the reactivation of pyramidal cell assemblies during subsequent sleep/rest. When applied during spatial learning of new goal locations, dopaminergic photostimulation improved the later recall of neural representations of space and stabilized memory performance. These findings reveal that midbrain dopaminergic neurons promote hippocampal network dynamics associated with memory persistence. Brain representations of space are encoded by pyramidal cell assemblies in the hippocampus during active behavior 1-3. However new representations, such as those formed during exploration of novel environments or learning of new goal locations, are initially labile and thus require stabilization to persist as memories 4-6. Pharmacological studies have implicated the neurotransmitter dopamine in the stability of hippocampus-dependent memory. Blockade of D1/D5 dopaminergic receptors during spatial learning impairs memory persistence 7 while blockade during exploration of novel environments curtails the stability of new spatial maps 8 and also prevents novelty-facilitated synaptic plasticity 9. However the contribution of dopamine towards hippocampal neuronal dynamics associated with memory persistence remains to be identified 10. In the hippocampus memory stabilization is thought to be supported by 'sleep reactivation' whereby assembly firing patterns expressed during exploration are reactivated in subsequent sleep/rest periods during sharp wave/ripple (SWR, 135-250Hz) oscillatory events 11,12. Indeed, electrical disruption of SWRs after learning impairs spatial memory 13. Here we tested whether activation of midbrain dopaminergic neurons during spatial exploration and learning enhances reactivation of newly-encoded hippocampal representations and improves memory performance. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Psychoneuroendocrinology, 2007
It is now widely accepted that new neurons continue to be added to the brain throughout life incl... more It is now widely accepted that new neurons continue to be added to the brain throughout life including during normal aging. The finding of adult neurogenesis in the hippocampus, a structure involved in the processing of memories, has favored the idea that newborn neurons might subserve cognitive functions. Recent work on human post-mortem tissues and mice models of Alzheimer's disease (AD) has reported persistent hippocampal proliferative capacity during pathological aging. Although it is not yet clear whether neurogenesis leads to the production of fully functional mature neurons in AD brains, these findings open prospects for cell-replacement therapies. Strategies aimed at promoting neurogenesis may also contribute to improve cognitive deficits caused by normal or pathological aging.
Proceedings of the National Academy of Sciences, 2009
The dentate gyrus (DG), a hippocampal subregion, continuously produces new neurons in the adult m... more The dentate gyrus (DG), a hippocampal subregion, continuously produces new neurons in the adult mammalian brain that become functionally integrated into existing neural circuits. To what extent this form of plasticity contributes to memory functions remains to be elucidated. Using mapping of activity-dependent gene expression, we visualized in mice injected with the birthdating marker 5-bromo-2′-deoxyuridine the recruitment of new neurons in a set of controlled water maze procedures that engage specific spatial memory processes and require hippocampal–cortical networks. Here, we provide new evidence that adult-generated hippocampal neurons make a specific but differential contribution to the processing of remote spatial memories. First, we show that new neurons in the DG are recruited into neuronal networks that support retrieval of remote spatial memory and that their activation is situation-specific. We further reveal that once selected, new hippocampal neurons are durably incorpo...
Neuroscience, 2010
New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. T... more New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. These newly generated neurons become functionally integrated into existing hippocampal neuronal networks, such as those that support retrieval of remote spatial memory. Here, we sought to examine whether the contribution of newly born neurons depends on the type of learning and memory task in mice. To do so, we reduced neurogenesis with a cytostatic agent and examined whether depletion of young hippocampal neurons affects learning and/or memory in two hippocampal-dependent tasks (spatial navigation in the Morris water maze and object location test) and two hippocampal-independent tasks (cued navigation in the Morris water maze and novel object recognition). Double immunohistofluorescent labeling of the birth dating marker 5-bromo-2'deoxyuridine (BrdU) together with NeuN, a neuron specific marker, was employed to quantify reduction of hippocampal neurogenesis. We found that depletion of young adult-generated neurons alters recent and remote memory in spatial tasks but spares non-spatial tasks. Our findings provide additional evidence that generation of new cells in the adult brain is crucial for hippocampal-dependent cognitive functions.
Neurobiology of Aging, 2013
Levels of educational and occupational attainment, as components of cognitive reserve, may modify... more Levels of educational and occupational attainment, as components of cognitive reserve, may modify the relationship between the pathological hallmarks and cognition in Alzheimer's disease (AD). We examined whether exposure of a Tg2576 transgenic mouse model of AD to environmental enrichment (EE) at a specific period during the amyloidogenic process favored the establishment of a cognitive reserve. We found that exposure to EE during early adulthood of Tg2576 mice-before amyloidogenesis has started-reduced the severity of AD-related cognitive deficits more efficiently than exposure later in life, when the pathology is already present. Interestingly, early-life exposure to EE, while slightly reducing forebrain surface covered by amyloid plaques, did not significantly impact aberrant inhibitory remodeling in the hippocampus of Tg2576 mice. Thus, transient early-life exposure to EE exerts long-lasting protection against cognitive impairment during AD pathology. In addition, these data define the existence of a specific life time frame during which stimulatory activity most efficiently builds a cognitive reserve, limiting AD progression and favoring successful aging.
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Papers by Stephanie Trouche