Papers by Noelia Weisstaub
Neuronal signaling, Feb 1, 2019
Background: Acute treatment with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (F... more Background: Acute treatment with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (Flx), induces anxiety-like behavioral effects. The serotonin 2A receptor (5-HT 2A ) is implicated in the modulation of anxiety-like behavior, however its contribution to the anxiogenic effects of acute Flx remains unclear. Here, we examined the role of the 5-HT 2A receptor in the effects of acute Flx on anxiety-like behavior, serum corticosterone levels, neural activation and immediate early gene (IEG) expression in stress-responsive brain regions, using 5-HT 2A receptor knockout (5-HT 2A -/-) mice of both sexes. Methods: 5-HT 2A -/-and wild-type (WT) male and female mice received a single administration of Flx or vehicle, and were examined for anxiety-like behavior, serum corticosterone levels, FBJ murine osteosarcoma viral oncogene homolog peptide (c-Fos) positive cell numbers in stress-responsive brain regions of the hypothalamus and prefrontal cortex (PFC), and PFC IEG expression. Results: The increased anxiety-like behavior and enhanced corticosterone levels evoked by acute Flx were unaltered in 5-HT 2A -/-mice of both sexes. 5-HT 2A -/-female mice exhibited a diminished neural activation in the hypothalamus in response to acute Flx. Further, 5-HT 2A -/-male, but not female, mice displayed altered baseline expression of several IEGs (brain-derived neurotrophic factor (Bdnf), Egr2, Egr4, FBJ osteosarcoma gene (Fos), FBJ murine osteosarcoma viral oncogene homolog B (Fosb), Fos-like antigen 2 (Fosl2), Homer scaffolding protein (Homer) 1-3 (Homer1-3), Jun proto-oncogene (Jun)) in the PFC. Conclusion: Our results indicate that the increased anxiety and serum corticosterone levels evoked by acute Flx are not influenced by 5-HT 2A receptor deficiency. However, the loss of function of the 5-HT 2A receptor alters the degree of neural activation of the paraventricular nucleus (PVN) of the hypothalamus in response to acute Flx, and baseline expression of several IEGs in the PFC in a sexually dimorphic manner.
Frontiers in Behavioral Neuroscience
Frontiers in Systems Neuroscience
IntroductionThe ability to separate similar experiences into differentiated representations is pr... more IntroductionThe ability to separate similar experiences into differentiated representations is proposed to be based on a computational process called pattern separation, and it is one of the key characteristics of episodic memory. Although pattern separation has been mainly studied in the dentate gyrus of the hippocampus, this cognitive function if thought to take place also in other regions of the brain. The perirhinal cortex is important for the acquisition and storage of object memories, and in particular for object memory differentiation. The present study was devoted to investigating the importance of the cellular mechanism of endocytosis for object memory differentiation in the perirhinal cortex and its association with brain-derived neurotrophic factor, which was previously shown to be critical for the pattern separation mechanism in this structure.MethodsWe used a modified version of the object recognition memory task and intracerebral delivery of a peptide (Tat-P4) into the...
Hippocampus
Differentiating between similar memories is a crucial cognitive function that enables correct epi... more Differentiating between similar memories is a crucial cognitive function that enables correct episodic memory formation. The ability to separate the components of memories into distinct representations is thought to rely on a computational process known as pattern separation, by which differences are amplified to disambiguate similar events. Although pattern separation has been localized to the dentate gyrus (DG) of the hippocampus and shown to occur in a spatial domain, this cognitive function takes place also during processing of other types of information. In particular, there is some debate on whether the DG participates in pattern separation of nonspatial representations. Considering the classic role of the Prh in the acquisition and storage of object memories in general and tasks with similar features in particular, this cognitive function could rely more heavily on perirhinal regions when objectrelated information is processed. Here we show that two plasticity-related proteins, BDNF, and Arc, are required in the DG for nonspatial mnemonic differentiation. Moreover, we found that the crucial role of the DG is transient since activity of AMPAR is only required in the Prh but not the DG during differentiated object memory retrieval. Additionally, this memory is not modifiable by postacquisition rhBDNF infusions in the DG that are known to improve memory when given in the Prh. This highlights a differential role of Prh and DG during differentiated object memory consolidation. Additionally, we found that these molecular mechanisms actively interact in the DG and Prh for the formation of distinguishable memories, with infusions of rhBDNF in the Prh being able to rescue mnemonic deficits caused by reduced Arc expression in the DG. These results reveal a complex interaction between plasticity mechanisms in the Prh and DG for nonspatial pattern separation and posit the Prh as the key structure where unique object representations are stored.
Serotonin Type 2a Receptor in the Prefrontal Cortex Controls Perirhinal Cortex Excitability During Object Recognition Memory Recall
Neuroscience
Hippocampal-medial prefrontal cortex network dynamics predict performance during retrieval in a context-guided object memory task
Proceedings of the National Academy of Sciences
Significance Recovering relevant information, while ignoring the irrelevant, is crucial for episo... more Significance Recovering relevant information, while ignoring the irrelevant, is crucial for episodic memory (remembering a particular event at a specific temporal and spatial context). Information presented at any time could drive the retrieval of more than one memory trace; thus, there should be a mechanism to select the retrieval of the most relevant trace. However, how the brain controls memory interference is not well understood. Here, we analyzed the communication between ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC) during the resolution of an episodic memory task in rats. We found an increased synchronization between the vHPC and mPFC and identified specific mPFC neural subpopulations that selectively respond to object–context associations, and their firing preference correlates with the animals’ behavioral responses.
Frontiers in Neural Circuits, 2020
Successful memory involves not only remembering over time but also keeping memories distinct. Com... more Successful memory involves not only remembering over time but also keeping memories distinct. Computational models suggest that pattern separation appears as a highly efficient process to discriminate between overlapping memories. Furthermore, lesion studies have shown that the dentate gyrus (DG) participates in pattern separation. However, these manipulations did not allow identifying the neuronal mechanism underlying pattern separation. The development of different neurophotonics techniques, together with other genetic tools, has been useful for the study of the microcircuit involved in this process. It has been shown that less-overlapped information would generate distinct neuronal representations within the granule cells (GCs). However, because glutamatergic or GABAergic cells in the DG are not functionally or structurally homogeneous, identifying the specific role of the different subpopulations remains elusive. Then, understanding pattern separation requires the ability to man...
Author response: 5-HT2a receptor in mPFC influences context-guided reconsolidation of object memory in perirhinal cortex
Episodic memory establishes and stores relations among the different elements of an experience, w... more Episodic memory establishes and stores relations among the different elements of an experience, which are often similar and difficult to distinguish. Pattern separation, implemented by the dentate gyrus, is a neural mechanism that allows the discrimination of similar experiences by orthogonalizing synaptic inputs. Granule cells support such disambiguation by sparse rate coding, a process tightly controlled by highly diversified GABAergic neuronal populations, such as somatostatin-expressing cells which directly target the dendritic arbor of granule cells, massively innervated by entorhinal inputs reaching the molecular layer and conveying contextual information. Here, we tested the hypothesis that somatostatin neurons regulate the excitability of the dentate gyrus, thus controlling the efficacy of pattern separation during memory encoding in mice. Indeed, optogenetic suppression of dentate gyrus somatostatin neurons increased spiking activity in putative excitatory neurons and trigg...
Neurobiology of Learning and Memory, 2018
Successful memory involves not only remembering information over time but also keeping memories d... more Successful memory involves not only remembering information over time but also keeping memories distinct and less confusable. Discrimination of overlapping representations has been investigated in the dentate gyrus (DG) of the hippocampus and largely in the perirhinal cortex (Prh). In particular, the DG was shown to be important for discrimination of overlapping spatial memories and Prh was shown to be important for discrimination of overlapping object memories. In the present study, we used both a DG-dependent and a Prh-dependent task and manipulated the load of similarity between either spatial or object stimuli during information encoding. We showed that N-methyl-D-aspartate-type glutamate receptors (NMDAr) and BDNF participate of the same cellular network during consolidation of both overlapping object and spatial memories in the Prh and DG, respectively. This argues in favor of conserved cellular mechanisms across regions despite anatomical differences.
Neuronal Signaling, 2019
Background: Acute treatment with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (F... more Background: Acute treatment with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (Flx), induces anxiety-like behavioral effects. The serotonin2A receptor (5-HT2A) is implicated in the modulation of anxiety-like behavior, however its contribution to the anxiogenic effects of acute Flx remains unclear. Here, we examined the role of the 5-HT2A receptor in the effects of acute Flx on anxiety-like behavior, serum corticosterone levels, neural activation and immediate early gene (IEG) expression in stress-responsive brain regions, using 5-HT2A receptor knockout (5-HT2A−/−) mice of both sexes. Methods: 5-HT2A−/− and wild-type (WT) male and female mice received a single administration of Flx or vehicle, and were examined for anxiety-like behavior, serum corticosterone levels, FBJ murine osteosarcoma viral oncogene homolog peptide (c-Fos) positive cell numbers in stress-responsive brain regions of the hypothalamus and prefrontal cortex (PFC), and PFC IEG expression. Results: Th...
Mitochondria in neurons in addition to their primary role in bioenergetics also contribute to spe... more Mitochondria in neurons in addition to their primary role in bioenergetics also contribute to specialized functions including regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT2A receptor-mediated recruitment of the SIRT1-PGC-1α axis, which is relevant to the neuroprotective action of 5-HT. 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial genes. This was accompanied by increased cellular ATP levels, basal and maximal respiration, as well as spare respiratory capacity. Mechanistically the effects of 5-HT were mediated via the 5-HT2A receptor and master modulators of mitochondrial biogenesis, ...
The Journal of Neuroscience, 2003
Most neuropharmacological agents and many drugs of abuse modulate the activity of heptahelical G-... more Most neuropharmacological agents and many drugs of abuse modulate the activity of heptahelical G-protein-coupled receptors. Although the effects of these ligands result from changes in cellular signaling, their neurobehavioral activity may not correlate with results ofin vitrosignal transduction assays. 5-Hydroxytryptamine 2A receptor (5-HT2AR) partial agonists that have similar pharmacological profiles differ in the behavioral responses they elicit.In vitrostudies suggest that different agonists acting at the same receptor may establish distinct patterns of signal transduction. Testing this hypothesis in the brain requires a global signal transduction assay that is applicablein vivo. To distinguish the cellular effects of the different 5-HT2AR agonists, we developed an assay for global signal transduction on the basis of high throughput quantification of rapidly modulated transcripts. Study of the responses to agonists in human embryonic kidney 293 cells stably expressing 5-HT2ARs ...
Nature Communications, 2018
Forgetting is a ubiquitous phenomenon that is actively promoted in many species. How and whether ... more Forgetting is a ubiquitous phenomenon that is actively promoted in many species. How and whether organisms’ behavioral goals drive which memories are actively forgotten is unknown. Here we show that processes essential to controlling goal-directed behavior trigger active forgetting of distracting memories that interfere with behavioral goals. When rats need to retrieve particular memories to guide exploration, it reduces later retention of other memories encoded in that environment. As with humans, this retrieval-induced forgetting is competition-dependent, cue-independent and reliant on prefrontal control: Silencing the medial prefrontal cortex with muscimol abolishes the effect. cFos imaging reveals that prefrontal control demands decline over repeated retrievals as competing memories are forgotten successfully, revealing a key adaptive benefit of forgetting. Occurring in 88% of the rats studied, this finding establishes a robust model of how adaptive forgetting harmonizes memory ...
Frontiers in behavioral neuroscience, 2018
Many psychiatric disorders, despite their specific characteristics, share deficits in the cogniti... more Many psychiatric disorders, despite their specific characteristics, share deficits in the cognitive domain including executive functions, emotional control and memory. However, memory deficits have been in many cases undervalued compared with other characteristics. The expression of Immediate Early Genes (IEGs) such as, , and are selectively and promptly upregulated in learning and memory among neuronal subpopulations in regions associated with these processes. Changes in expression in these genes have been observed in recognition, working and fear related memories across the brain. Despite the enormous amount of data supporting changes in their expression during learning and memory and the importance of those cognitive processes in psychiatric conditions, there are very few studies analyzing the direct implication of the IEGs in mental illnesses. In this review, we discuss the role of some of the most relevant IEGs in relation with memory processes affected in psychiatric conditions.
eNeuro
Successful memory involves not only remembering over time but also keeping memories distinct. The... more Successful memory involves not only remembering over time but also keeping memories distinct. The ability to separate similar experiences into distinct memories is a main feature of episodic memory. Discrimination of overlapping representations has been investigated in the dentate gyrus of the hippocampus (DG), but little is known about this process in other regions such as the perirhinal cortex (Prh). We found in male rats that perirhinal brain-derived neurotrophic factor (BDNF) is required for separable storage of overlapping, but not distinct, object representations, which is identical to its role in the DG for spatial representations. Also, activity-regulated cytoskeletal-associated protein (Arc) is required for disambiguation of object memories, as measured by infusion of antisense oligonucleotides. This is the first time Arc has been implicated in the discrimination of objects with overlapping features. Although molecular mechanisms for object memory have been shown previously...
Neurobiology of Stress, 2017
Chronic stress enhances risk for psychiatric disorders, and in animal models is known to evoke de... more Chronic stress enhances risk for psychiatric disorders, and in animal models is known to evoke depression-like behavior accompanied by perturbed neurohormonal, metabolic, neuroarchitectural and transcriptional changes. Serotonergic neurotransmission, including serotonin 2A (5-HT 2A ) receptors, have been implicated in mediating specific aspects of stress-induced responses. Here we investigated the influence of chronic unpredictable stress (CUS) on depression-like behavior, serum metabolic measures, and gene expression in stress-associated neurocircuitry of the prefrontal cortex (PFC) and hippocampus in 5-HT 2A receptor knockout (5-HT À=À 2A ) and wild-type mice of both sexes. While 5-HT À=À 2A male and female mice exhibited a baseline reduced anxiety-like state, this did not alter the onset or severity of behavioral despair during and at the cessation of CUS, indicating that these mice can develop stressevoked depressive behavior. Analysis of metabolic parameters in serum revealed a CUS-evoked dyslipidemia, which was abrogated in 5-HT À=À 2A female mice with a hyperlipidemic baseline phenotype. 5-HT À=À 2A male mice in contrast did not exhibit such a baseline shift in their serum lipid profile. Specific stress-responsive genes (Crh, Crhr1, Nr3c1, and Nr3c2), trophic factors (Bdnf, Igf1) and immediate early genes (IEGs) (Arc, Fos, Fosb, Egr1-4) in the PFC and hippocampus were altered in 5-HT À=À 2A mice both under baseline and CUS conditions. Our results support a role for the 5-HT 2A receptor in specific metabolic and transcriptional, but not behavioral, consequences of CUS, and highlight that the contribution of the 5-HT 2A receptor to stress-evoked changes is sexually dimorphic.
Behavioural Brain Research, 2015
Prefrontal Cortex is required for episodic memory in humans. Object Recognition tasks can mod... more Prefrontal Cortex is required for episodic memory in humans. Object Recognition tasks can model aspects of episodic memory in rodents. mPFC in rodents is required for recognition of an object in a particular context. mPFC might be involved in acquisition, consolidation and control of retrieval of episodic-like memories in rodents.
Neuron, 2007
Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly ... more Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT 2A receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric G i/o proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.
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Papers by Noelia Weisstaub