Pierre-Marie Lledo

• PhD
• Head of Department at Pasteur Network

The vascular system regulates brain clearance through arterial blood flow and lymphatic drainage of cerebrospinal fluid (CSF). Idiopathic intracranial hypertension (IIH), characterized by elevated intracranial pressure and dural venous sinus stenoses, can be treated by restoring venous blood flow via venous stenting, suggesting a role for venous bl...

Negative bias is an essential characteristic of depressive episodes leading patients to attribute more negative valence to environmental cues. This negative bias affects all levels of information processing including emotional response, attention and memory, leading to the development and maintenance of depressive symptoms. In this context, pleasan...

In most mammals, new neurons are not only produced during embryogenesis but also after birth. Soon after adult neurogenesis was discovered, the influence of recruiting new neurons on cognitive functions, especially on memory, was documented. Likewise, the late process of neuronal production also contributes to affective functions, but this outcome...

Sepsis, a life-threatening syndrome caused by a dysregulated host response to infection, induces a range of acute effects on the brain, including sickness behaviour and sepsis-associated encephalopathy. In addition, sepsis can lead to durable changes in neuronal circuits, resulting in long-term impairments such as post-traumatic stress disorder (PT...

Anosmia was identified as a hallmark of COVID-19 early in the pandemic, however, with the emergence of variants of concern, the clinical profile induced by SARS-CoV-2 infection has changed, with anosmia being less frequent. Here, we assessed the clinical, olfactory and neuroinflammatory conditions of golden hamsters infected with the original Wuhan...

The central nervous system regulates systemic immune responses by integrating the physiological and behavioral constraints faced by an individual. Corticosterone (CS), the release of which is controlled in the hypothalamus by the paraventricular nucleus (PVN), is a potent negative regulator of immune responses. Using the mouse model, we report that...

Chronic stress constitutes a major risk factor for depression that can disrupt various aspects of homeostasis, including the gut microbiome (GM). We have recently shown that GM imbalance affects adult hippocampal (HPC) neurogenesis and induces depression-like behaviors, with the exact mechanisms being under active investigation. Here we hypothesize...

A recent study showed that GDF11 stimulates autophagy via inhibition of mTOR and that this action is necessary for the enhancement of neuronal activity mediated by GDF117. These findings point to a common mechanism that might be shared by food deprivation, rapamycin treatment or physical exercise and suggest the exciting possibility of a new class...

Cognitive decline and mood disorders increase in frequency with age. Many efforts are focused on the identification of molecules and pathways to treat these conditions. Here, we demonstrate that systemic administration of growth differentiation factor 11 (GDF11) in aged mice improves memory and alleviates senescence and depression-like symptoms in...

Negative emotional bias is an essential hallmark of depression reflected by negative shift in hedonic valence assignment to emotional stimuli. Pleasant cues become less attractive and unpleasant ones more aversive. Given the crucial role of amygdala in valence coding, we hypothesize that specific basolateral amygdala (BLA) circuits alterations migh...

In the olfactory system, the olfactory cortex sends glutamatergic projections back to the first stage of olfactory processing, the olfactory bulb (OB). Such corticofugal excitatory circuits — a canonical circuit motif described in all sensory systems— dynamically adjust early sensory processing. Here, we uncover a corticofugal inhibitory feedback t...

Chronic stress constitutes a major risk factor for depression that can disrupt various aspects of homeostasis, including the gut microbiome (GM). We have recently shown that GM imbalance affects adult hippocampal (HPC) neurogenesis and induces depression-like behaviors, with the exact mechanisms being under active investigation. Here we hypothesize...

Introduction Bipolar disorder has been repeatedly associated with abnormalities of white matter. However, DTI is intrinsically limited and the precise cellular mechanisms that underlie these alterations remains unknown. Objectives Our aim was to investigate microscopical characteristics of white matter using MRI in patients with bipolar and health...

Anosmia was identified as a hallmark of COVID-19 early in the pandemic, however, with the emergence of variants of concern, the clinical profile induced by SARS-CoV-2 infection has changed, with anosmia being less frequent. Several studies have focused on the neuropathogenesis of the original SARS-CoV-2, but little is known about the neuropathologi...

Growing evidence implicates the bacterial populations in the nose as an important factor for personal and global health. Here, we provide a brief overview of the nasal microbiome and speculate on its potential roles in olfactory processing and neurodegeneration, with a particular focus on Parkinson’s disease (PD).

Aging is known to be associated with hippocampus-dependent memory decline, but the underlying causes of this age-related memory impairment remain yet highly debated. Here we showed that fecal microbiota transplantation (FMT) from aged, but not young, animal donors in young mice is sufficient to trigger profound hippocampal alterations including ast...

Background: Zika Virus (ZIKV) infection has been associated with Guillain-Barré Syndrome (GBS). Yet, little is known about the consequence of ZIKV infection on olfaction in humans. Methods: Just right before the COVID-19 outbreak, we prospectively investigated the olfactory capacities of 19 patients with ZIKV-associated GBS from the French West Ind...

Bipolar disorders are defined by recurrences of depressive and manic episodes. The pathophysiology is still unknown, and translating clinical symptoms into behaviors explorable in animal models is challenging. Animal models of bipolar disorder do not exist because cyclicity of the disease is impossible to mimic, and it is therefore necessary to stu...

The nervous system and the immune system both rely on an extensive set of modalities to perceive and act on perturbations in the internal and external environments. During feeding, the intestine is exposed to nutrients that may contain noxious substances and pathogens. Here we show that Vasoactive Intestinal Peptide (VIP), produced by the nervous s...

Congenital cytomegalovirus (CMV) infection leads to olfactory bulb lesions in the fetus, yet little is known about its impact on olfaction after birth. Here, we have assessed in a prospective study conducted on children in two French hospitals from 2016 to 2019, infection severity and olfactory performance after congenital CMV infection. Children w...

Sepsis is a life-threatening condition induced by a deregulated host response to severe infection. Post-sepsis syndrome includes long-term psychiatric disorders, such as persistent anxiety and post-traumatic stress disorder, whose neurobiological mechanisms remain unknown. Using a reference mouse model of sepsis, we showed that mice that recovered...

Gut bacteria influence brain functions and metabolism. We investigated whether this influence can be mediated by direct sensing of bacterial cell wall components by brain neurons. In mice, we found that bacterial peptidoglycan plays a major role in mediating gut-brain communication via the Nod2 receptor. Peptidoglycan-derived muropeptides reach the...

Despite recent therapeutic advances, ischemic stroke is still a leading cause of death and disability. There is renewed attention on peripheral inflammatory signaling as a way of modulating the post-ischemic neuro-inflammatory process. The immune-brain crosstalk has long been the focus for understanding the mechanisms of sickness behavior, which is...

Hematopoietic stem cell transplantation (HSCT) is a therapy used for multiple malignant and nonmalignant diseases, with chemotherapy used for pretransplantation myeloablation. The post-HSCT brain contains peripheral engrafted parenchymal macrophages, despite their absence in the normal brain, with the engraftment mechanism still undefined. Here we...

Three-dimensional imaging is at the core of medical imaging and is becoming a standard in biological research. As a result, there is an increasing need to visualize, analyze and interact with data in a natural three-dimensional context. By combining stereoscopy and motion tracking, commercial virtual reality (VR) headsets provide a solution to this...

Résumé Les troubles bipolaires sont caractérisés par une alternance de phases dépressives et d’exaltations. Il s’agit d’une pathologie fréquente, survenant chez l’adulte jeune, qui peut avoir un l’impact considérable sur le fonctionnement des patients du fait de la fréquence et de la sévérité des épisodes, des comorbidités psychiatriques et somatiq...

Although pneumonia and acute respiratory failure are the most frequent and severe complications of patients with SARS-CoV-2 infection, many of them also develop neurological signs and symptoms. From sickness behavior to coma, neurological disorders are associated with impairment of consciousness and dysautonomia, resulting from brainstem dysfunctio...

Understanding how SARS-CoV-2 spreads within the respiratory tract is important to define the parameters controlling the severity of COVID-19. Here we examine the functional and structural consequences of SARS-CoV-2 infection in a reconstructed human bronchial epithelium model. SARS-CoV-2 replication causes a transient decrease in epithelial barrier...

The devastating pandemic due to SARS-CoV-2 and the emergence of antigenic variants that jeopardize the efficacy of current vaccines create an urgent need for a comprehensive understanding of the pathophysiology of COVID-19, including the contribution of inflammation to disease. It also warrants for the search of immunomodulatory drugs that could im...

Neonates are highly susceptible to bacterial meningitis as compared to children and adults. Group B streptococcus (GBS) is a major cause of neonatal meningitis. Neonatal meningitis can result from GBS intestinal colonization and translocation across the intestinal barrier (IB). Here, we show that the immaturity of the neonatal intestinal microbiota...

Whereas recent investigations have revealed viral, inflammatory and vascular factors involved in SARS-CoV-2 lung pathogenesis, the pathophysiology of neurological disorders in COVID-19 remains poorly understood. Olfactory and taste dysfunction are common in COVID-19, especially in mildly symptomatic patients. Here, we conducted a virologic, molecul...

Aging is known to be associated with hippocampus-dependent memory decline, but the underlying causes of this age-related memory impairment are not yet elucidated. Here we show that the colonization of mice with the gut microbiota from aged, but not young animals is sufficient to trigger profound hippocampal alterations including astrogliosis, decre...

Neuronal dendritic spine dynamics provide a plasticity mechanism for altering brain circuit connectivity to integrate new information for learning and memory. Previous in vivo studies in the olfactory bulb (OB) showed that regional increases in activity caused localized spine stability, at a population level, yet how activity affects spine dynamics...

In sensory systems, cortical areas send excitatory projections back to subcortical areas to dynamically adjust sensory processing. Here, we uncover for the first time the existence of a cortical inhibitory feedback to subcortical sensory areas. Investigating the olfactory system, we reveal that a subpopulation of GABAergic neurons in the anterior o...

Depression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that UCMS mice display phenotypic alterations, which could be transferred from UCM...

The devastating coronavirus disease 2019 (COVID-19) pandemic, due to SARS-CoV-2, has caused more than 47 million confirmed cases and more than 1.2 million human deaths around the globe ¹ , and most of the severe cases of COVID-19 in humans are associated with neurological symptoms such as anosmia and ageusia, and uncontrolled inflammatory immune re...

40 While recent investigations have revealed viral, inflammatory and vascular factors involved in SARS-41 CoV-2 lung pathogenesis, the pathophysiology of neurological disorders in COVID-19 remains poorly 42 understood. Yet, olfactory and taste dysfunction are rather common in COVID-19, especially in pauci-43 symptomatic patients which constitutes t...

Background It is unclear whether olfactory deficits improve after remission in depressed patients. Therefore, we aimed to assess in drug-free patients the olfactory performance of patients with major depressive episodes (MDE) and its change after antidepressant treatment. Methods In the DEP-ARREST-CLIN study, 69 drug-free patients with a current M...

1 2 Understanding how SARS-CoV-2 spreads within the respiratory tract is important to define the 3 parameters controlling the severity of COVID-19. We examined the functional and structural 4 consequences of SARS-CoV-2 infection in a reconstituted human bronchial epithelium model. 5 SARS-CoV-2 replication caused a transient decrease in epithelial b...

Because of our classification system limitations for defining psychiatric disorders and understanding their physiopathology, a new research area based on dimensions has emerged. It consists of exploring domains derived from fundamental behavioral components linked to neurobiological systems. Emotional processing is among the most affected dimension...

BACKGROUND Bipolar disorder (BD) is a chronic illness associate with increased rates of premature mortality and dementia. Patients with BD frequently present mood instability likely associated with risk of relapse, impaired functioning, and suicidal behavior, indicating that the illness is active. OBJECTIVE This 3-month feasibility study, carried...

Background: Diagnosis and management of bipolar disorder (BD) are limited by the absence of available biomarkers. Patients with BD frequently present mood instability, even during remission, likely associated with risk of relapse, impaired functioning, and suicidal behavior, indicating that the illness is active. Objective: This research protoco...

Major depressive disorders (MDDs) constitute a leading cause of disability worldwide and current pharmacological treatments are partially effective. The gut microbiota (GM) has recently emerged as a target of therapeutic interest for MDDs. In this study, we transfer GM from mice that sustained unpredictable chronic mild stress (UCMS) to healthy rec...

Background: Olfactory deficits (OD) are reported as markers for a large spectrum of neuro-psychiatric disorders. Alterations can concern perception, identification, discrimination and assignment of odour's valence of olfaction process. We propose a comprehensive review to summarize which kind of OD were reported in bipolar disorders (BD) and in wh...

The main olfactory system of the mammalian brain is responsible for encoding, processing, and ultimately perceiving an extraordinarily complex and diverse olfactory environment, providing information about food, predators, and conspecifics that are crucial for survival. This feat is achieved across a surprisingly compact neural architecture that la...

We thank Dmitry Ershov from the Bioinformatics and Biostatistics Hub (Institut Pasteur, USR 3756CNRS) and the Image Analysis Hub for their help with the image and/or data analysis. We thank George M. Haustant and Thomas Cokelaer (Biomics Platform, C2RT, Institut Pasteur, Paris, France, supported by France Génomique (ANR-10-INBS-09-09) and IBISA) fo...

Aging is a negative regulator of general homeostasis, tissue function, and regeneration. Changes in organismal energy levels and physiology, through systemic manipulations such as calorie restriction and young blood infusion, can regenerate tissue activity and increase lifespan in aged mice. However, whether these two systemic manipulations could b...

Depression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota, but causality remains yet to be established. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that the UCMS mice display phenotypic...

OBJECTIVE: To characterize the full spectrum, relative frequency, and prognosis of the neurologic manifestations in Zika virus (ZIKV) postnatal infection. METHODS: We conducted an observational study in consecutive ZIKV-infected patients presenting with neurologic manifestations during the French West Indies 2016 outbreak. RESULTS: Eighty-seven...

Olfaction is the first sensory modality to develop during fetal life in mammals, and plays a key role in the various behaviors of neonates such as feeding and social interaction. Odorant cues (i.e., mother or predator scents) can trigger potentiation or inhibition of ultrasonic vocalizations (USV) emitted by pups following their isolation. Here, we...

Olfaction is the first sensory modality to develop during fetal life in mammals, and plays a key role in the various behaviors of neonates such as feeding and social interaction. Odorant cues (i.e., mother or predator scents) can trigger potentiation or inhibition of ultrasonic vocalizations (USV) emitted by pups following their isolation. Here, we...

Chronic stress constitutes one of the strongest risk factors for depression and can disrupt various aspects of homeostasis, including gut microbiota composition. We found that stress-induced changes in gut microbiota promote depression and decrease adult hippocampal neurogenesis upon transfer to antibiotic-treated recipient mice. Subdiaphragmatic v...

In developed countries, cytomegalovirus (CMV)-infected newborns are at high risk of developing sensorineural handicaps, such as hearing loss, requiring extensive follow-up. However early prognostic tools for auditory damage in children are not yet available. In the fetus, CMV infection leads to early olfactory bulb (OB) damage, suggesting that olfa...

Using new methods to functionally dissect circuits, two papers from 2015 found enhanced synaptic properties of the inputs and outputs of hippocampal adult-born neurons specifically during a critical period of their development. These studies provided a circuit-level view of unique roles for new neurons and how they cope with the ever-changing envir...

Significance Odor–reward association during appetitive learning is a fundamental process that requires multiple forms of plasticity. In the adult olfactory bulb, the continual production of newborn interneurons contributes to the functional plasticity of the system, placing the newcomers in a key position to participate in olfactory associative lea...

Adult neurogenesis emerges as a tremendous form of plasticity with the continuous addition and loss of neurons in the adult brain. It is unclear how preexisting adult circuits generated during development are capable of modifying existing connections to accommodate the thousands of new synapses formed and exchanged each day. Here we first make para...

The olfactory bulb (OB) is a highly plastic structure that can change organizational networks depending on environmental inputs in adult mammals. Particularly, in rodents, adult neurogenesis underlies plastic changes in the OB circuitry by continuously adding new interneurons to the network. We addressed the question of whether microglia, the immun...

For hundreds of years, the sense of smell has generated great interest in the world literature, oenologists, and perfume makers but less of scientists. Only recently this sensory modality has gained new attraction in neuroscience when original tools issued from physiology, anatomy, or molecular biology were available to decipher how the brain makes...

In the mammalian brain, the anatomical structure of neural circuits changes little during adulthood. As a result, adult learning and memory are thought to result from specific changes in synaptic strength. A possible exception is the olfactory bulb (OB), where activity guides interneuron turnover throughout adulthood. These adult-born granule cell...

Most organisms use their olfactory system to detect and analyze chemical cues from the external world to guide essential behaviors. From worms to vertebrates, chemicals are detected by odorant receptors expressed by olfactory sensory neurons, which in vertebrates send an axon to the primary processing center called the olfactory bulb (OB). Within t...

Soignant, prendre des décisions est notre quotidien. Notre art est rendu plus difficile par la pression sociétale, l’information omniprésente à la pertinence pas toujours éprouvée, des règles imposées par des pratiques toujours plus cadrées. LA décision fonde le présent : un avant et un après pour celui dont nous devons « prendre soin ». Et pourtan...

Unlabelled: Numerous clinical reports underscore the frequency of olfactory impairments in patients suffering from major depressive disorders (MDDs), yet the underlying physiopathological mechanisms remain poorly understood. We hypothesized that one key link between olfactory deficits and MDD lies in hypercortisolemia, a cardinal symptom of MDD. C...

The olfactory brain is flexible, from cognitive areas all the way down to the peripheral areas in which sensory information is encoded so as to facilitate the subsequent extraction of relevant information. It is becoming increasingly clear that olfactory adaptability operates at the level of neural circuits. In the adult olfactory bulb circuit, new...

For a long time, the mammalian brain has been perceived to be a static organ. However, the discovery of adult neurogenesis in most mammalian species, including humans, monkeys, and rodents, has disrupted this view. As this continuous regeneration has an effect on established behavioral patterns, it holds promising therapeutic potential. However, be...

During brain development neural cell migration is a crucial, well-orchestrated, process, which leads to the proper whole brain structural organization. As development proceeds, new neurons are continuously produced and this protracted neurogenesis is maintained throughout life in specialized germinative areas inside the telencephalon: the subventri...

Olfactory dysfunction has been correlated with alterations in the emotional processes in several neuropsychiatric disorders. However, there is little research on olfactory processing and emotional regulation in bipolar disorder. We aim to explore the potential relationship between these two relevant dimensions (olfaction and emotional response) in...

Subventricular zone (SVZ) neurogenesis continuously provides new GABA- and dopamine (DA)-containing interneurons for the olfactory bulb (OB) in most adult mammals. DAergic interneurons are located in the glomerular layer (GL) where they participate in the processing of sensory inputs. To examine whether adult neurogenesis might contribute to regene...

Significance The olfactory bulb (OB) receives newly born neurons through adulthood. This process constitutes another means, in addition to molecular or synaptic changes within individual neurons, by which the OB can make changes to its functional circuitry. In this study, we show that adult-born OB neurons display adaptive changes in response to th...

This book introduces the concepts of “cerebral plasticity” and the “regenerating brain,” describing what we know now about the processes through which the brain constantly reconstructs itself and the potential benefits this knowledge could have in addressing concerns for neurological, cognitive, and emotional health. It begins with a survey of the...

The olfactory system is a dynamic place. In mammals, not only are sensory neurons located in the sensory organ renewed through adult life, but also its first central relay is reconstructed by continuous neuronal recruitment. Despite these numerous morphological and physiological changes, olfaction is a unique sensory modality endowed with a privile...

Hunger arouses sensory perception, eventually leading to an increase in food intake, but the underlying mechanisms remain poorly understood. We found that cannabinoid type-1 (CB1) receptors promote food intake in fasted mice by increasing odor detection. CB1 receptors were abundantly expressed on axon terminals of centrifugal cortical glutamatergic...

Les avancées récentes en neurobiologie ont quelque peu modifié l’idée d’une relative stabilité des composants structuraux du cerveau mature. Chez les mammifères, on découvre aujourd’hui que des milliers de nouvelles cellules nerveuses apparaissent chaque jour dans le cerveau adulte. Cette neurogenèse, qualifiée de secondaire par opposition à la pro...

Gamma oscillations are commonly observed in sensory brain structures, notably in the olfactory bulb. The mechanism by which gamma is generated in the awake rodent and its functional significance are still unclear. We combined pharmacological and genetic approaches in the awake mouse olfactory bulb to show that gamma oscillations required the synapt...

Neuronal regeneration occurs naturally in a few restricted mammalian brain regions, but its functional significance remains debated. Here we search for unique features in the synaptic outputs made by adult-born granule cell interneurons in the mouse olfactory bulb using optogenetic targeting of specific neuronal ages. We find that adult-born intern...

Neurogenesis underlies plastic changes in defined neuronal circuits in the postnatal and adult brain. Here we identify connective tissue growth factor (CTGF) as a critical factor in the mouse olfactory bulb (OB) in determining the efficiency of incorporation of postnatally born inhibitory neurons, thus gating the output of glomeruli, the first rela...

Problems relating to smell and taste can have a big impact on our lives. Because these senses contribute substantially to our enjoyment of life, our desire to eat, and to be social, smelling and tasting disorders can lead to depression and other mental disorders related to feeling disconnected with the external world. When smell and taste are impai...

Although adult neurogenesis has been conserved in higher vertebrates like primates and humans, timing of generation, migration and differentiation of new neurons appear to differ from rodents. Sheep could represent an alternative model to studying neurogenesis in primates since they possess a brain as large as macaque monkey and a similar lifespan....

Neurosciences – a comprehensive approach This textbook covers neuroscience from cellular and molecular mechanisms to behavior and cognitive processing. We also address evolution of the nervous system, computational neuroscience, the history of neuroscience as a discipline and neurophilosophy – to name but a few. The book provides the newest state-...

Modern neuroscience has demonstrated how the adult brain has the ability to profoundly remodel its neurons in response to changes in external stimuli or internal states. However, adult brain plasticity, although possible throughout life, remains restricted mostly to subcellular levels rather than affecting the entire cell. New neurons are continuou...

The generation of new neurons is sustained throughout life in the olfactory system. In recent years, tremendous progress has been made toward understanding the proliferation, differentiation, migration, and integration of newborn neurons in the olfactory bulb. Here, we discuss recent findings that shed light on different aspects of the integration...