NeuroLeman Network

How flexible are association cortices? I will present a series of fMRI experiments addressing this question by investigating individuals born without hands, who use their feet as effectors to perform everyday actions. These results suggest that computations in association cortices are abstracted from visuomotor features and experience, similarly to the visual -independence of the association networks in people born blind, highlighting these regions’ ability to compensate for experience in any specific modality. These findings also open new avenues to utilize effector-independence in the action system for motor rehabilitation.

Growing evidence suggests the ventral pallidum (VP) is critical for drug intake and seeking behaviors. Receiving dense projections from the nucleus accumbens as well as dopamine inputs from the midbrain, the VP plays a central role in the control of motivated behaviors. Repeated exposure to cocaine is known to alter VP neuronal firing and neurotransmission. Surprisingly, there is limited information on the molecular adaptations occurring in VP neurons following cocaine intake.To provide insights into cocaine-induced transcriptional alterations we performed RNA-sequencing on VP of mice following cocaine self-administration. Gene Ontology analysis pointed toward alterations in dendrite- and spinerelated genes. Subsequent transcriptional regulator analysis identified the transcription factor Nr4a1 as a common regulator for these sets of morphology-related genes.Consistent with the central role of the VP in reward, its neurons project to several key regions associated with cocaine-mediated behaviors. We thus assessed Nr4a1 expression levels in various projection populations.Following cocaine self-administration, VP neurons projecting to the mediodorsal thalamus (MDT) showed significantly increased Nr4a1 levels. To further investigate the role of Nr4a1 in cocaine intake and relapse, we bidirectionally manipulated its expression levels selectively in VP neurons projecting to the MDT. Increasing Nr4a1 levels resulted in enhanced relapse-like behaviors accompanied by a blockage of cocaine-induced spinogenesis.However, decreasing Nr4a1expression levels completely abolished cocaine intake and consequential relapse-like behaviors. Together, our preliminary findings suggest that drug-induced neuronal remodeling in pallido-thalamic circuits is critical for cocaine intake and relapse-like behaviors.

Broadly, the Mauro Costa-Mattioli laboratory (The MCM Lab) encompasses two complementary lines of research. The first one, more traditional but very important, aims at unraveling the molecular mechanisms underlying memory formation (e.g., using state-of-the-art molecular and cell-specific genetic approaches). Learning and memory disorders can strike the brain during development (e.g., Autism Spectrum Disorders and Down Syndrome), as well as during adulthood (e.g., Alzheimer’s disease). We are interested in understanding the specific circuits and molecular pathways that are primarily targeted in these disorders and how they can be restored. To tackle these questions, we use a multidisciplinary, convergent and cross-species approach that combines mouse and fly genetics, molecular biology, electrophysiology, stem cell biology, optogenetics and behavioral techniques. The second line of research, more recent and relatively unexplored, is focused on understanding how gut microbes control CNS driven-behavior and brain function. Our recent discoveries, that microbes in the gut could modulate brain function and behavior in a very powerful way, have added a whole new dimension to the classic view of how complex behaviors are controlled. The unexpected findings have opened new avenues of study for us and are currently driving my lab to answer a host of new and very interesting questions: - What are the gut microbes (and metabolites) that regulate CNS-driven behaviors? Would it be possible to develop an unbiased screening method to identify specific microbes that regulate different behaviors? - If this is the case, can we identify how members of the gut microbiome (and their metabolites) mechanistically influence brain function? - What is the communication channel between the gut microbiota and the brain? Do different gut microbes use different ways to interact with the brain? - Could disruption of the gut microbial ecology cause neurodevelopmental dysfunction? If so, what is the impact of disruption in young and adult animals? - More importantly, could specific restoration of selected bacterial strains (new generation probiotics) represent a novel therapeutic approach for the targeted treatment of neurodevelopmental disorders? - Finally, can we develop microbiota-directed therapeutic foods to repair brain dysfunction in a variety of neurological disorders?

The developmental journey of cortical interneurons encounters several activity-dependent milestones. During the early postnatal period in developing mice, GABAergic neurons are transient preferential recipients of thalamic inputs and undergo activity-dependent migration arrest, wiring and programmed cell-death. But cortical GABAergic neurons are also specified by very early developmental programs. For example, the earliest born GABAergic neurons develop into hub cells coordinating spontaneous activity in hippocampal slices. Despite their importance for the emergence of sensory experience, their role in coordinating network dynamics, and the role of activity in their integration into cortical networks, the collective in vivo dynamics of GABAergic neurons during the neonatal postnatal period remain unknown. Here, I will present data related to the coordinated activity between GABAergic cells of the mouse barrel cortex and hippocampus in non-anesthetized pups using the recent development of all optical methods to record and manipulate neuronal activity in vivo. I will show that the functional structure of developing GABAergic circuits is remarkably patterned, with segregated assemblies of prospective parvalbumin neurons and highly connected hub cells, both shaped by sensory-dependent processes.

The synapse is the core component of the nervous system and synapse formation is the critical step in the assembly of neuronal circuits. The assembly and maturation of synapses requires the contribution of secreted and membrane-associated proteins, with neuronal activity playing crucial roles in regulating synaptic strength, neuronal membrane properties, and neural circuit refinement. The molecular mechanisms of synapse assembly and refinement have been so far largely examined on a gene-by-gene basis and with a perspective fully centered on neuronal cells. However, in the last years, the involvement of non-neuronal cells has emerged. Among these, microglia, the resident immune cells of the central nervous system, have been shown to play a key role in synapse formation and elimination. Contacts of microglia with dendrites in the somatosensory cortex were found to induce filopodia and dendritic spines via Ca2+ and actin-dependent processes, while microglia-derived BDNF was shown to promote learning-dependent synapse formation. Microglia is also recognized to have a central role in the widespread elimination (or pruning) of exuberant synaptic connections during development. Clarifying the processes by which microglia control synapse homeostasis is essential to advance our current understanding of brain functions. Clear answers to these questions will have important implications for our understanding of brain diseases, as the fact that many psychiatric and neurological disorders are synaptopathies (i.e. diseases of the synapse) is now widely recognized. In the last years, my group has identified TREM2, an innate immune receptor with phagocytic and antiinflammatory properties expressed in brain exclusively by microglia, as essential for microglia-mediated synaptic refinement during the early stages of brain development. The talk will describe the role of TREM2 in synapse elimination and introduce the molecular actors involved. I will also describe additional pathways by which the immune system may affect the formation and homeostasis of synaptic contacts.

In order to re-install neurogenesis after loss of neurons upon injury or neurodegeneration, we need to understand the basic principles of neurogenesis. I will first discuss about our discovery of a novel centrosome protein (Camargo et al., 2019) and discuss unpublished work about the great diversity of interphase centrosome proteomes and their relevance for neurodevelopmental disorders. I would then present work on a master regulator of neural stem cell amplification and brain folding (Stahl et al., 2013; Esgleas et al., 2020) to proceed presenting data on utilizing some of these factors for turning astrocytes into neurons. I will present data on the critical role of mitochondria in this conversion process (Gascon et al., 2016, Russo et al., 2020) and how it regulates the speed of conversion also showing unpublished data. If time permits I may touch on recent progress in in vivo reprogramming (Mattugini et al., 2019). Taken together, these data highlight the surprising specificity and importance of organelle diversity from centrosome, nucleolus and mitochondria as key regulators in development and reprogramming.

The risks of in utero and early exposure to environmental contaminants, such as heavy metals and persistent organic pollutants, on child neurodevelopment is now established, however our understanding of how these contaminants alter the human brain is very limited. To address this issue, more effort must be made to integrate brain imaging tools with epidemiological studies. In this seminar, I will be presenting EEG and MRI data collected in birth-cohort studies where impairments of cognitive and sensory functions were observed in association with prenatal exposure to mercury, lead, PCB or organophosphate insecticides. Results obtained in children and adolescents suggest that each pollutant might affect different levels of brain processing and that frontal regions are particularly vulnerable.

Major depressive disorder (MDD) is a sexually dimorphic disease. This sexual dimorphism is believed to result from sex-specific molecular alterations affecting functional pathways regulating the capacity of men and women to cope with daily life stress differently. Transcriptional changes associated with epigenetic alterations have been observed in the brain of men and women with depression and similar changes have been reported in different animal models of stress-induced depressive-like behaviors. In fact, most of our knowledge of the biological basis of MDD is derived from studies of chronic stress models in rodents. However, while these models capture certain aspects of the features of MDD, the extent to which they reproduce the molecular pathology of the human syndrome remains unknown and the functional consequences of these changes on the neuronal networks controlling stress responses are poorly understood. During this presentation, we will first address the extent by which transcriptional signatures associated with MDD compares in men and women. We will then transition to the capacity of different mouse models of chronic stress to recapitulate some of the transcriptional alterations associated with the expression of MDD in both sexes. Finally, we will briefly elaborate on the functional consequences of these changes at the neuronal level and conclude with an integrative perspective on the contribution of sex-specific transcriptional profiles on the expression of stress responses and MDD in men and women.

Every year, 30 million infants worldwide are delivered after intra-uterine growth restriction (IUGR) and 15 million are born preterm. These two conditions are the leading causes of ante/perinatal stress and brain injury responsible for neurocognitive and behavioral disorders in more than 9 million children each year. Both prematurity and IUGR are associated with perinatal systemic inflammation, a key factor associated with neuroinflammation and identified to be the best predictor of subsequent neurological impairments. Most of pharmacological candidates have failed to demonstrate any beneficial effect to prevent perinatal brain damage. In contrast, environmental enrichment based on developmental care, skin-to-skin contact and vocal/music intervention appears to confer positive effects on brain structure and function. However, mechanisms underlying these effects remain unknown. There is strong evidence that an adverse environment during pregnancy and the perinatal period can influence hormonal responses of the newborn with long-lasting neurobehavioral consequences in infancy and adulthood. Excessive cortisol release in response to perinatal stress induces pro-inflammatory and brain-programming effects. These deleterious effects are known to be balanced by Oxytocin (OT), a neuropeptide playing a key role during the perinatal period and parturition, in social behavior and regulating the central inflammatory response to injury in the adult brain. Using a rodent model of IUGR associated with perinatal brain damage, we recently reported that Carbetocin, a brain permeable long-lasting OT receptor (OTR) agonist, was associated with a significant reduction of activated microglia, the primary immune cells of the brain. Moreover this reduced microglia reactivity was associated to a long-term neuroprotection. These findings make OT a promising candidate for neonatal neuroprotection through neuroinflammation regulation. However, the causality between the endogenous OT and central inflammation response to injury has not been established and will be further studied by the lab.

The spatial patterning of each neurodegenerative disease relates closely to a distinct structural and functional network in the human brain. This talk will mainly describe how brain network-sensitive neuroimaging methods such as resting-state fMRI and diffusion MRI can shed light on brain network dysfunctions associated with pathology and cognitive decline from preclinical to clinical dementia. I will first present our findings from two independent datasets on how amyloid and cerebrovascular pathology influence brain functional networks cross-sectionally and longitudinally in individuals with mild cognitive impairment and dementia. Evidence on longitudinal functional network organizational changes in healthy older adults and the influence of APOE genotype will be presented. In the second part, I will describe our work on how different pathology influences brain structural network and white matter microstructure. I will also touch on some new data on how brain network integrity contributes to behavior and disease progression using multivariate or machine learning approaches. These findings underscore the importance of studying selective brain network vulnerability instead of individual region and longitudinal design. Further developed with machine learning approaches, multimodal network-specific imaging signatures will help reveal disease mechanisms and facilitate early detection, prognosis and treatment search of neuropsychiatric disorders.

Our senses are constantly bombarded with a myriad of diverse signals. Transforming this sensory cacophony into a coherent percept of our environment relies on solving two computational challenges: First, we need to solve the causal inference problem - deciding whether signals come from a common cause and thus should be integrated, or come from different sources and be treated independently. Second, when there is a common cause, we should integrate signals across the senses weighted in proportion to their sensory reliabilities. I discuss recent research at the behavioural, computational and neural systems level that investigates how the brain addresses these two computational challenges in multisensory perception.