Plenary lectures

How does our brain make us feel what others feel? How does it motivate us to help others? In humans, the somatosensory, insular and cingulate cortices are activated both when experiencing pain and while witnessing other do so. How and whether such vicarious activations cause us to share the distress of others and help remains difficult to test in humans. I will present a series of experiments showing that altering brain activity in these brain regions does alter emotional contagion and prosociality. In humans, activity in the somatosensory cortex of observers predicts helping and perturbing that activity perturbs helping. Single cell recordings in rats show that neurons involved in an animal’s own pain become reactivated while the animal witnesses another animal in pain. Strikingly, this occurs in area 24, the rodent homologue of the anterior cingulate cortex in which humans show activations while witnessing the pain of others. Rats normally freeze while witness a conspecific receiving footshocks – evidence of emotional contagion – and deactivating area 24 reduces such vicarious freezing demonstrating the causal role of this region in sharing the emotions of others. These data show the existence of an evolutionarily conserved mechanism that maps the pain of others onto an observer’s own pain circuitry and trigger emotional contagion. Finally, when a rat can choose between a lever that produces food for the rat itself, and one that produces food and triggers a footshock to another animal, rats learn to avoid the shock-lever. Deactivating area 24 abolishes this harm aversion, suggesting a causal link between emotional contagion and helping. In the light of these experiments, I will suggest that emotion sharing is an evolutionarily conserved mechanism that allows animals and humans to better prepare for yet unseen dangers by tuning into the state of those that have already detected them. This selfishly beneficial mechanism can promote prosociality, but does so in fewer animals and situations than the emotional contagion itself.

Precisely wired neuronal circuits process sensory information in a learning- and context-dependent manner in order to govern behavior. Simple whisker-dependent sensory decision-making tasks in mice reveal contributions of distinct cell types and brain regions participating in the conversion of sensory information into goal-directed motor output through reward-based learning. Task learning is accompanied by target-specific routing of sensory information to specific downstream brain regions. Current evidence from investigations of whisker-deflection detection tasks, in which thirsty head-restrained mice learn to lick a reward spout to obtain a water reward, is consistent with the hypothesis of learning-dependent changes in signalling from primary somatosensory barrel cortex to secondary somatosensory cortex and dorsolateral striatum, indirectly recruiting tongue-jaw motor cortex and higher-order cortical regions, such as medial prefrontal cortex and hippocampus. An important challenge for the future is to understand the brainwide neural circuit mechanisms underlying reward-based learning connecting cell type-specific processing of sensory information with the motor neurons ultimately responsible for goal-directed action initiation and motor control.

Several neurodegenerative diseases of the brain are characterized by the presence of intracellular protein inclusions. These inclusions were described at the beginning of last century as characteristic neuropathological features for diseases such as Alzheimer’s disease (AD), Pick’s disease, Parkinson’s disease. Now we know that the main component of the Lewy pathology of Parkinson's disease is the protein alpha-synuclein; the same is also true of dementia with Lewy bodies and multiple system atrophy. In Alzheimer's disease, Pick's disease and a number of other diseases, the abnormal filamentous inclusions are made of the microtubule-associated protein tau. Structural studies using cryo-EM have allowed a more refined classification of neurodegenerative diseases based on how tau or alpha-synuclein fold in the aggregates in the various conditions. They have also led to identification of the novel TMEM106B aggregates of yet unclear function. The importance of tau and alpha-synuclein in their specific diseases is supported by findings that genetic mutations in their genes cause neurodegeneration. Study on the distribution of Lewy bodies have suggested that alpha- synuclein aggregation starts at the periphery and spreads to the brain leading on the way to pre-motor and motor symptoms. In the brain of Parkinson’s patients, besides the large Lewy body inclusions in the substantia nigra, alpha-synuclein smaller aggregates are present at the synapse and by impairing neurotransmitter release they contribute to the early stages of neurodegeneration. We have reproduced the alpha-synuclein pathology observed in Parkinson’s disease in transgenic models where progressive neurodegeneration can be investigated. Similarly, transgenic mice reproducing tau aggregation reveal that not only neurons are involved in the pathological process but that glial cells also greatly contribute to tau-related neurodegeneration. The link between protein inclusions and neurodegeneration supports them as a target for the treatment of neurodegenerative diseases.

Microglia are the resident immune cells of the central nervous system (CNS) that have distinct ontogeny from other tissue macrophages and play a pivotal role in health and disease. Microglia rapidly react to the changes in their microenvironment and adapt a context-specific phenotype. Recent advances in transcriptomics and single-cell technologies allow studying microglia at high resolution and demonstrate the unforeseen heterogeneity of microglia and immune infiltrates in brain pathologies. A precise definition of microglia states is essential to design future immune-modulating therapies. Transcriptomics studies revealed both heterogeneity and plasticity of microglia and myeloid cells in stroke-neuroinflammation. Depression-like behavior is associated with a distinct microglia activation and triggers specific changes in gene expression in experimental mice. The changes could be modulated by behavioral strategies. Survival of microglia in CNS depends on colony stimulating factor 1 receptor (CSF1R) signaling and CSF1R inhibitors depletes 99% of microglia in a few weeks. Microglia repopulate within 1 week upon cessation of treatment in adult mice as demonstrated by TMEM119 immunohistochemical staining and flow cytometry. We investigated the origin and functionality of repopulated microglia in young and old mouse brains using single-cell RNA sequencing (scRNA-seq), flow cytometry and immunohistochemistry. Interestingly, confocal and Scholl analysis of microglial cell body and branching revealed that repopulated cells display distinct morphology. Repopulated microglia originating by proliferation from precursor microglia reconstitute the functional clusters but vary in morphology and express higher levels of pro-inflammatory genes than controls. Intriguingly, in old mice more repopulated microglia persist as proliferating cells and do not reach mature microglia phenotype. The results highlight subtle differences in the repopulation of microglia in aged brains that might contribute to deterioration of its protective functions with aging.

Conscious perception in mammals depends on precise circuit connectivity between the cerebral cortex and thalamus; the evolution and development of these structures are closely linked. During the wiring of reciprocal connections between cortex and thalamus, thalamocortical axons (TCAs) first navigate forebrain regions that had undergone substantial evolutionary modifications. In particular, the organization of the pallial subpallial boundary (PSPB) diverged significantly between mammals, reptiles, and birds. In mammals, transient cell populations in internal capsule and early corticofugal projections from subplate neurons closely interact with TCAs to enable PSPB crossing. Prior to TCA arrival, cortical areas are initially patterned by intrinsic genetic factors. TCAs then innervate cortex in a sensory modality specific manner to refine cortical arealization and form primary sensory areas. Here, I shall review the mechanisms underlying the guidance of TCAs across forebrain boundaries, the implications of PSPB evolution for TCA pathfinding, and the reciprocal influence between TCAs and cortical areas during development.

In addition to their well characterized supportive and homeostatic roles, pioneering studies have shown that astrocytes directly affect neuronal activity. In recent years, groundbreaking research revealed many surprising roles for astrocytes in modulating neuronal activity and even behavior. To directly and specifically modulate astrocytic activity we employed a chemogenetic approach: We expressed the Gq-coupled designer receptor hM3Dq or the Gi-coupled designer receptor hM4Di in astrocytes, which allowed their time-restricted activation or inhibition (respectively) by the application of the designer drug clozapine-N-oxide (CNO). We discovered that in-vivo, astrocytic Gq activation enhanced memory allocation, and memory performance, also in Alzheimer mice (non-published data). On the other hand, astrocytic Gi pathway activation during memory acquisition impairs remote, but not recent, recall. We show that this effect is mediated by a specific disrupting of the projection from the hippocampus to the anterior cingulate cortex by astrocytes. What other high brain functions can astrocytes affect? We chronically imaged dozens of CA1 astrocytes using 2-photon microscopy, in mice that ran on a linear treadmill and proceed in a virtual environment to obtain water rewards. We find that astrocytic activity persistently ramps towards the reward location in a familiar environment. When the reward location was changed in the same environment or when mice were introduced to a novel context, the ramping was not apparent. Following additional training, as the mice were familiarized with the new reward location or novel context, the ramping was reestablished, suggesting that spatial modulation of astrocytic activity is experience dependent. This is the first indication that astrocytes can encode position related information in learnt spatial contexts, thus broadening their known computational abilities, and their role in cognitive functions. We are continuing to look for higher brain function (now – memory engrams!, another piece of non-published data that I will present) in which astrocytes are involved.