Past events

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder, which is the most common cause of dementia. Among the key hallmarks of AD are neurofibrillary tangles, abnormal amyloid beta (A) aggregation, neuroinflammation and neuronal loss; altogether manifested in progressive cognitive decline. Numerous attempts were made to arrest or slow disease progression by directly targeting these factors, with a limited successes in having a meaningful effect on cognition. In the recent years, the focus of AD research has been extended towards exploring the local and systemic immune response. Yet, the role of the two main myeloid populations, the central nerve system (CNS) resident immune cells, microglia and blood-borne monocyte-derived macrophages (MDM) remain unclear. In my PhD, together with members of the teams, using behavioral, immunological, biochemical and single-cell resolution molecular techniques, we deciphered the distinct role of microglia and MDM in transgenic mouse models of AD pathology. Using single cell RNA sequencing (scRNA-seq) in 5xFAD amyloidosis mouse model, we have identified a new state of microglia, which we named disease associated microglia (DAM) that were found in close proximity to A plaques. The full activation of these cells was found to be dependent on Triggering receptor expressed on myeloid cells 2 (TREM2), a well-known risk factor in late onset AD. To get an insight to the role of MDM relative to microglia, we used an experimental paradigm of boosting the systemic immunity by modestly blocking the inhibitory immune checkpoint pathway, PD-1/PD-L1, which was previously shown to be beneficial in ameliorating AD in 5xFAD mice, via facilitating homing of MDM to the brain. We found that the same treatment is efficient also in mouse model of tauopathy and that the MDM homing to the brain following the treatment expressed a unique set of scavenger molecules, including macrophage scavenger receptor 1 (MSR1). We found that MDM expressing MSR1 are essential for the disease modification. Using the same immune-modulatory treatment in a mouse model deficient in TREM2 (Trem2-/-5xFAD) and thus in DAM, allowed us to distinguish between the contribution to the disease modification of MDM and DAM. We found, that MDM display a Trem2-independent role in the cognitive improvement. In both Trem2-/-5xFAD and Trem2+/+5xFAD mice the treatment effect on behavior was accompanied by a reduction in the levels of hippocampal water-soluble Aβ1-42, a fraction of A that contains toxic oligomers. In Trem2+/+5xFAD mice, the same treatment seemed to activate additional Trem2-dependent mechanism, that could involve facilitation of removal of Aβ plaques by DAM or by other TREM2-expressing microglia. Collectively, our finding demonstrates the distinct role of activated microglia and MDM in therapeutic mechanism of AD pathology. They also support the approach of empowering the immune system to facilitate MDM mobilization as a common mechanism for treating AD, regardless of primary disease etiology and TREM2 genetic polymorphism.

Positive view of oneself is central for social motivation and emotional well-being. Such views largely depend on the known positive-bias of social feedbacks, as well as on the value one gives to social attributes such as power or affiliation. Diminished positive self views are a common denominator in depression and social anxiety, suggesting a transdiagnostic biomarkers, yet its neural mechanism is unclear. My talk will describe a series of studies using multiscale imaging and behavioral accounts and their modeling to address the interaction between self related cognition, motivation and learning from experience. Zoom link to join- https://weizmann.zoom.us/j/96608033618?pwd=SEdJUkR2ZzRBZ3laUUdGbWR1VFJTdz09 Meeting ID: 966 0803 3618 Password: 564068 Host: Dr. Rita Schmidt rita.schmidt@weizmann.ac.il tel: 9070

We often study plasticity of highly synthetic environments that may not necessarily form the substrate of more realistic conditions. We study sensory systems using both synthetic and more natural forms of plasticity in hope to find common brain mechanisms. On one hand we study perceptual and category learning and on the other hand parental plasticity; both in the auditory and olfactory systems. Using mice we exploit the available experimental toolkit to reveal anatomical, physiological and behavioral manifestation of plasticity in both synthetic and more natural conditions. I will discuss our efforts to study auditory plasticity in the context of mother-infant bonding, an interaction that rapidly develops following parturition. Specifically, I will describe how pup vocalizations are represented in the brain of naïve mice and in mothers, when they first start caring for their newborn pups. I will also share our recent efforts to study perceptual and category learning of synthetic (both simple and complex) environments. Zoom link to join- https://weizmann.zoom.us/j/96608033618?pwd=SEdJUkR2ZzRBZ3laUUdGbWR1VFJTdz09 Meeting ID: 966 0803 3618 Password: 564068 Host: Dr. Rita Schmidt rita.schmidt@weizmann.ac.il tel: 9070

Neural circuits display complex spatiotemporal patterns of activity on the millisecond timescale during behavior. Understanding how these activity patterns drive behavior is a fundamental problem in neuroscience, and remains a major challenge due to the complexity of their spatiotemporal dynamics. The ability to manipulate activity in genetically defined sets of neurons on the millisecond timescale using optogenetics has provided a powerful new tool for making causal links between neuronal activity and behavior. I will discuss novel approaches that combine simultaneous two-photon calcium imaging and two-photon targeted optogenetic photostimulation with the use of a spatial light modulator (SLM) to provide ‘all-optical’ readout and manipulation of the same neurons in vivo. This approach enables reading and writing of activity in neural circuits with single-cell resolution and single action potential precision during behavior. I will describe the power, limitations and future potential of this approach; and discuss how it can be used to address many important problems in neuroscience, including transforming our search for the neural code and the links between neural circuit activity and behavior. Zoom link to join- https://weizmann.zoom.us/j/96608033618?pwd=SEdJUkR2ZzRBZ3laUUdGbWR1VFJTdz09 Meeting ID: 966 0803 3618 Password: 564068 Host: Dr. Rita Schmidt rita.schmidt@weizmann.ac.il tel: 9070