All events, All years

Brain-wide networks underlying behavior - Insights from functional ultrasound imaging

Lecture
Date:
Tuesday, November 2, 2021
Hour: 12:30 - 13:30
Location:
Dr. Emilie Macé
|
Max Planck Institute of Neurobiology, Martinsried, Germany

Functional ultrasound imaging (fUS) is an emerging neuroimaging tool capable of measuring brain-wide vascular signals linked to neuronal activity with a high spatial-temporal resolution (100 µm, 10 Hz) in real-time. This technology is portable, affordable and adaptable to many species, and has already found applications in areas ranging from basic research to the clinic. Focusing on fundamental neuroscience, I will outline some of the recent technical advancements of fUS, such as the capacity to image the entire rodent brain while manipulating specific neuronal circuits with optogenetics. I will exemplify how promising this imaging technique is for shedding new light on the brain-wide circuits underlying behavior, as fUS is one of the few methods that enables imaging of activity deep in the brain of behaving mice. Zoom link: https://weizmann.zoom.us/j/95406893197?pwd=REt5L1g3SmprMUhrK3dpUDJVeHlrZz09 Meeting ID: 954 0689 3197 Password: 750421

Nonoscillatory coding and multiscale representation of very large environments in the bat hippocampus by Tamir Eliav and There is Chemistry in Social Chemistry by Inbal Ravreby

Lecture
Date:
Tuesday, October 26, 2021
Hour: 12:30 - 13:30
Location:
Gerhard M.J. Schmidt Lecture Hall
Tamir Eliav, Prof. Nachum Ulanovsky Lab and Inbal Ravreby, Prof. Noam Sobel Lab, Dept of Brain Sciences

Nonoscillatory coding and multiscale representation of very large environments in the bat hippocampus Abstract: The hippocampus plays a key role in memory and navigation, and forms a cognitive map of the world: hippocampal ‘place cells’ encode the animal’s location by activating whenever the animal passes a particular region in the environment (the neuron’s ‘place field’). Over the last 50 years of hippocampal research, almost all studies have focused on rodents as animal models, using small laboratory experimental setups. In my research, I explored hippocampal representations in a naturalistic settings, in a unique animal model – the bat. My talk will outline two main stories: (i) In rodents, hippocampal activity exhibits ‘theta oscillations’. These oscillations were proposed to support multiple functions, including memory and sequence formation. However, absence of clear theta in bats and humans has questioned these proposals. Surprisingly, we found that in bats hippocampal neurons exhibited nonoscillatory phase-coding. This highlights the importance of phase-coding, but not oscillations per se, for hippocampal function across species – including humans. (ii) Real-world navigation requires spatial representation of very large environments. To investigate this, we wirelessly recorded from hippocampal dorsal CA1 neurons of bats flying in a long tunnel (200 meters). Place cells displayed a multifield multiscale code: Individual neurons exhibited multiple place fields of diverse sizes, ranging from 0.6 to 32 meters, and the fields of the same neuron differed up to 20-fold in size. Theoretical analysis showed that the multiscale code allows representing large environments with much better accuracy than other codes. Thus, by increasing the spatial scale, we uncovered a neural code that is radically different from classical spatial codes. Together, these results highlight the power of the comparative approach, and demonstrate that studying the brain under naturalistic settings and behavior enables discovering new unknown aspects of the neural code. There is Chemistry in Social Chemistry Abstract: Non-human terrestrial mammals constantly sniff themselves and each-other, and based on this decide who is friend or foe. Humans also constantly sniff themselves and each-other, but the functional significance of this behavior is unknown. Given that humans seek friends who are similar to themselves, we hypothesized that humans may be smelling themselves and others to subconsciously estimate body-odor similarity, and that this may then promote friendship. To test this hypothesis, we recruited non-romantic same-sex friend dyads who had initially bonded instantaneously, or so called click-friends, and harvested their body-odor. In a series of experiments, we then found that objective ratings obtained with an electronic nose, and subjective ratings obtained from independent human smellers, converged to suggest that click-friends smell more similar to each other than random dyads. To then estimate whether this similarity was merely a consequence of friendship, or a driving force of friendship, we recruited complete strangers, smelled them with an electronic nose, and engaged them in non-verbal same-sex dyadic interactions. Remarkably, we observed that dyads who smelled more similar had better dyadic interactions. In other words, we could predict social bonding with an electronic nose. This result implies that body-odor similarity is a causal factor in social interaction, or in other words, there is indeed chemistry in social chemistry.

Social Behavior in a Social Context: Lessons from Studying Genetic and Neuronal Manipulations affecting Social Behavior in a Complex Environment

Lecture
Date:
Tuesday, October 19, 2021
Hour: 10:00 - 11:00
Location:
Noa Eren (PhD Thesis Defense)
|
Prof. Alon Chen Lab Department of Brain Sciences

As methods for highly specific and precise manipulations of genetics and neuronal activity become the standard in neuroscience, there is growing demand for behavioral paradigms to evolve as well, beyond the simplified and reductive tests which are commonly used. This is especially evident in social behavior, where standard testing paradigms are typically short, involve only a pair of animals, and take place in stimulus-poor environments. Here, we present a series of studies using the Social Box, an experimental setup developed in our lab to automatically track groups of mice living in an enriched environment over days, and extract dozens of behavioral readouts at the individual, dyadic, and group level. We manipulated neuronal populations expressing the socially-relevant neuropeptides oxytocin (OXT) and urocortin3 (UCN3), and utilized genetic mouse models of human disorders affecting sociability – autism spectrum disorder (ASD) and Williams-Beuren Syndrome (WBS) – to demonstrate the importance of the social context in studying mouse behavior. Repeated optogenetic activation of Oxt+ cells recapitulated the known effect of reducing aggressive behavior in the classical resident-intruder paradigm, but in a group of conspecifics it led to an increase in such behaviors on the second day of activation. In parallel, chemogenetic activation of Oxt+ or Ucn3+ cells, separately or together, increased aggressive behavior in the context of a territorial conflict. Finally, behavior of ASD-like mice was mediated by the group composition, such that single-genotype groups showed greater genotype separation in multi-behavioral space than mixed-genotype groups. These findings emphasize the importance of considering contextual and environmental factors when designing and interpreting behavioral studies, which could affect the translatability of findings from mouse to human. Zoom link to join: https://weizmann.zoom.us/j/94822556146?pwd=VnY2eDVGeWdSNmFCVC9zZDVrWUtvUT09 Meeting ID: 948 2255 6146 Password: 884034

To be announced

Lecture
Date:
Tuesday, October 12, 2021
Hour: 12:30
Location:
Gerhard M.J. Schmidt Lecture Hall
Tamir Eliav / Inbal Ravreby
|
Dept of Neurobiology, WIS

Time and experience dependent evolution of hippocampal memory codes

Lecture
Date:
Monday, October 11, 2021
Hour: 13:30 - 14:30
Location:
Nitzan Geva (PhD Defense)
|
Dr. Yaniv Ziv Lab, Dept of Brain Sciences

Hippocampal place cells fire in a spatially selective manner and are thought to support the formation of a cognitive-map that allows the association of an event to its spatial context. It has long been thought that within familiar spatial contexts, such cognitive maps should be stable over time, and that individual place cells should retain their firing properties. However, recent findings have demonstrated that hippocampal spatial codes gradually change over timescales of minutes to weeks. These finding raised several fundamental questions: What are the contributions of the passage of the time and the amount of experience to the observed drift in hippocampal ensemble activity? To what extent are different aspect of place code stability affected by time and experience? To address these questions, I conducted a series of Ca2+ imaging experiments in which mice repeatedly explored familiar environments. Different environments were visited at different intervals, which allowed distinguishing between the contribution of time and experience to code stability. I found that time and experience differentially affected distinct aspects of hippocampal place codes: changes in activity rates were mostly affected by time, whereas changes in spatial tuning was mostly affected by experience. These findings suggest that different biological mechanisms underlie different aspects of representational drift in the hippocampus. These findings add to the growing body of research suggesting that representational drift is an inherent property of neural networks in vivo, and point to the different candidate mechanisms that could underlie this drift. https://weizmann.zoom.us/j/98861083979?pwd=Q1FmbDBYNHR2QnNKSUNpeHlLdm94dz09 Meeting ID: 988 6108 3979 Password: 682422

Episodic Memory from First Principles

Lecture
Date:
Thursday, October 7, 2021
Hour: 14:00 - 15:00
Location:
Michelangelo Naim (PhD Oral Defense)
|
Prof. Misha Tsodyks Lab Dept of Neurobiology

Our everyday conscious memories are an intricate network of images and associations, constituting a record of our personal experiences that is continuously updated through an active organization of new information within the context of previous experience. Recollection is similarly recreative, and the course of remembering is determined by the nature of our memory organization. This type of memory is called episodic memory, and is therefore a multifaceted process involving a synthesis of episodic representations with our framework of general semantic knowledge that mediates our capacity for recollection. It is therefore typically considered to be too complex to be described by physics-style universal mathematical laws. In this thesis we characterize some of the processes governing episodic recall and point out the basic principles behind them. More specifically, we propose a search process governing recall of unconnected events, mathematically computed recall capacity and tested the resulting relationship in dedicated experiments. Next, we proposed how structured information may be encoded in the human brain and compared model predictions with available experimental data. In both cases experimental data were consistent with proposed mechanisms. Since time is an essential part of episodic memory we also studied the interaction between absolute and ordinal time representation in the brain. We found that ordinal information take precedence in the inference about absolute event times. Overall, the results presented in this thesis opens opportunity that complicated cognitive processes can be described by universal mathematical laws. Zoom link to join: https://weizmann.zoom.us/j/99774936375?pwd=QUhMTG56UkJkd3l1bUJ1ZDhhTTlEUT09 Meeting ID: 997 7493 6375 Password: 402616

To be announced

Lecture
Date:
Tuesday, October 5, 2021
Hour: 12:30
Location:
Matteo Carandini
|
UCL

To be announced

Lecture
Date:
Tuesday, October 5, 2021
Hour: 12:30
Location:
Matteo Carandini
|
UCL

Merging of cues and hunches by the mouse cortex

Lecture
Date:
Tuesday, October 5, 2021
Hour: 12:30 - 13:00
Location:
Prof. Matteo Carandini
|
University College London

Everyday decisions are often based on both external cues and internal hunches. How does the brain put these together? We addressed this question in mice trained to make decisions based on combinations of sensory cues and history of reward value or probability. While mice made these decisions, we recorded from thousands of neurons throughout the brain and causally probed the roles of cortical areas. The results are not what we thought based on textbook notions of how the brain works. This talk is based on work led by Nick Steinmetz, Peter Zatka-Haas, Armin Lak, and Pip Coen, in the laboratory I share with Kenneth Harris. Zoom link: https://weizmann.zoom.us/j/95406893197?pwd=REt5L1g3SmprMUhrK3dpUDJVeHlrZz09 Meeting ID: 954 0689 3197 Password: 750421

Deciphering the role of brain- resident and infiltrating myeloid cells in Alzheimer’s disease

Lecture
Date:
Sunday, September 19, 2021
Hour: 14:00 - 15:30
Location:
Raz Dvir-Szternfeld (PhD Thesis Defense)
|
Prof. Michal Schwartz Lab, Dept of Neurobiology and Prof. Ido Amit Lab, Dept of Immunology, WIS

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.

Pages

All events, All years

Brain-wide networks underlying behavior - Insights from functional ultrasound imaging

Lecture
Date:
Tuesday, November 2, 2021
Hour: 12:30 - 13:30
Location:
Dr. Emilie Macé
|
Max Planck Institute of Neurobiology, Martinsried, Germany

Functional ultrasound imaging (fUS) is an emerging neuroimaging tool capable of measuring brain-wide vascular signals linked to neuronal activity with a high spatial-temporal resolution (100 µm, 10 Hz) in real-time. This technology is portable, affordable and adaptable to many species, and has already found applications in areas ranging from basic research to the clinic. Focusing on fundamental neuroscience, I will outline some of the recent technical advancements of fUS, such as the capacity to image the entire rodent brain while manipulating specific neuronal circuits with optogenetics. I will exemplify how promising this imaging technique is for shedding new light on the brain-wide circuits underlying behavior, as fUS is one of the few methods that enables imaging of activity deep in the brain of behaving mice. Zoom link: https://weizmann.zoom.us/j/95406893197?pwd=REt5L1g3SmprMUhrK3dpUDJVeHlrZz09 Meeting ID: 954 0689 3197 Password: 750421

Nonoscillatory coding and multiscale representation of very large environments in the bat hippocampus by Tamir Eliav and There is Chemistry in Social Chemistry by Inbal Ravreby

Lecture
Date:
Tuesday, October 26, 2021
Hour: 12:30 - 13:30
Location:
Gerhard M.J. Schmidt Lecture Hall
Tamir Eliav, Prof. Nachum Ulanovsky Lab and Inbal Ravreby, Prof. Noam Sobel Lab, Dept of Brain Sciences

Nonoscillatory coding and multiscale representation of very large environments in the bat hippocampus Abstract: The hippocampus plays a key role in memory and navigation, and forms a cognitive map of the world: hippocampal ‘place cells’ encode the animal’s location by activating whenever the animal passes a particular region in the environment (the neuron’s ‘place field’). Over the last 50 years of hippocampal research, almost all studies have focused on rodents as animal models, using small laboratory experimental setups. In my research, I explored hippocampal representations in a naturalistic settings, in a unique animal model – the bat. My talk will outline two main stories: (i) In rodents, hippocampal activity exhibits ‘theta oscillations’. These oscillations were proposed to support multiple functions, including memory and sequence formation. However, absence of clear theta in bats and humans has questioned these proposals. Surprisingly, we found that in bats hippocampal neurons exhibited nonoscillatory phase-coding. This highlights the importance of phase-coding, but not oscillations per se, for hippocampal function across species – including humans. (ii) Real-world navigation requires spatial representation of very large environments. To investigate this, we wirelessly recorded from hippocampal dorsal CA1 neurons of bats flying in a long tunnel (200 meters). Place cells displayed a multifield multiscale code: Individual neurons exhibited multiple place fields of diverse sizes, ranging from 0.6 to 32 meters, and the fields of the same neuron differed up to 20-fold in size. Theoretical analysis showed that the multiscale code allows representing large environments with much better accuracy than other codes. Thus, by increasing the spatial scale, we uncovered a neural code that is radically different from classical spatial codes. Together, these results highlight the power of the comparative approach, and demonstrate that studying the brain under naturalistic settings and behavior enables discovering new unknown aspects of the neural code. There is Chemistry in Social Chemistry Abstract: Non-human terrestrial mammals constantly sniff themselves and each-other, and based on this decide who is friend or foe. Humans also constantly sniff themselves and each-other, but the functional significance of this behavior is unknown. Given that humans seek friends who are similar to themselves, we hypothesized that humans may be smelling themselves and others to subconsciously estimate body-odor similarity, and that this may then promote friendship. To test this hypothesis, we recruited non-romantic same-sex friend dyads who had initially bonded instantaneously, or so called click-friends, and harvested their body-odor. In a series of experiments, we then found that objective ratings obtained with an electronic nose, and subjective ratings obtained from independent human smellers, converged to suggest that click-friends smell more similar to each other than random dyads. To then estimate whether this similarity was merely a consequence of friendship, or a driving force of friendship, we recruited complete strangers, smelled them with an electronic nose, and engaged them in non-verbal same-sex dyadic interactions. Remarkably, we observed that dyads who smelled more similar had better dyadic interactions. In other words, we could predict social bonding with an electronic nose. This result implies that body-odor similarity is a causal factor in social interaction, or in other words, there is indeed chemistry in social chemistry.

Social Behavior in a Social Context: Lessons from Studying Genetic and Neuronal Manipulations affecting Social Behavior in a Complex Environment

Lecture
Date:
Tuesday, October 19, 2021
Hour: 10:00 - 11:00
Location:
Noa Eren (PhD Thesis Defense)
|
Prof. Alon Chen Lab Department of Brain Sciences

As methods for highly specific and precise manipulations of genetics and neuronal activity become the standard in neuroscience, there is growing demand for behavioral paradigms to evolve as well, beyond the simplified and reductive tests which are commonly used. This is especially evident in social behavior, where standard testing paradigms are typically short, involve only a pair of animals, and take place in stimulus-poor environments. Here, we present a series of studies using the Social Box, an experimental setup developed in our lab to automatically track groups of mice living in an enriched environment over days, and extract dozens of behavioral readouts at the individual, dyadic, and group level. We manipulated neuronal populations expressing the socially-relevant neuropeptides oxytocin (OXT) and urocortin3 (UCN3), and utilized genetic mouse models of human disorders affecting sociability – autism spectrum disorder (ASD) and Williams-Beuren Syndrome (WBS) – to demonstrate the importance of the social context in studying mouse behavior. Repeated optogenetic activation of Oxt+ cells recapitulated the known effect of reducing aggressive behavior in the classical resident-intruder paradigm, but in a group of conspecifics it led to an increase in such behaviors on the second day of activation. In parallel, chemogenetic activation of Oxt+ or Ucn3+ cells, separately or together, increased aggressive behavior in the context of a territorial conflict. Finally, behavior of ASD-like mice was mediated by the group composition, such that single-genotype groups showed greater genotype separation in multi-behavioral space than mixed-genotype groups. These findings emphasize the importance of considering contextual and environmental factors when designing and interpreting behavioral studies, which could affect the translatability of findings from mouse to human. Zoom link to join: https://weizmann.zoom.us/j/94822556146?pwd=VnY2eDVGeWdSNmFCVC9zZDVrWUtvUT09 Meeting ID: 948 2255 6146 Password: 884034

To be announced

Lecture
Date:
Tuesday, October 12, 2021
Hour: 12:30
Location:
Gerhard M.J. Schmidt Lecture Hall
Tamir Eliav / Inbal Ravreby
|
Dept of Neurobiology, WIS

Time and experience dependent evolution of hippocampal memory codes

Lecture
Date:
Monday, October 11, 2021
Hour: 13:30 - 14:30
Location:
Nitzan Geva (PhD Defense)
|
Dr. Yaniv Ziv Lab, Dept of Brain Sciences

Hippocampal place cells fire in a spatially selective manner and are thought to support the formation of a cognitive-map that allows the association of an event to its spatial context. It has long been thought that within familiar spatial contexts, such cognitive maps should be stable over time, and that individual place cells should retain their firing properties. However, recent findings have demonstrated that hippocampal spatial codes gradually change over timescales of minutes to weeks. These finding raised several fundamental questions: What are the contributions of the passage of the time and the amount of experience to the observed drift in hippocampal ensemble activity? To what extent are different aspect of place code stability affected by time and experience? To address these questions, I conducted a series of Ca2+ imaging experiments in which mice repeatedly explored familiar environments. Different environments were visited at different intervals, which allowed distinguishing between the contribution of time and experience to code stability. I found that time and experience differentially affected distinct aspects of hippocampal place codes: changes in activity rates were mostly affected by time, whereas changes in spatial tuning was mostly affected by experience. These findings suggest that different biological mechanisms underlie different aspects of representational drift in the hippocampus. These findings add to the growing body of research suggesting that representational drift is an inherent property of neural networks in vivo, and point to the different candidate mechanisms that could underlie this drift. https://weizmann.zoom.us/j/98861083979?pwd=Q1FmbDBYNHR2QnNKSUNpeHlLdm94dz09 Meeting ID: 988 6108 3979 Password: 682422

Episodic Memory from First Principles

Lecture
Date:
Thursday, October 7, 2021
Hour: 14:00 - 15:00
Location:
Michelangelo Naim (PhD Oral Defense)
|
Prof. Misha Tsodyks Lab Dept of Neurobiology

Our everyday conscious memories are an intricate network of images and associations, constituting a record of our personal experiences that is continuously updated through an active organization of new information within the context of previous experience. Recollection is similarly recreative, and the course of remembering is determined by the nature of our memory organization. This type of memory is called episodic memory, and is therefore a multifaceted process involving a synthesis of episodic representations with our framework of general semantic knowledge that mediates our capacity for recollection. It is therefore typically considered to be too complex to be described by physics-style universal mathematical laws. In this thesis we characterize some of the processes governing episodic recall and point out the basic principles behind them. More specifically, we propose a search process governing recall of unconnected events, mathematically computed recall capacity and tested the resulting relationship in dedicated experiments. Next, we proposed how structured information may be encoded in the human brain and compared model predictions with available experimental data. In both cases experimental data were consistent with proposed mechanisms. Since time is an essential part of episodic memory we also studied the interaction between absolute and ordinal time representation in the brain. We found that ordinal information take precedence in the inference about absolute event times. Overall, the results presented in this thesis opens opportunity that complicated cognitive processes can be described by universal mathematical laws. Zoom link to join: https://weizmann.zoom.us/j/99774936375?pwd=QUhMTG56UkJkd3l1bUJ1ZDhhTTlEUT09 Meeting ID: 997 7493 6375 Password: 402616

To be announced

Lecture
Date:
Tuesday, October 5, 2021
Hour: 12:30
Location:
Matteo Carandini
|
UCL

To be announced

Lecture
Date:
Tuesday, October 5, 2021
Hour: 12:30
Location:
Matteo Carandini
|
UCL

Merging of cues and hunches by the mouse cortex

Lecture
Date:
Tuesday, October 5, 2021
Hour: 12:30 - 13:00
Location:
Prof. Matteo Carandini
|
University College London

Everyday decisions are often based on both external cues and internal hunches. How does the brain put these together? We addressed this question in mice trained to make decisions based on combinations of sensory cues and history of reward value or probability. While mice made these decisions, we recorded from thousands of neurons throughout the brain and causally probed the roles of cortical areas. The results are not what we thought based on textbook notions of how the brain works. This talk is based on work led by Nick Steinmetz, Peter Zatka-Haas, Armin Lak, and Pip Coen, in the laboratory I share with Kenneth Harris. Zoom link: https://weizmann.zoom.us/j/95406893197?pwd=REt5L1g3SmprMUhrK3dpUDJVeHlrZz09 Meeting ID: 954 0689 3197 Password: 750421

Deciphering the role of brain- resident and infiltrating myeloid cells in Alzheimer’s disease

Lecture
Date:
Sunday, September 19, 2021
Hour: 14:00 - 15:30
Location:
Raz Dvir-Szternfeld (PhD Thesis Defense)
|
Prof. Michal Schwartz Lab, Dept of Neurobiology and Prof. Ido Amit Lab, Dept of Immunology, WIS

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.

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Memory In The Brain: From Learning To Forgetting

Conference
Date:
Tuesday, June 11, 2019
Hour: 08:30 - 18:00
Location:
David Lopatie Conference Centre

Homepage

Prof. Itzchak Steinberg Memorial Symposium

Conference
Date:
Monday, March 26, 2018
Hour: 08:00
Location:
Dolfi and Lola Ebner Auditorium

Windows to the Brain: Advances in Optical Imaging for Understanding Neural Circuit Function

Conference
Date:
Tuesday, January 16, 2018
Hour: 08:30 - 17:30
Location:
David Lopatie Conference Centre

From perception to action: imaging human brain function

Conference
Date:
Sunday, December 24, 2017
Hour: 08:30 - 13:30
Location:
David Lopatie Conference Centre

Homepage

Prefrontal mechanisms of cognitive control

Conference
Date:
Wednesday, May 20, 2015
Hour:
Location:
Arthur and Rochelle Belfer Building for Biomedical Research

Homepage

Challenges in the frontiers of brain and cognition research

Conference
Date:
Monday, February 9, 2015
Hour:
Location:
David Lopatie Conference Centre

Homepage

Engineering the Brain

Conference
Date:
Wednesday, February 4, 2015
Hour: 09:00 - 14:00
Location:
David Lopatie Conference Centre

Engineering the Brain

Conference
Date:
Wednesday, February 4, 2015
Hour: 09:00 - 14:00
Location:
David Lopatie Conference Centre

Advances in Brain Sciences: RIKEN BSI and WIS Workshop

Conference
Date:
Wednesday, January 21, 2015
Hour:
Location:
Dolfi and Lola Ebner Auditorium

Homepage

Challenges and Debates at the Frontiers of Brain&Cognition

Conference
Date:
Wednesday, December 25, 2013
Hour: 08:00 - 17:00
Location:
David Lopatie Conference Centre

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