Seminars

UC Berkeley Molecular & Cell Biology seminar (Division of Genetics, Genomics & Development) by Barak Cohen of Washington University in Saint Louis on massively parallel experimental studies of enhancer function.

Klemens Rottner (Helmholtz Centre for Infection Research, Braunschweig) presents evidence that profilin acts as a master regulator of actin filament dynamics essential for cell migration and growth, controlling both formin- and Arp2/3 complex-dependent actin assembly pathways.

Although stress can be considered as an ongoing process that helps an organism to cope with present and future challenges, when it is too intense or uncontrollable, it can lead to adverse consequences for physical and mental health. Social stress specifically, is a highly prevalent traumatic experience, present in multiple contexts, such as war, bullying and interpersonal violence, and it has been linked with increased risk for major depression and anxiety disorders. Nevertheless, not all individuals exposed to strong stressful events develop psychopathology, with the mechanisms of resilience and vulnerability being still under investigation. During this talk, I will identify key gaps in our knowledge about stress vulnerability and I will present our recent data from our contextual fear learning protocol based on social defeat stress in mice.

Traditionally, touch is associated with exteroception and is rarely considered a relevant sensory cue for controlling movements in space, unlike vision. We developed a technique to isolate and measure tactile involvement in controlling sliding finger movements over a surface. Young adults traced a 2D shape with their index finger under direct or mirror-reversed visual feedback to create a conflict between visual and somatosensory inputs. In this context, increased reliance on somatosensory input compromises movement accuracy. Based on the hypothesis that tactile cues contribute to guiding hand movements when in contact with a surface, we predicted poorer performance when the participants traced with their bare finger compared to when their tactile sensation was dampened by a smooth, rigid finger splint. The results supported this prediction. EEG source analyses revealed smaller current in the source-localized somatosensory cortex during sensory conflict when the finger directly touched the surface. This finding supports the hypothesis that, in response to mirror-reversed visual feedback, the central nervous system selectively gated task-irrelevant somatosensory inputs, thereby mitigating, though not entirely resolving, the visuo-somatosensory conflict. Together, our results emphasize touch’s involvement in movement control over a surface, challenging the notion that vision predominantly governs goal-directed hand or finger movements.

The Nature versus Nurture debate has generally been considered from the lens of genome versus experience dichotomy and has dominated our thinking about behavioral individuality and personality traits. In contrast, the role of nonheritable noise during brain development in behavioral variation is understudied. Using the Drosophila melanogaster visual system, I will discuss our efforts to dissect how individuality in circuit wiring emerges during development, and how that helps generate individual behavioral variation.

Shimon Sakaguchi, Mary E. Brunkow and Fred Ramsdell explain how peripheral immune tolerance prevents the immune system from attacking the body. Sakaguchi follows the identification of regulatory T cells, the CD25 marker, and the relationship between central tolerance and active suppression of self-reactive cells. He considers how changing regulatory T-cell activity could support cancer treatment and transplantation. Brunkow describes genetic investigation of scurfy mice, identification of FOXP3, and the connection between mutations in this gene and human IPEX syndrome. The work establishes a molecular basis for the development and function of regulatory T cells. Ramsdell traces the move from these basic discoveries toward therapeutic strategies, including engineering a patient’s regulatory T cells to target inflammation in rheumatoid arthritis. He discusses early clinical investigation and the ambition of restoring immune balance; these approaches are presented as developing treatments rather than established cures.

Accurate perception of the environment is a constructive process that requires integration of external bottom-up sensory signals with internally-generated top-down information reflecting past experiences and current aims. Decades of work have elucidated how sensory neocortex processes physical stimulus features. In contrast, examining how memory-related-top-down information is encoded and integrated with bottom-up signals has long been challenging. Here, I will discuss our recent work pinpointing the outermost layer 1 of neocortex as a central hotspot for processing of experience-dependent top-down information threat during perception, one of the most fundamentally important forms of sensation.

Thalamic networks, at the core of thalamocortical and thalamosubcortical communications, underlie processes of perception, attention, memory, emotions, and the sleep-wake cycle, and are disrupted in mental disorders, including schizophrenia and autism. However, the underlying mechanisms of pathology are unknown. I will present novel evidence on key organizational principles, structural, and molecular features of thalamocortical networks, as well as critical thalamic pathway interactions that are likely affected in disorders. This data can facilitate modeling typical and abnormal brain function and can provide the foundation to understand heterogeneous disruption of these networks in sleep disorders, attention deficits, and cognitive and affective impairments in schizophrenia and autism, with important implications for the design of targeted therapeutic interventions

The cortex comprises many neuronal types, which can be distinguished by their transcriptomes: the sets of genes they express. Little is known about the in vivo activity of these cell types, particularly as regards the structure of their spike trains, which might provide clues to cortical circuit function. To address this question, we used Neuropixels electrodes to record layer 5 excitatory populations in mouse V1, then transcriptomically identified the recorded cell types. To do so, we performed a subsequent recording of the same cells using 2-photon (2p) calcium imaging, identifying neurons between the two recording modalities by fingerprinting their responses to a “zebra noise” stimulus and estimating the path of the electrode through the 2p stack with a probabilistic method. We then cut brain slices and performed in situ transcriptomics to localize ~300 genes using coppaFISH3d, a new open source method, and aligned the transcriptomic data to the 2p stack. Analysis of the data is ongoing, and suggests substantial differences in spike time coordination between ET and IT neurons, as well as between transcriptomic subtypes of both these excitatory types.

Cellular crosstalk is an essential process during brain development and is influenced by numerous factors, including cell morphology, adhesion, the local extracellular matrix and secreted vesicles. Inspired by mutations associated with neurodevelopmental disorders, we focus on understanding the role of extracellular mechanisms essential for the proper development of the human brain. Therefore, we combine 2D and 3D in vitro human models to better understand the molecular and cellular mechanisms involved in progenitor proliferation and fate, migration and maturation of excitatory and inhibitory neurons during human brain development and tackle the causes of neurodevelopmental disorders.