Seminar Series

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Roger Nicoll, MD

University of California, San Francisco

Department of Cellular and Molecular Pharmacology

A molecular machine for memory

Monday, September 11, 2023 3:00 PM Hosted by Amy Lee

Roger Nicoll at UCSF ↗

Abstract

CaMKII and long-term potentiation (LTP) were discovered within a decade of each other and have been inextricably intertwined ever since. Francis Crick proposed that a memory molecule should possess two properties. First, it should be a multimeric protein with identical subunits that can phosphorylate each other. Second, to address how memories outlast molecular turnover he proposed that naïve unphosphorylated subunits could exchange into the phosphorylated multimer and become phosphorylated. Within two years CaMKII was shown to satisfy the first property. In my talk I will show that the autophosphorylation of CaMKII, indeed, maintains LTP (memory) by the synaptic capture of AMPA receptors and that this memory survives the protein turnover of CaMKII.

Claudia Lucchinetti, MD

Dean, Dell Medical School, The University of Texas at Austin

Department of Neurology

Multimodal Imaging of Multiple Sclerosis Pathlogy: From Structure to Function

Monday, September 18, 2023 3:00 PM Hosted by Dr. Bob Messing

Lucchinetti, Dell Med Dean ↗

Abstract

Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system, pathologically characterized by focal demyelination, inflammation, scar formation, and variable axonal destruction. Lesion evolution in MS is highly dynamic and not well understood likely contributing to the inability to halt or reverse disease progression. The presence of mitochondrial dysfunction, oxidative injury, and metabolic changes in MS raises the possibility of influencing metal equilibrium and the behavior of vital macromolecules, such as lipids, proteins, nucleic acids, and carbohydrates. This study aims to characterize MS lesion features through a multidisciplinary approach to gain a comprehensive understanding of the disease.

Methods: Human formalin-fixed biopsy and autopsy tissue of MS patients were investigated with immunohistochemistry for the classification of demyelinating pathology. Synchrotron-based X-ray fluorescence (XRF) microscopy was used to map transition metals with high precision, revealing distinct metal distributions among different immunopatterns of MS lesions. Fourier-transformed infrared (FTIR) spectroscopy was employed to investigate alterations in biomolecules within lesions, providing insights into oxidative stress-induced changes in lipids, proteins, and other constituents. We utilized laser capture microdissection and proteomics to interrogate mechanisms that may be driving lesion progression.

Results: XRF microscopy revealed heterogeneous iron accumulation across MS immunopatterns, suggesting diverse disease mechanisms. Early active lesions of immunopattern II display greater iron accumulation compared to immunopattern III, potentially due to variations in macrophage polarization and origin. This study also uncovers the interplay between iron and zinc under hypoxic conditions, linking metal imbalances to HIF-1α expression and astrocyte demise. Iron's role in remyelination is explored, highlighting its potential facilitation through astrocyte-driven iron efflux. However, in an inflammatory context, uncontrolled iron release may exacerbate oxidative damage and neurodegeneration. FTIR spectroscopy revealed MS lesion-specific alterations in lipids and proteins indicative of oxidative damage. These changes include shortened lipid chains, increased unsaturation, and shifts in protein secondary structures. Additional FTIR peaks corresponding to glycogen suggest altered energy metabolism in chronic MS lesions, potentially involving anaerobic pathways. Proteomics analysis of inactive lesions and periplaque white matter identified differentially expressed proteins that may be important in myelination, metabolic function, focal adhesions, and cellular homeostasis.

Conclusion: Overall, these results suggest that the integration of different imaging platforms and region-specific proteome changes can enhance our understanding of the evolution of lesion progression in MS. Iron's dual role as a cofactor and source of oxidative stress underscores its complex contribution to MS pathogenesis. These findings unveil distinct metal distributions among MS immunopatterns, lesion-specific lipid, protein, and energy metabolism alterations, revealing complexities beyond routine histopathology. This comprehensive framework offers valuable insights into MS mechanisms, potentially leading to biomarker discoveries and novel therapeutic interventions.

Erik Jorgensen, PhD

University of Utah, Department of Biomedical Engineering

Howard Hughes Medical Institute

Synaptic Transmission in Time (ms) and in Space (nm)

Monday, September 25, 2023 3:00 PM Hosted by Dr. Jon Pierce

Erik Jorgensen ↗

Abstract

Neurons couple to one another at synapses and can track action potentials firing at 100-1000 times a second. How do synapses fire at these rates with fidelity and at the same time remain robust for high frequency stimulation. To explore membrane dynamics at synapses we are pursuing a forward genetic strategy using the nematode C. elegans and validate our findings in cultured rodent neurons using superresolution fluorescence microscopy, time-resolved electron microscopy and electrophysiology.

Exocytosis. Synaptic vesicles dock and are poised to fuse with the plasma membrane. Fusion is initiated by calcium influx into the synapse. The speed of fusion is maintained by coupling synaptic vesicles to calcium channels at docking sites, so that calcium reaches the fusion site within microseconds.

Endocytosis. Synaptic vesicle proteins and membrane must be recovered after fusing to the synaptic membrane. To capture images of endocytosis in a living organism, we combined optogenetics, high-pressure freezing and electron microscopy. We observed that in mouse neurons membrane is recycled within 50 to 300 milliseconds after stimulation. This novel form of membrane recovery is called ultrafast endocytosis, and it allows the synapses to recover synaptic vesicle components to maintain neurotransmission.

Krešimir Josić, PhD

University of Houston

Department of Mathematics

Plasticity, balance and the structure of neuronal networks

Monday, October 9, 2023 3:00 PM Hosted by Thibaud Taillefumier

Kresimir Josic at UH ↗

Abstract

I will first describe how to extend the theory of balanced networks to account for synaptic plasticity. This theory can be used to show when a plastic network will maintain balance, and when it will be driven into an unbalanced state. I will next discuss how this approach provides evidence for a novel form of rapid compensatory inhibitory plasticity. Experimental evidence for such plasticity comes from optogenetic activation of excitatory neurons in primate visual cortex (area V1) which induces a population-wide dynamic reduction in the strength of neuronal interactions over the timescale of minutes during the awake state, but not during rest. I will shift gears in the final part of the talk, and discuss how community detection algorithms can help uncover the large scale organization of neuronal networks using connectome data.

Kristina Nielsen, PhD

The Johns Hopkins University

Zanvyl Krieger Mind/Brain Institute

Representation of 3D and 2D shape in visual area V4

Monday, October 16, 2023 3:00 PM Hosted by Dr. Nicholas Priebe

Nielsen Lab ↗

Abstract

Shape coding in mid-level visual area V4 has generally been discussed in terms of processing of flat or 2D shapes. Yet, the world around us is 3-dimensional and filled with solid, volumetric objects. In this talk, I will discuss our recent findings that 3D, volumetric shape is robustly represented in V4, showing that this complex tuning property emerges at a much earlier processing stage than commonly assumed. In addition to tuning for 3D shape parameters, we also used 2-photon imaging to demonstrate that preference for 3D or 2D shape is reflected in the micro-organization of V4, with neurons clustering according to their preference for either type of shape. This further highlights the importance of 3D shape encoding in V4, and is an important addition to early shape-processing models that so far have largely focused on 2D pattern processing..

Shantanu Jadhav, PhD

Brandeis University

Department of Psychology

Neural coordination mechanisms for memory-guided behavior

Monday, October 30, 2023 3:00 PM Hosted by Dr. Laura Colgin

Jadhav Lab ↗

Abstract

Our brains are remarkably plastic, giving us the ability to learn from our daily experiences and to use memories of these experiences to guide our behavior. My lab studies coordination of activity in neural circuits distributed across multiple brain regions that enable animals to learn, to store and retrieve memories, and to make decisions. I will present recent findings that elucidate the role of prominent neurophysiological activity patterns in coordinating ensembles of neurons in the hippocampus and prefrontal cortex to support learning and memory-guided decision making. We show that these activity patterns underlie state-dependent coordination of neural ensembles at multiple timescales to mediate memory-guided behavior in rodent spatial memory models. These results suggest a framework in which multiple-timescale mechanisms coordinate cell assemblies for governing cognitive functions and highlight a critical link between neural dynamics and cognition.

Priya Rajasethupathy, MD, PhD

The Rockefeller University

Laboratory of Neural Dynamics and Cognition

Exploring genetic contributions to variation in attention and short-term memory

Monday, November 6, 2023 3:00 PM Hosted by Dr. Lief Fenno

Priya Rajasethupathy at Rockefeller ↗

Abstract

How are transient stimuli converted into lasting internal representations? And are there unique strategies to achieve memory on different time scales. Our lab addresses these questions by bridging functional genomics with systems neuroscience to provide cross-disciplinary insights. On one hand, we perform genetic mapping in outbred mice for unbiased discovery of genes, cell types, and circuits relevant for memory across different time scales. In parallel, we develop and apply methodologies to record and manipulate high resolution neural activity from relevant circuits in the behaving animal. In this talk, I will discuss how these approaches have led to insights into the genetic contributions and long-range circuit dynamics that facilitate both short- and long- term memory.

Gek-Ming Sia, PhD

UT Health San Antonio

Department of Pharmacology

Immune mechanisms that shape brain circuitry in health and disease

Monday, November 27, 2023 3:00 PM Hosted by Dr. Jennifer Donegan

Gek-Ming Sia at UT Health ↗

Abstract

The brain has historically been considered an immune-privileged organ devoid of immune activity. However, there is mounting evidence that the complement cascade of the innate immune system acts through microglia in the brain to selectively prune synapses during brain development and disease. In this talk, I will present two projects from our lab. The first project examines the role of a complement inhibitor in regulating synapse elimination during brain development. The second project examines how chronic stress acts through microglial phagocytosis of synapses to cause synapse loss in the prefrontal cortex and working memory deficits. Taken together, our work shows that immune processes in the brain can directly modify neural circuits and organism behavior through removal of synapses.