The Ruth K. Broad Foundation Seminar Series on Neurobiology and Disease at Duke University seeks to promote Translational Neuroscience by facilitating the interactions of fundamental and clinical neuroscientists. Translational Neuroscience applies insights gained through fundamental research on brain structure and function to develop novel pharmacological, surgical, and behavioral therapies of these diseases. This seminar series will feature national and international neuroscientists of the highest caliber. Neuroscientists from Duke and other academic institutions, government, and pharmaceutical and biotechnology institutions throughout the region are welcome to attend.
This lectureship series is made possible by the generous support of the Ruth K. and Shepard Broad Biomedical Research Foundation.
Richard W. Tsien
Homeostatically retuning synapses and spikes using “Hebbian” mechanisms
September 22, 2020
Abstract: There is no question that synaptic homeostasis exists and is important to keep circuits in tune in the face of activity deprivation (think stroke) or overactivity (think epilepsy). The prevailing view is that synaptic homeostasis is a slow, negative feedback system, quite distinct from LTP and other forms of Hebbian plasticity. This talk will present provocative data that challenges some of these ideas. We’ll share unpublished evidence that synapses undergo a damped oscillatory response to homeostatic interventions that calls on spine depolarization, voltage-sensitive calcium entry and CaM kinases. The result is a faster, functionally powerful and potentially synapse-specific adjustment in strength. We will segue to a quick overview of a Cell 2020 paper (Li, Suutari et al.) that shows how such synaptic homeostasis lies at the heart of homeostasis of action potential width, once again involving Hebbian players like NMDA receptors. Along the way, we found out how commands to the nuclear machinery originate at the synapse, travel to the nucleus, and alter channel splicing. The overall mechanism is the first full instantiation of the classic negative feedback loop proposed by Marder, Abbott and colleagues a quarter century ago. Each leg of the loop is supported by protein encoded by a neuropsychiatric disease-associated gene.
All-optical interrogation of neural circuits during behaviour
September 29, 2020
Abstract: Understanding the causal relationship between activity patterns in neural circuits and behavior requires the ability to perform rapid and targeted interventions in ongoing neuronal activity. I will describe a novel closed-loop all-optical strategy for dynamically controlling neuronal activity patterns in awake mice. This involves rapid tailoring and delivery of two-photon optogenetic stimulation based on readout of activity using simultaneous two-photon imaging of the same neural population. This closed-loop feedback control can be used to clamp spike rates at pre-defined levels, boost weak sensory-evoked responses, and activate network ensembles based on detected activity. By optically 'yoking together' neighboring neurons, it can also be used to induce long-term changes in network dynamics. This approach thus allows the rate and timing of activity patterns in neural! circuits to be flexibly manipulated ‘on the fly’ during behavior, enabling new approaches for probing the neural code.
Eukaryotic organelles: deciphering their interdependency, structure and dynamics with new imaging technologies
November 3, 2020
Abstract: Powerful new ways to image the internal structures and complex dynamics of cells are revolutionizing cell biology and bio-medical research. In this talk, I will focus on how emerging fluorescent technologies are increasing spatio-temporal resolution dramatically, permitting simultaneous multispectral imaging of multiple cellular components. In addition, results will be discussed from whole cell milling using Focused Ion Beam Electron Microscopy (FIB-SEM), which reconstructs the entire cell volume at 4 voxel resolution. Using these tools, it is now possible to begin constructing an “organelle interactome”, describing the interrelationships of different cellular organelles as they carry out critical functions. The same tools are also revealing new properties of organelles and their trafficking pathways, and how disruptions of their normal functions due to genetic mutations may contribute to important diseases.
Acetylcholine signaling in the basolateral amygdala: influence on emotional behaviors
November 17, 2020
Abstract: Acetylcholine (ACh) signaling is important for optimal cognitive function. Both muscarinic and nicotinic receptor (nAChR) function is essential for cognition, but our work suggests that nAChR signaling is particularly important for adaptive and maladaptive behavioral responses to stress and for linking previously neutral cues to both rewarding and aversive stimuli. In particular, ACh activity in the basolateral amygdala (BLA) is important for both unconditioned and learned responses to stress and reward. However the microcircuits through which ACh mediates these effects are not fully understood. We have used a novel, cell-type selective method to decrease expression of proteins of interest locally in adult mice and to determine the role of nAChRs on specific cell types in stress-related behaviors. In addition to molecular manipulations, we have measured ACh release and circuit activity using in vivo optical recording by fiber photometry. Finally, we have used pharmacology and optogenetic methods to perturb ACh signaling in BLA and link activity to relevant mouse behaviors. Together, these studies show that nAChR signaling at multiple levels of BLA alters behavioral responses to stress and reward, and provides a framework for understanding how ACh signaling contributes to shaping brain responses to emotional stimuli.
Molecular Mechanisms of Neural Circuit Assembly
December 8, 2020
Abstract: The human brain contains ~1011 neurons, making >1014 synaptic connections that enable us to sense, think, remember, and act. How is this vast number of neurons organized into circuits to process information? How are these circuits correctly assembled during development? We use model neural circuits in the less numerically complex brains of the fruit fly (~105 neurons) and mouse (~108 neurons) to address these questions. In this talk, I will discuss our recent work on the assembly of the fly olfactory circuit and mouse hippocampal circuit, using molecular-genetic, transcriptomic, and proteomic approaches.
Population coding in the cerebellum
January 19, 2021
Abstract: How does one organize activities of neurons into populations? In the cerebral cortex, the current approach is to apply techniques that rely on similarity in the activities of the neurons, such as principal component analysis. In the cerebellum, however, it is possible to take a different approach, one that relies on anatomy and requirements of machine learning. Here, I consider the activity of Purkinje cells of the cerebellum in macaques and marmosets during saccadic eye movements. I suggest that Purkinje cells may be organized by the inferior olive into populations that share a preference for error. This error-based organization of cells into a population may describe population coding in the cerebellum.
A role for inflammation and astroglial uncoupling in epileptogenesis
February 2, 2021
Abstract: Antiepileptic therapies mainly target neurons, but most patients with temporal lobe epilepsy (TLE) do not respond adequately to treatments and none of the available drugs cure the disorder. Consequentially, new strategies for the development of antiepileptogenic drugs are needed. In hippocampal tissue from TLE patients with sclerosis (TLE-HS), surviving glia completely lacks gap junction coupling. To decide whether this dysfunction plays a causative role in epileptogenesis we developed an intracortical kainate TLE-HS model, which closely mimics the human pathology. Ipsilaterally, astrocyte coupling was reduced by ~50% immediately after status epilepticus, and completely in the chronic phase. This dysfunction is caused by proinflammatory cytokines and entails extracellular K+ accumulation, neuronal hyperexcitability and epileptogenesis (Bedner et al., Brain 138:1208, 2015). We treated mice with a dominant-negative inhibitor, which binds soluble TNFα and prohibits TNFR1-signalling. Applying this compound prior to kainate injection prevented uncoupling, development of chronic seizures, sclerosis and granule cell dispersion. Treatment with the inhibitor after kainate rescued astrocyte coupling, decreased chronic seizure frequency and attenuated HS-specific morphological alterations. In TNFR1 ko mice, kainate neither induced astrocyte uncoupling nor epileptogenesis. Thus, TNFα mediates astrocyte uncoupling and plays a key role in initiation of TLE-HS. Rescuing astrocyte coupling might represent a new antiepileptogenic strategy.
Pharmacoresistant focal epilepsy: from mechanisms to gene therapy
March 2, 2021
Abstract: Focal (partial-onset) epilepsy often responds poorly to anti-seizure drugs and represents a major unmet need. Of the advanced therapies that have been proposed, gene therapy is arguably closest to the clinic. I shall describe several strategies that have been pursued in my laboratory to achieve constitutive, on-demand or closed-loop suppression of seizure activity in rodent epilepsy models. Some of these strategies build on insights into how inhibitory restraint breaks down in and around seizure foci. I will also consider the path to the first clinical trial scheduled to start in early 2022.
Understanding human brain development and disease: from embryos to organoids
April 27, 2021