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Visiting Speakers

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Meningeal lymphatic drainage in aging and Alzheimer’s disease

Sandro Da Mesquita, Ph.D. - Department of Neuroscience
Center for Brain Immunology and Glia (BIG)
University of Virginia

 Jan 21, 2020 @ 4:00 p.m.

Under physiological conditions, the brain parenchyma is devoid of lymphatic vasculature. The (re)discovery of lymphatic vessels in the dura of the meninges, with an access to the subarachnoid space, led us to re-evaluate the fluid dynamics and macromolecule drainage mechanisms within the central nervous system (CNS). We have shown that impaired drainage of CSF, induced by interference with meningeal lymphatic structure and function, impacts on brain perivascular macromolecule influx/efflux (glymphatic function), learning and memory in adult and aged mice and modulates amyloid beta (A?) accumulation in the brain of Alzheimer’s disease (AD) transgenic mice. Interestingly, ablation of meningeal lymphatic vessels in AD transgenic mice exacerbated A? pathology not only in the brain parenchyma but also in the meningeal dural layer, both pathological features that closely resemble what is observed in the CNS of AD patients. We now show that increased level and aggregation of A? leads to changes in the transcriptome of mouse meningeal lymphatic endothelial cells (LECs) and morphology of lymphatic vasculature. Using state-of-the-art techniques, such as mass cytometry (CyTOF), we are also further exploring the effect of impaired meningeal lymphatic function and altered meningeal immune response on different aspects of brain cell dysfunction and pathology in models of AD. We also show that altered meningeal lymphatic vessel morphology and drainage capacity affect the efficiency of anti-A? immunotherapy. Altogether, our results highlight the potential therapeutic value of developing new methods to improve meningeal lymphatic drainage and/or modulate meningeal immunity in AD or other aging-associated neurodegenerative conditions.

 Medical Center | K-207 (2-6408)

Host: Dept. Neuroscience Faculty Search Committee

Neutrophil adhesion in brain capillaries contribute to cortical blood flow decrease and impaired memory function in mouse models of Alzheimer’s disease

Oliver Bracko, Ph.D. - Postdoctoral Associate
Meinig School for Biomedical Engineering
Cornell University

 Jan 23, 2020 @ 4:00 p.m.

It has been known for decades that Alzheimer’s Disease (AD) patients and AD mouse models display reduced cerebral blood flow (CBF). Using in vivo two-photon imaging, we recently identified the cellular mechanism that underlies this hypoperfusion. We found that neutrophils transiently adhere to the endothelial cell wall in about 2% of capillaries in the APP/PS1 mouse model of AD, plugging blood flow in those capillary segments (0.4% in wild-type mice). Blocking this adhesion using an antibody against a neutrophil surface protein increased CBF in APP/PS1 mice to near wild-type levels and led to a rapid improvement in cognitive function. The molecular drivers that link amyloid-beta pathology to this capillary plugging remain unknown. Here, we report that inhibiting NOX2-containing NAPDH-oxidase, a reactive oxygen species producing enzyme shown to be activated in APP/PS1 mice, for two weeks with a small peptide, gp91 ds – tat, decreased the fraction of capillaries with stalled blood flow by 67%, increased CBF by 29%, and improved performance on object replacement and y-maze spatial memory tasks. A scrambled version of the peptide inhibitor did not lead to any of these changes. This study implicates the NOX2 pathway as a new molecular mechanism underlying capillary stalling and CBF reductions APP/PS1 mice and could represent a molecular pathway with potential therapeutic opportunities for AD.

 Medical Center | Adolph Auditorium (Lower) 1-7619

Host: Dept. Neuroscience Faculty Search Committee

A Neural Basis for Rhythmic Selective Attention

Ian Fiebelkorn, Ph.D. - Associate Research Scholar
Princeton Neuroscience Institute
Department of Psychology
Princeton University

 Feb 11, 2020 @ 4:00 p.m.

Imagine New York’s Times Square: tall buildings, flashing lights, a swarm of people. The brain has limited processing resources and must therefore rely on filtering mechanisms to effectively navigate such complex scenes. This filtering of the visual environment occurs largely through a combination of two interacting functions: spatial attention (i.e., enhanced sensory processing of relevant locations) and saccades (i.e., exploratory shifts of gaze to relevant locations). A shared network of brain regions, the ‘attention network’, directs both of these functions, prompting the following fundamental question: how does a single network control both the sensory (i.e., spatial attention) and the motor (i.e., saccades) aspects of environmental sampling? In contrast to classic views, which assumed that attention-related sampling is continuous, I will present behavioral and neurophysiological evidence that spatial attention samples the visual environment in rhythmic cycles. I will then synthesize evidence that sensory and motor functions of the attention network are temporally isolated, alternating over time. Finally, I will discuss the implications of such rhythmic coordination on how the brain prioritizes information for processing. The overarching goal of my research is to understand how the brain flexibly allocates its limited processing resources in natural environments to improve behavioral outcomes.

 Medical Center | K-207 (2-6408)

Host: Department of Neuroscience - Faculty Search Committee

Shedding Light on Stimulus Valence

Diego Restrepo, Ph.D. - Univ. of Colorado School of Medicine

 Mar 05, 2020 @ 4:00 p.m.

This seminar will delve on understanding of valence (is the stimulus rewarded?) for the olfactory system – smell. Olfaction is a sensory system that deals with rapid decision-making on the basis of a complex fluctuating multi-dimensional input (the odorant plume). Volatile chemical features are detected by hundreds of olfactory receptors that convey information to the olfactory bulb (OB). A particularly interesting feature of this sensory system is that early processing of the signal on odorant identity in the OB is modified by centrifugal input from downstream brain areas. Here I will first discuss a recent study on circuit oscillations in the OB showing that contextual odorant identity (is the odorant rewarded?) can be decoded from peak theta frequency-referenced gamma frequency bursts of electrical activity in animals proficient in odorant discrimination, but not in naïve mice. Thus, as the animal learns to detect a rewarded odorant in an odorant associative learning task stimulus processing in the OB is altered, resulting in more accurate signal processing for the rewarded odorant, a process analogous to the auditory cocktail party effect (Losacco, Ramirez-Gordillo, et al. 2019, BioRxiv doi: https://doi.org/10.1101/758813). I will then follow with a study of the role of molecular layer interneurons (MLIs) of the cerebellum in ensuring quick decision making in an odorant discrimination task. The cerebellum, a structure classically known for efficient error correction in sensorimotor tasks, has recently been implied in processing reward in associative learning. Using two-photon microscopy and chemogenetics we find that MLIs have a role in learning odorant valence and speedy decision-making in the cerebellum (Ma et al., 2019, BioRxiv https://doi.org/10.1101/2019.12.14.876201). Finally, I will discuss how our multidisciplinary OPeN team is studying the circuit basis of the complex task of odorant plume navigation using custom-made miniature multiphoton miniature fiber coupled microscopes (Ozbay et al., 2018, doi: 10.1038/s41598-018-26326-3).

 Medical Center | K-207 (2-6407)

Host: Univ. Rochester School of Medicine and Dentistry, Dept. Neuroscience, and the Del Monte Institute for Neuroscience

Identifying Neural Signatures of Stress and Anxiety Psychopathologies

Benjamin Suarez-Jimenez, Ph.D. - Assistant Professor
Department of Psychiatry
Columbia University

 Jul 29, 2020 @ 1:30 p.m.

My research lies at the intersection of the behavioral and neural aspects of psychopathology. It is motivated by my desire to find ways in which I can use big data analysis to guide new diagnostic and treatment tools. My research focuses on two areas: 1) developing and validating innovative virtual reality (VR) tasks to study brain networks of complex behavior and 2) using big data sets to study psychopathologies of anxiety and stress. I am committed to developing comprehensive models of mechanisms that link stress and anxiety to chronic disease risk, particularly from a learning and memory perspective. Such assessment is instrumental in identifying when those with severe stress and anxiety deviate from their resilient counterparts with respect to the physiological and behavioral processes that increase the risk of chronic disease. With these novel VR platforms and multiple-level analytical approaches, I aim to guide much-needed ways to advance personalized treatment options for patients.

Host: University of Rochester School of Medicine and Dentistry Department of Neuroscience and the Del Monte Institute for Neuroscience

Toward a Speech Neuroprosthesis

Edward F. Chang, MD - Chair
Department of Neurosurgery
UCSF School of Medicine

 Sep 25, 2020 @ 9:00 a.m.

Dr. Edward Chang, newly appointed Neurosurgery Chair at UCSF, is an internationally renowned surgeon–scientist, who specializes in the treatment of epilepsy, brain tumors, and cranial nerve disorders. A world leader in the evolving field of human brain mapping, Dr. Chang uses sophisticated techniques to preserve critical areas for speech and motor function. His research focuses on the brain mechanisms that underlie the perception and production of speech. With publications in Cell, Science, Nature, Nature Neuroscience and Neuron, Dr. Chang has made fundamental discoveries that provide the basis for the translational development of future speech prosthetic devices.

As co-director of the Center for Neural Engineering and Prostheses, Chang leads a collaboration between scientists at UCSF and the University of California, Berkeley, which is focused upon restoring neurological function in patients with paralysis and speech disorders.

A Howard Hughes Medical Institute Faculty Scholar with over 200 peer-reviewed publications, Dr. Chang’s interests also extend to improving methods of seizure localization and epilepsy treatments, neural circuits of depression and pain and potential targets for therapeutic neurostimulation.

Host: Department of Neurosurgery, 24th Frank P. Smith Visiting Professor

Molecular Mechanisms of Glia-Neuron Interactions

Aakanksha Singhvi, Ph.D. - Assistant Professor
Division of Basic Sciences
Fred Hutchinson Cancer Research Center, Seattle, WA

 Nov 09, 2020 @ 4:00 p.m.

We use our nervous system throughout life to sense the world around us and respond with meaningful behaviors. Enabling this are its two major cell types, neurons and glia, which exist in about equal numbers in the human brain. Constant glia-neuron molecular interactions are critical for nervous system development, function and aging and their impairment correlates with many neurological diseases. However, roles of glia in neural functions remain poorly understood in molecular mechanistic detail. We previously helped establish C. elegans as a powerful experimental platform to molecularly dissect glia-neuron interactions in vivo. This has led us to uncover novel molecular pathways and logic by which glia regulate neuron shape and animal behaviors. This includes our recent discovery that C. elegans glia prune neuron-endings through life, like mammalian glia. Our uncovering the underlying machinery at single glia-neuron resolution led us to find that glia actively direct pruning to control neuron shape and function, and identify the glial molecular rheostat tuning this process. Broad conservation and disease-relevance of all C. elegans glial cues and functions we are uncovering underscores the potential of this genetically tractable model to define glial roles in neural health and disease with exquisite speed and molecular precision.

Host: Neuroscience Graduate Program