Joseph R. Fetcho, Ph.D., Cornell University
Dept. of Neurobiology & Behavior
Ithaca, NY 14853
GRASS FELLOWS IN NEUROSCIENCE:
Timothy Balmer, MS., Georgia State University
PROJECT TITLE: The contribution of perineuronal nets to regulation of neuronal activity
Perineuronal nets (PNNs) are specialized condensations of extracellular matrix that surround the somata of neurons throughout the brain. Because PNNs surround fast-spiking neurons and are highly negatively charged, it has been proposed that they act as a buffering system for cations, supporting fast and precise action potential generation. Electrophysiological recordings paired with enzymatic digestion of PNNs will allow me to test the role of PNNs in supporting fast-spiking and timing accuracy, and buffering potassium ions that contribute to fast repolarization of action potentials. These experiments will identify how PNNs contribute to neuronal function and how PNNs could contribute to pathologies of neuronal activity such as epilepsy.
Diego Bohorquez, Ph.D., Duke University Medical Center
PROJECT TITLE: Function of a gut-brain neural circuit modulating satiety
Our gut is thought to transmit sensory information to the brain through the paracrine action of hormones. This is because enteroendocrine cells, the epithelial sensors of the intestine, are thought to lack synaptic connections with nerves. However, I recently discovered a physical connection between enteroendocrine cells and underlying sensory neurons. This neuro-epithelial junction may constitute the first point of integration between food sensed in the gut and satiety perceived in the brain. Hence, my objective for the Grass Fellowship would be to study the function of this enteroendocrine cell-neuron circuit by documenting its ultrastructure and electrical properties.
Christopher Chen, M.S., Albert Einstein College of Medicine
PROJECT TITLE: Corticothalamic modulation of cerebellar gain
It is well known that attention sharpens and increases sensory perception. Similarly, attention is critical for the completion of complex motor tasks, but the neural mechanisms of this are unknown. In sensory systems, corticothalamic modulation of thalamic activity is a significant substrate for these increases in perception. Comparable circuits also exist in the motor system, suggesting that corticothalamic inputs at the thalamus can increase the gain of motor systems. Moreover, there are significant inputs from the frontal cortex to the origins of these corticothalamic axons, suggesting that executive control areas may exert control over cerebellar outputs at the thalamus. Successful completion of this project will extend attentional mechanisms to the motor system and advance our understanding of corticothalamic modulation of subcortical computations.
Fabio Echeverry, B.Sc., Center of Advanced European Studies and Research
PROJECT TITLE: Physiological Role of cNMP-modulated Channels on Scallop Ciliary Photoreceptors
Ciliary photoreceptors of the scallop (Pecten irradians) respond to light with a hyperpolarization. Patch-clamp studies have shown that intracellular dialysis of cGMP opens light-activated K+ channels. In order to identify the light-activated channel, I have molecularly identified different ion channels that harbor a cyclic-nucleotide binding domain (HCN, CNG and ERG channels), expressing in the ciliary photoreceptors of Pecten. I aim to study the physiological role played by these ion channels in native ciliary photoreceptors of the scallop by using the patch-clamp technique. This approach will help to deeper understand the different photo-transduction pathways present through the ciliary photoreceptor lineage.
Alexander Groh Ph.D., Technical University Munich & Max-Planck Institute of Neurobiology
PROJECT TITLE: The role of electrical synaptic transmission in synchronizing thalamic activity
The role of synchronized activity in the thalamus is crucial to understanding key brain functions such as perception or attentional shifts. How such synchronized activity is influenced by electrical coupling (EC) in thalamic circuits has been only sparsely addressed. Recent evidence for thalamic EC in the intact brain from my own recordings triggered my interest in addressing this issue in a simplified system (brain slices). This allows the application of both electrophysiological and imaging techniques for a systematic assessment of thalamic EC and a putative function of EC in synchronizing thalamo-cortical activity.
Yeowool Huh, Ph.D., University of Science and Technology, South Korea
PROJECT TITLE: Gating of pain pathways by activity-dependent recruitment of inhibitory circuits
The cortex and the thalamus are intricately coordinated to modulate sensory information. All sensory inputs, except for olfaction, are passed through the thalamus and the characteristic ability of thalamic neurons to switch between tonic and firing has been suggested to play a role in sensory modulation before transmitting sensory signals to the cortex. Of the two firing modes, altered burst firing has been repeatedly implicated with pathological pain condition, which suggests that maintaining a certain form of thalamic bursts could be crucial for controlling pain. Moreover, results of a thalamic stimulation study have shown that electrical stimulations mimicking specific elements of the naturally occurring bursts were important in producing an anti-nociceptive effect. It also suggested that the anti-nociceptive effect may occur via the recruitment of cortical inhibitory interneurons, but actual activation of cortical inhibitory neurons or the type of interneurons recruited by specific burst stimulations has not been directly demonstrated. Therefore, the current study proposes to directly investigate the relationship between cortical inhibitory interneuron activity and thalamic burst stimulations utilizing the slice patch recording technique. Results of the proposed study is expected to determine part of the cortical network involved in the action mechanism of nociceptive signal modulation occurring by thalamic burst stimulations and may possibly offer a therapeutic target for pain control.
Reyna I. Martinez-De Luna, Ph.D., SUNY Upstate Medical University
PROJECT TITLE: The role of intermediate filament proteins in neural degeneration and regeneration
The expression of intermediate filament proteins (IFPs) in glial cells has been implicated in the inability of some vertebrates to regenerate the central nervous system. Taking advantage of the ability of Xenopus laevis to regenerate the retina, I will use the XOPNTR transgenic line, a model of rod degeneration and regeneration, to determine the role of IFPs in these two processes. Specifically, I will investigate if the IFPs glial fibrillary acidic protein (GFAP) and Vimentin are important regulators of retinal degeneration and the ability of the Xenopus retina to regenerate. The results of this study will determine if upregulation of GFAP and Vimentin IFPs is required for Müller cell reactivity, retinal degeneration and restricting the regenerative capacity of the retina.
Rebecca Mease, Ph.D., Technical University Munich & Max-Planck Institute of Neurobiology
PROJECT TITLE: A conductance-based model of higher-order thalamic encoding of cortical feedback
Corticothalamic feedback projections in the mammalian brain exert strong control over single thalamic neurons, thereby shaping how information propagates in thalamocortical circuits implicated in sensation and global brain states. In the rodent whisker system, one such pathway is cortical layer 5B (L5B) to posterior medial (POm) thalamus, which can drive spiking in thalamic target neurons and serves to integrate cortical activity with incoming sensory information. Due to the combination of pronounced synaptic depression and intrinsic POm bursting, spike transfer from L5B to POm is highly nonlinear and dependent on past activity. I propose to model this pathway by fitting a detailed model of POm neurons and L5B depressing synapses. The resulting model will be used to investigate thalamic encoding of low- and high- frequency information present in in vivo L5B spike trains.
Benjamin Rost, Ph.D., German Center for Neurodegenerative Diseases, Berlin
PROJECT TITLE: Physiological correlates of fast postsynaptic endocytosis
In hippocampal neurons, long-term depression (LTD) can be induced by prolonged low-frequency stimulation and activation of NMDARs, or activation of metabotropic glutamate receptors. LTD may also be caused by presynaptic transmitter release shortly after a postsynaptic back-propagating action potential that has unblocked synaptic NMDARs (pairing LTD). In consequence, clathrin mediates endocytosis of AMPARs residing outside of the postsynaptic density, on a time-scale of 20 s and longer. Recent experiments using precisely timed optogenetic stimulation and high-pressure freezing followed by electron-microscopy provided evidence for much faster postsynaptic endocytic events. If rapid postsynaptic endocytosis removes AMPARs from the surface it should cause synaptic depression. To test this hypothesis, I will determine the kinetics and the extent of fast AMPAR endocytosis in living neurons. In combination with genetic or pharmacological manipulations, I will then investigate the molecular machinery underlying this novel form of AMPAR surface regulation.
Yuyu Song, Ph.D., HHMI/Yale School of Medicine
PROJECT TITLE: Synaptic Actions of misfolded ALS-associated G*%R-SOD1 protein
Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that affects motor neurons and causes progressive muscle weakness, atrophy and paralysis. The best studied subtype of ALS results from mutations in the SOD1 gene (e.g. G85R), whose protein products are misfolded and may cause dysfunction of neuromuscular junctions (NMJ), loss of synapses, “dying-back” degeneration of axons, and neuronal death. Early changes in NMJ suggest an essential role of synaptic dysfunction in ALS pathology. However, the molecular mechanism for the altered synaptic function in ALS is poorly understood, partially due to the lack of a motor neuron system where acute effects can be studied. Using a unique model of squid giant synapse, I will start to answer questions like whetherG85R-SOD1 directly inhibits synaptic transmission, if so, what is the underlying molecular mechanism? Can we prevent or rescue synaptic dysfunction with chaperones? These approaches will help us understand ALS neuropathology, as well as identify potential therapeutic targets for clinical intervention.
Shigeki Watanabe, Ph.D., University of Utah
PROJECT TITLE: Mechanisms of synaptic plasticity in mouse hippocampal synapses
Use-dependent synaptic potentiation and depression are thought to underlie memory formation in the mammalian brain. One pathway for long-term depression is mediated by calcium influx through NMDA receptors, which triggers AMPA-type glutamate receptor endocytosis. I have developed two techniques in electron microscopy; “Flash-and-freeze” electron microscopy (EM) combines optogenetic neuronal stimulation (“flash”) with rapid, high-pressure freezing (“freeze”) to capture endocytosis on a millisecond timescale; nano-fEM combines super-resolution fluorescence microscopy with EM to visualize fluorescently tagged proteins within their sub-cellular context. Using these techniques, I will test how AMPA receptors are endocytosed from the surface.
Meg Younger, Ph.D., The Rockefeller University
PROJECT TITLE: Processing of human odorants in the mosquito antennal lobe.
Female mosquitoes show intense human host-seeking behavior. Attraction to components of human odor such as lactic acid is enhanced by carbon dioxide (CO2). This sensitization to otherwise unattractive human cues is poorly understood. The aim of my project as a Grass Fellow is to understand how human odor processing occurs downstream of Olfactory Sensory Neurons in the brain of the Dengue fever mosquito, Aedes aegypti.