If Only Viruses Weren’t so Virulent

Viruses are microscopic (non-living) infectious agents with a some-what terrifying potential to invade our nervous system. In fact, there are likely thousands of latent viral particles lying dormant in your body as you read this blog post, but don’t worry! Fortuitously, viruses such as John Cunningham virus, which infects 70 -90% of the human population, only becomes pathological when it is reactivated during immunodeficiency of immunosuppression. At some point or another, we have all likely been infected with a virus via inhalation, ingestion, an insect bite, or by other means. Evolutionarily, our bodies have developed many protective methods to keep these foreign invaders out of our delicate nervous system. Primarily, the blood brain and blood cerebrospinal fluid barriers, prevent large molecules from invading the brain. Unfortunately, viruses have developed several ways to circumvent these CNS barriers. Viruses can infect vascular endothelial cells and directly cross the blood brain barrier. They also enter the brain through the choroid plexus or circumventricular organs, which lack blood brain barriers. Viruses, such as polio and rabies virus, even migrate from infected peripheral nerves or infect exposed olfactory dendrites to enter the brain. Sadly, infants are the most susceptible to viral infections of the nervous system due to greater proliferation of viral particles as cells differentiate and migrate across the parenchyma during development.

So what do viruses do? CNS viruses can infect neurons in the spinal cord (myelitis), meninges (meningitis), parenchyma (encephalitis) or both (meningoencephalitis). Once inside, viruses hijack the molecular machinery of infected cells, replicating and assembling new viral particles. This process inevitably destroys the host cell but not before the virus has self-assembled enough new particles to infect more living tissue and continue its path of destruction1.1-s2.0-S1879625715000115-gr3

If CNS barriers fail to keep viruses out of the brain, the body mounts a rapid inflammatory response to combat the infection.

 

 

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Microglia, macrophages, lymphocytes (as seen here) and dendritic cells are recruited to the site of injury to clear away dead tissue and remove viral particles.

 

 

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However, some viruses, such as lymphocytic choriomeningitis virus (LCMV), have found ways to become invisible to the body’s innate immune response system.

 

In a recent paper from the McGavern lab at the National Institutes of Health, genetically modified mice were infected with noncytopathic LCMV in order to elucidate innate immune activity in response to CNS viral infection. They utilized microarray analysis of gene regulation and 2-phton imaging to investigate the progression and effects of LCMV. Surprisingly, they found that the production of type 1 interferons (IFN-1) are an essential element in combating viral infection. IFN-1s are part of a non-redundant signaling pathway that induces a protective inflammatory response including activation of microglia and recruitment to the vasculature to clear viral agents2.

Microglia (green) surrounding blood vessel (blue) and astrocytes (red).

IFN-1 signaling is an incredibly important process in fighting viral infection. It is the single orchestrator of innate immune gene expression and there is no redundant mechanism to mount an alternative counter-response. Without the activity of IFN-1, viruses such as LCMV can run rampant in the nervous system, spreading from the meninges to parenchymal astrocytes and oligodendrocytes. Current research is uncovering what neurotropic viruses are affected by IFN-1 signaling. This research has the potential to facilitate the development of therapeutics to modulate anti-viral immunity in the CNS.

To learn more about the nature of viruses and their effect on the global community, come hear Axel Nimmerjahn speak at the CNBC, Tuesday, May 19th at 4:00 pm.

 

  1. Swanson, P. A. 2nd and McGavern D. B. (2015). Viral Diseases of the Central Nervous SystemCurrent Opinion Virology,11;11C:44-45
  2. Nayak, D., Johnson, K. R., Heydari, S., Roth, T. L., Zinselmeyer, B. H., & McGavern, D. B. (2013). Type I Interferon Programs Innate Myeloid Dynamics and Gene Expression in the Virally Infected Nervous System. PLoS Pathogens, 9(5), e1003395.

 

Bankole Aladesuyi is a first-year Neurosciences student currently rotating with Dr. Tom Hnasko. Although a little less worried about common viruses like LCMV, in his spare time he tirelessly labors to find a vaccine for the rare zombies virus.

The Magic School Bus, Tumbleweeds, and Neurodegeneration

With an aging population, the topic of neurodegeneration – in its myriad forms – has quickly come to the fore. These are diseases that have diverse symptoms such as memory loss, confusion, and loss of motor function but only reach a common ground in that they are progressive, terminal, and currently have no cure.

Though if you were able to shrink yourself down, Magic School Bus style, and travel into the brains of these affected individuals you may be surprised by what you see. Splashing along the ventricular river, you float about in the lateral ventricles, before scooching through the foramen of Monro, and sloshing through the cerebral aqueduct. Alright. Recess is over. Let’s see what’s going on here!038976160282_1 (1)

You shoot out of the ventricles into intercellular space. Before you, cells loom like whales in a dark ocean. You see glia wrapping themselves around telephone-pole-sized axons that zig and zag in all directions. Dendrites branch and branch in fractal-like perpetuity. Onto the basal ganglia! The cells here are packed close together. You put on special glasses so you can see them communicating with one another (patent pending). Your face is glued to the window. You are looking aghast at the beauty of this intricate system, when you hear Ms. Frizzle (still single, though definitely available) gasp.

“Would you look at that?”

The whole class crams over to one side of the bus. Inside of one of these beautiful, Moby Dick-sized cells you see what looks, for all the world, like a tumbleweed (but those wordy scientists like to refer to them as neur-o-fib-ril-lary tangles). You’re not sure what it’s doing (that’s okay, neither are most researchers!), but it is clear it is not supposed to be there.

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You take the express route out of this patient’s brain, through the Olfactory tract, past dendrites sticking their legs through the epithelium in the nose just to make contact with pinballing particles floating about. This patient has Parkinson’s disease. Maybe this was a one-time thing. He happened to eat some particularly nasty supermarket sushi and got stuck with tumbleweeds in his brain. That’s plausible, right?

Another day, another patient, another field trip. This one with fronto-temporal dementia. This time you take a circuitous and bumpy route up gyri and down sulci, across fissures, decussating, and re-decussating until you reach your destination. This time you gasp. Those beautiful pyramidal cells with their apical dendrites protruding like antennae, and their prominent somas looking like a giant heart, are filled with tumbleweeds. Ms. Fizzle sighs a long unrelated sigh. She has been persistently trying to record a Snapchat to her newest date, however it seems no one has any good ideas on how to record in the frontal lobe.

Day three of this trilogy of field trips. You were promised a roller coaster. Tintinnabulating off the tympanic membrane, you loop-d-loop around the cochlea, hop-scotch across the basilar membranes, corkscrew up tracts, and nose-dive until you come to the main event: that loop within a loop, the hippocampus. Racing along the cell layer in CA3 you hear a screeching sound. The bus is slowing down. It’s not going to make it! You look out the window and there they are again. Those tumbleweeds, infesting everything.

Ms. Fizzle was “out sick” today (read: her date went well) and you have an incredibly overqualified substitute teacher. Dr. Mel Feany of Harvard University. You ask, “Dr. Feany, we’ve been in three brains of three patients with very different diseases, but every time we’ve seen these tumbleweeds. What are they and how are they messing everything up?”

She looks at you with a coy smile and says:

Come to my talk entitled, Genetic Analysis of Neurodegeneration at 4:00PM in CNCB Marilyn Farquhar Seminar Room and I’ll set you straight. For surely, you don’t know the half of it!”

——-

the IT paper to read by Doctor Feany:

“Tau Promotes Neurodegeneration through Global Chromatin Relaxation”

Image Sources:

http://eshop.me100fun.com.hk/the-magic-school-bus-brain-station.html (Magic School Bus)

adaptation of image from: http://www.brightfocus.org/alzheimers/about/understanding/plaques-and-tangles.html

——-

This blog post was brought to you by Sage Aronson, a First-Year Graduate Student in the Neurosciences Program at UCSD. An avid lover of wool socks, things with two wheels, and guacamole — Sage has recently joined the lab of Roberto Malinow and is currently interested in electrophysiology and shining lights into brains.

Hippocampal-cortical interactions underlie memory consolidation

“We have, each of us, a life-story, an inner narrative whose continuity, whose sense, is, our lives. It might be said that each of us constructs and lives, a ‘narrative’, and that this narrative is us, our identities … to be ourselves, we must have ourselves … we must recollect ourselves …”

Oliver Sacks, who authored this quote, is a neurologist well known for his compelling essays about his case studies (excerpt from “A matter of identity” in The Man who mistook his wife for a hat, p.105). Here, he is reflecting on his patient Mr. Thompson, who suffers from severe Korsakoff’s syndrome. Anterograde amnesia is a major symptom of Korsakoff’s that prevents Mr. Thompson from forming new memories. Interestingly, Mr. Thompson continually fabricates seemingly genuine memories when talking to others, in an apparent attempt to replace the narrative that he has lost since he obtained amnesia. While reading about Mr. Thompson desperately trying to make sense of his life, the importance of a functional memory in going about our lives is painfully appreciated. Fortunately, labs across the world are researching to understand the mechanics of memory and how it catastrophically fails. Recent insights have come from the lab of Lila Davachi, the upcoming seminar speaker for UCSD neuroscience.

Memory is often understood as having three principal underlying processes: encoding, consolidation, and retrieval. In terms of anterograde amnesia, the pathology may arise from deficits in any of these three processes. First, perceptions must be encoded into the brain as a construct that can be efficiently accessed and computed on. For long-term function, the memories must be consolidated by stabilizing its neural representation, so that the past information can later be recalled (retrieval). A prevalent theory is that memory consolidation occurs as the neocortex and hippocampus communicate in order to establish a hippocampal-independent representation of the thing to be remembered. This idea is well supported, including recent work showing that disruption of hippocampal reactivation during slow wave sleep impairs subsequent memory performance (Girardeau et al, 2009).

Earlier this decade, Lila Davachi’s lab enhanced our knowledge of memory consolidation in humans (Tambini, Ketz, & Davachi, 2010). Using functional magnetic resonance imaging (fMRI), they were able to quantify the interactions between different brain regions by correlating the recorded blood-oxygen-level dependent (BOLD) signals between defined regions of interest (see Figure 1 below). Interestingly, specific cortico-cortical and hippocampal-cortical interactions were predictive of future memory performance.

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Figure 1. During and after an object-face association task, there was an increased correlation between the BOLD responses in the fusiform face area and the lateral occipital complex. (Figure 2A in Tambini, Ketz, & Davachi)

While in the scanner, subjects completed 2 different tasks, which both began and ended with a resting period for potential consolidation. In the first task, the subjects observed object-face pairs, while the second task contained several examples of scenes associated with faces. Importantly, subjects’ performance on subsequent memory tests were significantly different: object-face pairs were recalled more reliably than the scene-face pairs. This is because the scenes are less “distinct” from one another than pairs of objects, and so it is more difficult to make separable associations (to consolidate!).

This contrast in performance is related to the discrepancy in cortico-cortical interactions during the rest periods after each task. After the object-face (OF) association task, the cortical face region (fusiform face area, FFA) and the cortical object region (lateral occipital complex, LO) maintained higher functional connectivity (see Figure 2 below). However, this was not the case after the scene-face (SF) association task, as the correlation between the FFA and the cortical region for scenes (parahippocampal face area, PPA) was unchanged from baseline rest conditions.

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Figure 2. Functional connectivity between relevant cortical regions was increased after the object-face association task, but not the scene-face association task. (Figure 2D in Tambini, Ketz, & Davachi)

 

Tambini, Ketz, and Davachi also quantified functional connectivity between the hippocampus and cortex. They found that the these interactions were also increased only for the rest period immediately following the object-face association task. Together with the behavioral results, these findings support the previously mentioned theory that hippocampal-cortical interactions underlie memory consolidation.

The cross-subject relationship between this functional hippocampal-cortical connectivity and subsequent memory performance is the most exciting finding of this paper. As seen in Figure 3 below, subjects with higher hippocampal-LO correlations following a task tended to retain those memories better.

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Figure 3. Differences among individuals in their subsequent memory performance can be explained by the degree of hippocampal-cortical interactions during the post-task rest period. (Figure 3D in Tambini, Ketz, & Davachi)

 

It is possible that active rehearsal by the subjects could confound the observed effect. Rehearsal would suggest correlations between the prefrontal cortex and the lateral occipital cortex. However, this correlation did not carry information about subsequent memory performance, so rehearsal was likely not confounding.

This is the first time that hippocampal-cortical interactions have been directly implicated in enhancing long-term memory consolidation. Additionally, this study is groundbreaking in that it demonstrates memory consolidation improvements in an awake rest period, as prior studies had only proven this association during sleep periods. Hippocampal-cortical and cortico-cortical correlations had been seen in human resting-state fMRI, but their behavioral relevance was not identified until the current study.

Interested in learning about the more recent developments in our knowledge of memory consolidation? On Tuesday, April 28 at 4pm, Dr. Lila Davachi will give a talk entitled “Behavioral and neural investigations of human memory consolidation”, in the Center for Neural Circuits and Behavior Marilyn C. Farquhar Conference Room.

 

Scott Cole is a first-year Neurosciences student currently rotating with Dr. Eric Halgren. When his memory encoding and retrieval are operational, he likes to compare and critique carne asada burritos across San Diego, which make the optimal post-volleyball meal. You can follow him on Twitter @scottrcole.

Reloading the Synapse

The nervous system is remarkably flexible in dealing with information across different timescales.  We can react to emergencies in milliseconds, yet also store treasured memories for years. How the nervous systems navigates information with various timing demands is a major question in the field of neuroscience.

One of the strategies the nervous system uses to meet these timing challenges is to transmit information in two different ways. Electrical signals give the nervous system speed. Chemical signals give it flexibility to modulate signals across time. These two signals interface at the synapse.

The synapse is the location where one neuron connects to another. When a neuron “fires”, it is transmitting a fast electrical signal down its axon to the synapse at the axon terminal. At the synapse, the fast electrical signal is converted into a slow chemical signal. Neurotransmitters (such as glutamate or dopamine) wait at the axon terminal, where they are packaged into vesicles. When the electrical signal reaches the synapse, the vesicles are triggered to fuse with the membrane and release their contents into the synapse. The neurotransmitter subsequently binds to receptors on the surface of the receiving neuron – effectively transmitting information from one neuron to another. Critically, the chemical signaling is an opportunity for the nervous system to modulate the information being transmitted, such as by switching the amount or type of neurotransmitter available. In 2013, the Nobel Prize in physiology and medicine was awarded to three scientists who discovered the molecular details of how neurons release their packaged vesicles of neurotransmitter.

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Dr. Erik Jorgensen is interested in what happens as the neuron begins to use up its available packages. The stock of packages is finite and most neurons fire quickly enough to use up their stores in a matter of seconds. It is thought that neurons are somehow able to quickly recycle their packages to counter act this problem, but evidence to support this idea has been scant.  Vesicles are too small to observe with a light microscope and neurons fire in about ten milliseconds. Being able to see what is occurring at the synapse over such a short timescale is a difficult task.

To address this question, Jorgensen worked with Dr. Shigeki Watanabe to develop a new technique which gave them the proper temporal and spatial resolution to understand how the neurotransmitter packages were being replenished. First, they introduced a light sensitive molecule to neurons – by turning on and off a light the researchers were able to precisely control when the neuron fired. Then, they would use a high pressure freezer, which could lock all vesicles in place within eight milliseconds. By freezing neurons at different time points, they could effectively create a time-lapse of what the vesicles were doing. Finally, by examining these snapshots of vesicles with an electron microscope, they had the spatial resolving power to examine the vesicles in detail.

Watanabe and Jorgensen found that the vesicles completely fused with the neuron membrane within 30 milliseconds, allowing the vesicles to dump out their neurotransmitter payload into the synapse. Remarkably, in less than 100 milliseconds, portions of the membrane began retracting to be recycled into new vesicles.  This ultra-fast recycling process of vesicles was previously unknown. A slower recycling method was known to take place in some cells, but this mechanism occurred too slowly to meet the demands of neurons. Jorgensen is now following up on this work to discover the details of how neurons are able to perform this ultra-fast feat.

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If you are interested in the details of this work, Katie Fife will be presenting the paper at journal club this Monday, April 20th at 5:30PM in Pacific Hall 3502.

Additionally, Dr. Erik Jorgensen will be giving a talk on this topic titled “Ultrafast endocytosis of synaptic vesicles” this Tuesday, April 21st at 4:00PM for the Neurosciences Graduate Program Dart NeuroScience Seminar Series. The talk is at the Center for Neural Circuits and Behavior (CNCB).


Watanabe S, Rost BR, Camacho-Pérez M, et al. Ultrafast endocytosis at mouse hippocampal synapses. Nature. 2013;504(7479):242-247. doi:10.1038/nature12809.


Peter Osseward is a first-year student in the Neurosciences PhD program at UCSD. He is currently rotating with Dr. Xin Jin. In his spare time, Peter likes to hike and play Ultimate Frisbee.

Galectin-1 (Gal1)ad to Reduce Inflammation after Spinal Cord Injury

Dr. Popovich (who may moonlight as a famous NBA coach on the side or just shares the name) has focused his research efforts on the complex interactions between the immune system and the regrowth and regeneration of the spinal cord after injury. In his lab’s recent work in the journal Molecular and Cellular Neuroscience, Dr. Popovich explores the interaction of Galectin-1 (Gal1) on macrophages and astrocytes at the site of injury in the central nervous system (CNS). As many may already know, a longstanding issue in the field is trying to understand why peripheral nervous tissue (PNS) can regenerate while CNS tissue cannot. Before this paper’s publishing, Gal1 was already known to elicit regeneration in the PNS via its effect on macrophages, but it remained an open question what if any were the effects in the CNS. The Popovich lab took a quantitative approach to answering this question by systematically identifying the expression levels of this protein over a four week time course following spinal cord injury. Interestingly, this work demonstrates a strong upregulation of Gal1 at the injury site as compared to uninjured spinal cord both in macrophages and astrocytes. This suggests a potential target of manipulation going forward in an attempt to tilt the immune-axis in the CNS towards a more conducive environment for regeneration.

Galectin-1 is a switch hitting molecule that changes its activity based on its redox state: when oxidized it is a monomer that acts much like a cytokine, but in its reduced form Gal1 dimerizes and subsequently has a stronger binding affinity with lectins. Of interest to spinal cord injury regeneration is this oxidized monomer form of Gal1, which may assist in axon regrowth. The expression of Gal1 was characterized using the full toolkit of molecular biology (western blots/qRT-PCR) along with immunohistochemistry to determine the localization of Gal1 at various time points. The spinal cord injury was formed using a standard method in which a contusion is applied to the spinal cord of an anesthetized rat.

As stated before, a clear increase in the protein Gal1 monomer at the injury site occurs at the 7 and 14 day time points, which is the height of the inflammatory response in spinal cord injury. mRNA was upregulated at the 3 day time point. Further, protein upregulation was confirmed by quantifying immunoreactivity density. The rest of the paper focuses on the localization and cell specific expression of Gal1. Using fluorescent microscopy, the Popovich lab demonstrates Gal1 up-regulation in macrophages and astrocytes in a series of beautiful images, but furthers the paper by quantifying their images rigorously to provide valuable data on where and when Gal1 is being upregulated in the CNS.
=Fig 1
 Figure 1:A comparison of Gal1 and OX42 a macrophage/microglia marker in uninjured (left) and injured (right) spinal cord. Notice the greater expression of Gal1 in macrophages in the injured tissue in e’ and e’’.

One of the issues raised near the conclusion of the paper is what the monomeric Gal1 is actually doing to macrophages. Gal1 may be reducing these macrophages overall inflammatory response or causing them to differentiate into a “reparative” phenotype. The final two figures of the paper demonstrate one aspect of Gal1 modulatory effect on macrophages: the protein seems to reduce their levels of phagocytosis. Using ED1 as a marker for phagocytic activity, the paper demonstrates a reduction in the colocalization of Gal1 and ED1 at 7 days. Further these macrophages seem to contain less phagocytosed lipids as imaged using the Oil Red O (ORO) stain. Running a linear regression between the coexpression of Gal1 and ORO showed a negative relationship between ORO and Gal1 expression. In sum these figure suggests that Gal1 promotes less phagocytosis in inflammatory macrophages.
=Fig 2
 Figure 2:A comparison of Gal1 and ORO (a marker for phagocytosed lipids). Notice the significant negative correlation between Gal1 immuno- positive cells and ORO density. Conversely, r-t represent a sub-population of macrophages that go against the trend and are highly Gal1+ and have high ORO density.

Overall this paper demonstrates a coherent and quantitative approach to the molecular biology of spinal cord injury, and brings clarity to much of the previous work done on Gal1. By stringently observing time points and quantifying not only expression but cellular localization the Popovich lab has provided a wealth of data on Gal1’s role in the immune response to spinal cord injury. It will be interesting to learn how this data is being used to potentially manipulate the immune response in spinal cord injury, perhaps by increasing Gal1’s expression levels at the injury site.

Marc Marino is a first year Neurosciences student currently rotating with Dr. Roberto Malinow. He is currently enjoying the fact that the San Diego Padres look like they were all injected with a bucket of Gal1 (no longer inflamed and terrible). 


Gaudet AD, Sweet DR, Polinski NK,Guan Z, Popovich PG. Galectin-1 in injured rat spinal cord: Implications for macrophage phagocytosis and neural repair. Molecular and Cellular Neuroscience. 2015; (64):84-94. doi: 10.1016/j.mcn.2014.12.006

Calcium translates between the electrical and chemical languages of the brain

The nervous system is incredibly fast. A dog runs across the street in front of you, and your foot instinctively jumps to the brake pedal. All of this occurs in a fraction of second, often before you even have time to fully process the scene in front of you (was it a dog? or a raccoon?).

The brain is fast because electrical signals in the brain travel fast (over 200 miles and hour, in some cases). And it isn’t just reflexive actions, like slamming your brakes, or lunging to catch a falling glass. We can make complex decisions in the blink of an eye, especially with a little practice and training:

And yet, our decisions and actions, which exist only for a brief instants of time, are captured as memories that can endure for decades.

Electrical signals provide speed, but the brain relies on biochemical reactions as a substrate for slower, more permanent processes like learning and memory. While a discrete electrical impulse typically lasts a few milliseconds, a newly synthesized protein can last for minutes, hours, days, or even years before being degraded. A fundamental question is how these two fundamental languages of the brain — electricity and biochemistry — communicate to each other, despite their widely varying time scales.

Dr. Richard Tsien has been studying this question for many years, and certainly ranks among the very top contributors to this field. His principal insight was that calcium ions participate in both electrical and biochemical signaling, allowing brain cells transmit information from rapid (electrical) signals to slow (chemical) processes that store memories and re-calibrate the system.

Back in 1985, Tsien was the first to characterize the various types of voltage-gated calcium channels [1]. These are proteins that form holes/pores in in the cell’s membrane, and open rapidly in response to an electrical potential. When these channels open, calcium ions (Ca2+) flow into the cell from the extracellular space. These ions carry electrical charge, but also interact with a stupefying number of biochemical pathways that regulate gene expression, protein synthesis and degradation, molecular trafficking, the release of hormones and neurotransmitters, and much more.

Dr. Tsien has tirelessly and meticulously chased down many of these calcium-activated pathways over the years. Far too many to enumerate in this brief summary. But the back-and-forth interplay between electrical and biochemical signaling emerges as a common theme of his work. For example, Tara Thiagarajan, Dr. Tsien, and others [2,3] discovered that chronically blocking electrical activity induces a biochemical response from neurons, causing them to increase the strength of their excitatory connections to other neurons. Calcium plays a pivotal role in this response, as outlined in the flow chart below:

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In this case, calcium works a bit like the thermometer in a thermostat: a drop in calcium signals that activity levels have dropped too low, and turns on the “heat” (excitatory connections between neurons) to compensate. In other work, Tsien and colleagues have studied the calcium-activated pathways that reconfigure synaptic connections to store long-term memories [4], and tune gene expression [5].

Given the privileged position of calcium between the electrical and chemical languages of the brain, it is not surprising that many neuropsychiatric disorders are associated with dysfunction in calcium signaling. For example, progressive memory loss in Alzheimer’s disease is associated with a slow creep in internal calcium levels [6]. Prescribing memantine (Namenda), one of the two approved classes of drugs for Alzheimer’s, can sometimes slow the rate of memory loss by partially blocking calcium ion flow into neurons. While most of Dr. Tsien’s work is focused on unraveling basic biological mechanisms, his lab has also published papers on the role of calcium dysregulation in schitzophrenia, Timothy syndrome, ataxia, and Down Syndrome.

If you are interested in diving into the details of this work, come see Sam Scudder discuss a recent paper from the Tsien lab (6pm, Monday journal club), which examines how calcium signals in distal dendrites regulate gene expression from afar:

Ma et al. γCaMKII Shuttles Ca2+/CaM to the Nucleus to Trigger CREB Phosphorylation and Gene Expression (2014). Cell 159(2): 281-294.

And be sure to stop by CNCB to see Dr. Tsien’s talk on April 7th at 4pm, in the CNCB auditorium.


Alex Williams is a first-year student in the Neurosciences PhD program at UCSD. He applies computational and theoretical techniques to study the molecular mechanisms of neural plasticity and stability. He tweets @ItsNeuronal. Also, Running. Lifting. Burritos.

Do you understand the words that are coming out of my mouth?

I watched Interstellar last month under the stars on campus here at UC San Diego. Several weeks later, the words of this Dylan Thomas poem still resonate within my mind. How is my brain able to understand and remember this spoken message? When I have reached the wise old age of the wonderful Michael Caine, how will my auditory cortex have changed its ability to process these words? Dr. David Woods of UC Davis’s Human Cognitive Neurophysiology Laboratory at the VA Medical Center in Martinez, California is in the business of evaluating age-related changes in speech perception and verbal memory.

Randy Glasbergen, http://glasbergen.com

Age-related decline in verbal processing is in part due to changes in central auditory processing, but little is known of how healthy aging affects the human auditory cortex. Dr. Woods’s laboratory seeks to evaluate age-related changes in speech perception and memory in groups of young and older subjects and correlate them with structural and functional changes in human auditory cortex using several magnetic resonance imaging (MRI) techniques. Dr. Woods proposes to first establish baseline behavioral measures in speech reception thresholds in noise and auditory verbal short-term memory, then investigate age-related changes in auditory cortex surface structure using high-resolution T1-weighted MRI combined with cortical surface mapping. This allows for the analysis of auditory cortex thickness, area, and curvature. Diffusion tensor imaging, an MRI technique used to look at water diffusion, is applied to measure age-related changes in neuropil density and fiber connectivity; this connectivity will then be correlated with prior measured changes in cortical thickness and curvature. Behavioral measures of aging subjects can lend insight into how anatomical changes are associated with behavioral impairment. Lastly, Dr. Woods ties all this structural and behavioral data together with functional organization in the auditory cortex. Using fMRI techniques, he examines the automatic and attention-dependent processing of simple tone stimuli and consonant-vowel-consonant (CVC) syllables. Comparison of tone and CVC processing will elucidate the regions of auditory association cortex that show specific activations to different auditory stimuli and the neural circuits engaged in speech processing.

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Fig. 1 | (A) Cortical surface locations of activation peaks associated with phonological processing of speech sounds from a meta-analysis by Turkeltaub and Coslett (2010). Red dots indicate cortical surface locations of the reported coordinates on the left hemisphere of 60 individual subjects, while blue dots indicate those on the right hemisphere. Cyan cross indicates median location of activations in the left hemisphere; yellow cross indicates that of right. (B) Cortical surface locations of regions responding to CV syllables in comparison to bird song elements, musical instruments, or animal sounds, from Leaver and Rauschecker (2010). See (A) for color associations.

Previous work by Dr. Woods has sought to use population-based cortical-surface analysis of fMRI data to characterize the processing of CVCs and spectrally matched amplitude-modulated noise bursts (AMNBs) in human auditory cortex. Using average auditory cortical field locations (Fig. 1) defined from tonotopic mapping in a previous study, Woods et al. found that activations in the auditory cortex were defined by two stimulus-preference gradients.

Fig. 2 | A schematic map of auditory cortical fields showing stimulus preferences for consonant-vowel-conosonants (CVCs - indicated in ORANGE) and amplitude-modulated noise bursts (AMNBs - indicated in GREEN). The ratio of orange to green reflects relative magnitude of activations with respect to each stimulus type.

Fig. 2 | A schematic map of auditory cortical fields showing stimulus preferences for consonant-vowel-conosonants (CVCs – indicated in ORANGE) and amplitude-modulated noise bursts (AMNBs – indicated in GREEN). The ratio of orange to green reflects relative magnitude of activations with respect to each stimulus type.

Medial belt auditory cortical fields preferred AMNBs (Fig. 2 – green fields), while lateral belt and parabelt fields preferred CVCs (Fig. 2 – orange fields). This preference extends to the core cortical fields, as shown by the medial regions of primary auditory cortex (Fig. 2 – A1) and the rostral field preferring AMNBs and lateral regions preferring CVCs.

Fig. 3 | Quantification of activations by color and brightness. (A) Mean percent signal change of activations coded by brightness. Colors shows stimulus preference (CVC = red, green = AMNB). Yellow regions are activated by both stimuli. (B) Auditory cortical field locations projected onto average curvature map of the superior temporal plane.

Fig. 3 | Quantification of activations by color and brightness. (A) Mean percent signal change of activations coded by brightness. Colors shows stimulus preference (CVC = red, green = AMNB). Yellow regions are activated by both stimuli. (B) Auditory cortical field locations projected onto average curvature map of the superior temporal plane.

Woods, et al. also found a difference in magnitude of activation amongst the different field groups to the two stimuli. Anterior ACFs showed smaller activations (Fig. 3 – dullness of anterior fields), but more clearly defined, singular stimulus preferences (Fig. 3 – only green or red in anterior fields, rather than mixing) than posterior fields (Fig. 3 – note brightness and yellow color in posterior fields).

Fig. 4 | Effects of attention on activation magnitudes in different field groups. UA = unimodal auditory, BA = bimodal auditory attention, BV = bimodal visual attention.

Fig. 4 | Effects of attention on activation magnitudes in different field groups. UA = unimodal auditory, BA = bimodal auditory attention, BV = bimodal visual attention.

Attention significantly enhanced responses throughout the auditory cortex and within every field group, indicating that attentional enhancements to CVCs and AMNBs had similar magnitudes and distributions over auditory cortex (Fig. 4 – mean % of attentional enhancement indicated). This demonstrates that preference gradients are unaffected by auditory attention, which suggests that the preferences of each auditory cortical field reflects automatic rather than attention-dependent processing of difference sound features.

The above investigations are only a brushstroke on Dr. David Woods’s eclectic experimental canvas. To hear more about his adventures in verbal processing and memory, come join in on a lively journal club presentation by Erik Kaestner, a graduate student in the UCSD Neurosciences Graduate Program, on Monday, March 30th at 5:30 PM in Pac Hall 3502. Then, come hear Dr. David Woods himself speak:

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Thanks for listening!

David L. Woods,Timothy J. Herron, Anthony D. Cate, Xiaojian Kang, and E. W. Yund. Phonological Processing in Human Auditory Cortical Fields. Front Hum Neurosci. 2011; 5: 42. Published online 2011 Apr 20. doi:  10.3389/fnhum.2011.00042


Eulanca Y. Liu is a first year graduate student in UCSD Neurosciences and third year in the UCSD Medical Scientist MD/PhD Training Program. When not studying the physiological basis of fMRI in the lab of Dr. Rick Buxton, she enjoys jet-setting, calligraphy and graphic design, opera/theatre/dance, a day at the museum, great single-malt scotch, a hot caffeinated beverage, and dabbling. She will spend the weekend watching the Formula 1 Malaysia Grand Prix whilst writing this post. She can be reached at eyl015 at ucsd.edu and read at medium.com/@ZanzibarByCar. Feedback is welcome!

How is your auditory cortex processing the engine sounds of this Ford Fiesta ST?

Acid on the Tongue: How Taste Cells Mediate Sour Transduction

Imagine what your childhood would have been like if you could never experience the tantalizing taste of a WarHead or the painfully-pleasing sensation of biting into a sour lemon? What if you suddenly couldn’t appreciate the sour beer filing your mug on a warm spring night? While most of our neurons are contained within our brain, life would certainly not be the same without the complete set of cells comprising our nervous system.

Dr. Emily Liman researches the physiological basis of perceiving sensations such as pain and taste. Recently, Dr. Liman revealed that sour transduction is mediated by a proton current enriched on the apical surface of taste cells. Strong acids can activate this proton current, causing the cell to fire a burst of action potentials and generate an acid-evoked inward current. Previously, the PKD2L1/PKD1L3 heterodimer was identified as a marker for sour taste cells, however the function of this channel is not necessary for perceiving sour taste. In the current study, Dr. Liman used transgenic mice, calcium imaging and electrophysiological recordings to identify the elusive mechanism of sour transduction.

Do you remember stuffing your mouth with a fistful of sour patch kids or gummy worms? A variety of acids were responsible for the delicious yet tarty taste you experienced. Similarly, Dr. Liman demonstrated that stimulating PKD2L1-expressing cells with hydrochloric acid (HCl; pH 5) or acetic acid (HOAc; pH 5) induced a rapidly inactivating inward current in those cells (Fig. 2A, B). This cellular response was even present in sour taste cells lacking functional PKD2L1/PKD1L3 channels (Fig. 2C), supporting that an alternative mechanism contributes to sour transduction. Since this acid-response must be mediated by some molecular mechanism, a variety of pharmacological agents were used to alter the concentration of Na+, Ca2+ or Cl, testing the possibility that a cation or anion mediates the cell’s response to acid. However, these manipulations revealed that a sour taste cell’s response to an acid is not mediated by an ionic conductance (Fig. 2C). Instead, H+ is the likely charge carrier allowing a sour taste cell to respond to extracellular acidification.

Liman Fig. 2

Interestingly, pharmacological agents such as Bafilomycin, Cd2+, Desipramine and Amiloride, which block proton currents, had no effect on reducing the acid-evoked inward current. Only Zn2+, which is known to block many channels including the proton channel, Hv1, could inhibit the acid-response in sour taste cells (Fig. 3D).

Liman Fig. 3

Additionally, Dr. Liman used UV uncaging of NPE-caged protons and Ca2+ microfluorimetry to measure how a cell might respond to extracellular acidification. In this manner, a proton current was simulated by uncaging protons at the apical surface of the sour taste cell. Calcium imaging showed that sour taste cells responded to the uncaged protons with a burst of action potentials, a large inward current, and an elevation of intracellular Ca2+ (Fig. 5B).

Liman fig. 5

While the specific mechanism underlying the proton current remains a mystery (a proton channel or transporter are the likely candidates), I’ll personally sleep better at night knowing that I’ll wake up with my sour taste cells intact and ready to enjoy a warm cup of tea infused with freshly cut lemon.

Come and hear Dr. Emily Liman’s talk Taste and the single cell: Uncovering mechanisms of sour transduction, Tuesday, March, 17th at 4pm in the Center for Neural Circuits and Behavior Marilyn C. Farquhar Conference Room.

Bankole Aladesuyi is a first-year Neurosciences student currently rotating with Dr. Xin Jin. When not reminiscing about a childhood spent eating candy for lunch, he enjoys playing soccer, making music and reading science fiction.


Chang, R. B., Waters, H., & Liman, E. R. (2010). A proton current drives action potentials in genetically identified sour taste cells. Proceedings of the National Academy of Sciences107(51), 22320-22325.

The Hidden Visceromotor Maps in Motor Cortex

This week UCSD is proud to feature the work of Peter Strick, Chair of Neurobiology at the University of Pittsburg. Dr. Strick’s lab investigates the circuitry of the brain, focusing on cortical motor areas as well as the basal ganglia and cerebellum.

Motor cortex has long been known to contain somatotopically organized motor “homunculi,” regions with point-for-point correspondence between the body and its representation in the brain. Recent work in Dr. Strick’s lab has discovered that primary motor cortex (M1) and rostromedial motor area (M2) also contain somatotopic map of visceromotor functions.

The autonomic nervous system is the functional subdivision of the central nervous system responsible for unconscious monitoring and control of visceral organs. It allows us to maintain homeostasis despite constant changes in temperature, food intake, and physical activity. This system is not exclusively reactionary, suggesting possible allostatic regulation in which higher brain centers generate anticipatory activity to prevent imbalances before they occur.

In this paper Strick injected rats’ kidneys with a modified rabies virus to identify the cortical origin of their autonomic innervations. Rabies virus is a useful tool for tracing circuits because it travels exclusively in the retrograde direction (from a postsynaptic neuron into the presynaptic neurons that contact it) and does so in a time-dependent fashion (infection spreads at a constant rate). Varying the time the virus is allowed to spread can tell us which neurons are involved in each stage of a circuit: first-order neurons (those directly innervating the kidneys) are infected first, followed by second-order, and so on and so forth.

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Figure 1. Retrograde transneuronal transport of rabies virus through neural circuits that innervate the kidney.

Contrary to classical models in which cingulate and insular cortex provide the primary cortical control of visceral function, the first cortical neurons infected were located overwhelmingly in M1 or M2. Further, these neurons were concentrated heavily in areas representing the trunk, consistent with the known spinal location of renal sympathetic preganglionic neurons. These results suggest that sympathetic visceromotor control originates in motor cortex and is organized in a somatotopic manner similar to motor control.

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Figure 2. The first neurons to reach cortex are located most densely in the trunk representations of M1 and M2.

The discovery of visceromotor control in motor cortex has important implications. M1 and M2 have different roles in the control of conscious movement; while M1 is involved in the execution of movement, M2 is critical to the planning and preparation of movements. If visceromotor control parallels this distinction, M2 may provide the anticipatory processing necessary for allostatic regulation. Further, interconnectivity between M1 and the basal ganglia (BG) may explain why some Parkinson’s patients (a neurodegenerative disease that affects the BG) experience autonomic dysfunction (symptoms often assuaged by deep brain stimulation of BG).

If you are interested in this and other work by the Strick lab, join us tomorrow at 4:00 at the UCSD Center for Neural Circuits and Behavior, where Dr. Strick will be speaking about unraveling the “brain-body” connection.

Levinthal DJ, Strick PL. The motor cortex communicates with the kidney. J Neurosci 32: 6726–6731, 2012.

Michael Metke is a first year graduate student in the Neuroscience program at UCSD.

Joshua Sanes: Regulation of Retinal Repulsion (and Rainbows)

This week, the Dart Neurosciences Seminar hosts Joshua Sanes, a professor of molecular and cellular biology at Harvard. Dr. Sanes’ scientific interests revolve around key fundamental questions in systems neuroscience: How do circuits form in development, how do they change over maturity, and how do they function to process signals in adulthood? To this end, Dr. Sanes has spent many years probing the retina as a model for the rest of the brain. In particular, he has been a pioneer in identifying retinal subtypes, probing their connectivity dynamics, and manipulating different parts of the circuit to evaluate their importance.

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Recently, Dr. Sanes and his lab members have focused on molecules that play in role in forming these synaptic connections- namely the cadherin superfamily. It has been known that in the retina, cells of the same subtype are spaced apart such that few neighboring cells are of the same subtype. However, a mechanism for the formation of such a mosaic was unknown. In a 2012 Nature paper, Jeremy Nay, Monica Chu, and Joshua Sanes identified two transmembrane proteins found in a subset of retinal cells that regulate positioning of Starburst Amacrine Cells (SACs) and Horizontal Cells (HCs) during development. In this paper, the group showed that these two proteins (MEGF10 and MEGF11) act as repulsive ligands, where cells that express these proteins will repel other cells expressing the same protein. They further showed that the protein is required as part of both the ligand and receptor sides, a homotypic interaction. This results in ‘exclusion zones’ around a particular cell, creating the mosaic spacing seen between cells of the same subtype in the retina. While the previous hypothesis was that each subtype had a unique ligand-receptor signal, these results show how two proteins work cooperatively to create a repulsive mosaic for horizontal cells, and how one of those proteins (MEGF10) also acts on SACs. As these two cell types are in different layers, it opens up the possibility that these mosaic ligands are layer specific, reducing the necessary diversity to create a structures, mosaic map in the retina.

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What is the importance of elucidating these mechanisms? As Dr. Sanes mentions frequently, the retina is an easy-to-access proxy for other brain areas. There are numerous examples of neuronal arrays throughout the CNS. This first evidence of homotyptic repulsion could lead to an understanding how uniformity is established in the brain.

Since the 1970s, Dr. Sanes has approached the question of neural synapses in different ways. From neuromuscular junctions in frogs, to discovering and cloning the protein lamin B2, he has tried to explore the molecules that form the junction, and how disturbing the system affects the synapse. With Jeff Lichtman, an expert in live imaging, Dr. Sanes hopes to continue probing the nature of cell-to-cell connections and synapse formation and change over time. In recent years, this duo has gained fame for the creation of ‘brainbow’ mice, lines of transgenic mice that express varying amounts of three fluorophores in each cell, creating a veritable rainbow of colors that allows visual separation of each cell and its axon from neighboring cells. The entire field of neuroscience will benefit as Dr. Sanes continues to push boundaries in the fields of development of retinal architecture, synapse formation, and circuit evolution.

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If you’d like to find out more about these studies, come listen to Dr. Joshua Sanes on Tuesday, March 3rd in the Center for Neural Circuits and Behavior Marylin C. Farquhar Conference Room!

(Sahil Shah is an M.D./Ph.D. student in the lab of Jeffrey Goldberg. He is studying protein synthesis and transport in the retinal ganglion cell as it relates to aging and disease.)

Kay, J. N., Chu, M. W., & Sanes, J. R. (2012). MEGF10 and MEGF11 mediate homotypic interactions required for mosaic spacing of retinal neurons. Nature483(7390), 465-469.