Download Full program and abstracts

The Hebrew University of Jerusalem,
Edmond and Lily Safra Center for Brain Sciences (ELSC)
Israel
Peking University, McGovern Institute for Brain Research
China
Symposium on:
Brain Research at the Molecular and Cellular Level
The Israel Institute for Advanced Studies
Feldman Building, Lecture Hall 130, The Hebrew University
Edmond J. Safra Campus, Givat Ram, Jerusalem
March 27, 2014
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List of speakers and titles
Alexander Binshtok: Hebrew University, ELSC
The Itching Line: Selective Silencing of Primary Afferents Reveals Two Distinct Itch-Specific
Sensory Lines
Ami Citri: Hebrew University, ELSC
Transcriptional Networks Provide Insight Into The Neural Circuitry of Addiction
Eran Meshorer: Hebrew University, ELSC
Hyperdynamic plasticity of linker histones in depolarized primary neurons
Baruch Minke: Hebrew University, ELSC
New insight on the gating mechanism of TRP channels
Hagai Bergman: Hebrew University, ELSC
Theoretical and physiological aspects of the basal ganglia and their disorders
Yuji Naya: Peking University, McGovern Institute for Brain Research
Signal flows substantiating semantic and episodic-like memory in the primate medial temporal
lobe
Shihui Han: Peking University, McGovern Institute for Brain Research
Racial in-group bias in human brain activity
Chenjian Li: Peking University, McGovern Institute for Brain Research
Animal Models for Neurodegenerative Diseases
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Program
Jerusalem, March 27, 2014
Brain Research at the Molecular and Cellular Level
Time
Program
March 27, 2014
Chair: Chenjian Li
9:00
Eilon Vaadia: ELSC Director, Opening Remarks
9:10
Yuji Naya: Peking University, McGovern Institute for Brain Research
Signal flow substantiating semantic and episodic-like memory in the primate
medial temporal lobe
9:50
Eran Meshorer: Hebrew University, ELSC
Hyperdynamic plasticity of linker histones in depolarized primary neurons
Coffee break
10:30
11:00
Baruch Minke: Hebrew University, ELSC
New insight on the gating mechanism of TRP channels
11:40
Alexander Binshtok: Hebrew University, ELSC
The itching line: Selective silencing of primary afferents reveals two distinct itchspecific sensory lines
Lunch Break
12:20
Chair: Alexander Binshtok
13:50
Chenjian Li: Peking University, McGovern Institute for Brain Research
Animal Models for Neurodegenerative Diseases
14:30
Hagai Bergman: Hebrew University, ELSC
Theoretical and physiological aspects of the basal ganglia and their disorders
15:10
Coffee break
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15:30
Ami Citri: Hebrew University, ELSC
Transcriptional networks provide insight into the neural circuitry of addiction
.
16:10
Shihui Han: Peking University, McGovern Institute for Brain Research
Racial in-group bias in human brain activity
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Abstracts
Signal flows substantiating semantic and episodic-like memory in the primate medial temporal
lobe
Prof. Yuji Naya
Abstract
Declarative memory, which depends on the medial temporal lobe (MTL) structures, consists of two subcategories: semantic memory and episodic memory. The former refers to general knowledge of facts,
while the latter refers to memories of autobiographical events containing items, times and places. In
this talk, I will present neurophysiological data examining the two memories in macaque brains.
Semantic memory was tested using an item-item association task in which monkeys were required to
retrieve a particular visual object when its paired object was presented as a cue stimulus. The singleunit data suggested that bidirectional signaling between the perirhinal cortex (PRC) of the MTL and
visual association area TE is involved in the encoding and retrieval of item-item association memories
of visual objects (Naya, Yoshida & Miyashita, 2001 & 2003). On the other hand, episodic memory was
tested using a temporal-order memory task in which monkeys were required to encode two visual items
and their temporal order. The data of single-unit recording indicated that the hippocampus (HPC)
provided incremental timing signals from one item presentation to the next while the PRC signaled the
conjunction of items and their relative temporal order. These results suggest the incremental timing
signal in HPC is conveyed to PRC via the entorhinal cortex, where it is integrated with item information
from TE and converted into a discrete item-based temporal order signal (Naya and Suzuki, 2011).
Hyperdynamic plasticity of linker histones in depolarized primary neurons
Prof. Eran Meshorer
Abstract
Neuronal stimulation leads to the expression of immediate early genes through calcium-dependent
mechanisms. Considerable attention has been devoted in recent years to the transcriptional responses
following neuronal stimulation, but relatively little is known about the changes in chromatin dynamics
that follow neuronal activation. Here we show that KCl-induced depolarization causes a rapid release
of the linker histone H1 from chromatin in primary cultured cortical neurons. This hyperdynamic
association, as well IEG expression, is PARP1-dependent. Using chromatin immunoprecipitation
(ChIP), we show that H1 is replaced by PARP1 on IEG promoters following neuronal stimulation, and
PARP1 inhibition blocks this reciprocal binding response. Our results demonstrate the relationship
between neuronal excitation and chromatin plasticity and identify PARP1-mediated linker histone
mechanism regulating IEG expression in stimulated neurons.
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New insights on the gating mechanism of TRP channels
Prof. Baruch Minke
Abstract
Transient receptor potential (TRP) channels constitute a large superfamily of polymodal channel
proteins with diverse roles in many transduction and sensory pathways. The TRP superfamily, which is
conserved through evolution, consists of seven subfamilies and its members are expressed in many cell
types. These channels participate in most sensory modalities and they either open directly in response
to ligands or physical stimuli or, indirectly, downstream of a signal transduction cascade. Currently,
there is no high-resolution information available on TRP channels and their gating mechanism is
unclear. We explored the role of critical amino acids in the highly conserved pore region of the
Drosophila TRP and TRPL, by generating specific point mutations, which affect the activation state of
the channel and may explain how the channel-lipid interactions determine the activation state of the
channel. The alignment of transmembrane region 5 of TRP channels reveals highly conserved amino
acids. To get insights into the gating mechanism and validate homology models, we bioinformatically
analyzed TRPL. We searched for highly conserved and comutating amino acids, as well as amino acids
shown to be of importance in other TRP channels. We identified the area surrounding the non-conserved
amino acid F557 in transmembrane region 5 as a critical regulator of TRPL activity. By a series of
mutations we could generate TRPL mutants which are constitutively active in HEK293 cells where
TRPL is normally not active, or show different responses to the non-specific TRP modulator
polyunsaturated fatty acid. By mutating amino acid pairs we were able to gain insights in the orientation
of the transmembrane domains and validate homology models. We conclude that despite sequence
differences and evolutionary separation, the gating mechanism and overall structure of TRP channels is
conserved.
The Itching Line: Selective Silencing of Primary Afferents Reveals Two Distinct Itch-Specific
Sensory Lines
Dr. Alex Binshtok
Abstract
Itch is a complex unpleasant cutaneous sensation that in some respects resembles pain, yet is different
in terms of its intrinsic sensory quality and the urge to scratch. At a cellular level there is a considerable
overlapping responsiveness of trigeminal (TG) and dorsal root ganglia (DRG) neurons to multiple painproducing algogens and itch-producing pruritogens, although the G-protein coupled receptors (GPCRs)
responsive to different specific pruritogens are quite distinct. Histamine-sensitive H1 receptors (H1Rs)
generate histamine itch and are expressed by TRPV1+/phospholipase-β-3 (PLCβ3)+ fibers, while the
itch evoked by chloroquine (CQ) and bovine adrenal medulla 8-22 peptide (BAM8-22) is mediated by
the Mas-related G-protein-coupled receptors A3 (MrgprA3) and C11 (MrgprC11), respectively.
Interestingly, co-activation of TRPV1 and H1R is required to produce histamine-dependent itch, and
that of TRPA1 and MrgprA3 or C11 for non histamine-mediated itch. In vitro calcium imaging
experiments indicate that neurons expressing MrgprA3 also respond to histamine, which has been
interpreted as indicating the presence of a single neuronal path for producing both histaminergic and
non-histaminergic itch. Supporting this, ablation of neurons expressing MrgprA3 has recently been
shown to reduce the scratching evoked by both CQ and histamine. However, other investigators report
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that while a responsiveness of primary sensory neurons to multiple itch mediators occurs in juvenile
mice, this decreases with age suggesting that in the adult, activation of afferents that respond only to
histamine or only to non-histamine pruritogens may be sufficient to independently generate the two
types of itch. This distinction is clinically important since therapies targeting neuronal activity
exclusively of histaminergic itch fibers might be therapeutically ineffective for the treatment of nonhistaminergic itch if the neurons mediating the two itches are functionally distinct in the mature nervous
system.
To study if histamine- and non histamine-mediated itch are functionally distinct we have utilized a
strategy of silencing specific subsets of pruritogen-sensitive primary sensory fibers by delivery of a
charged sodium channel blocker through active large pore channels to demonstrate that functional
blockade of the sensory fibers that mediate histamine itch does not affect the histamine-independent itch
evoked by chloroquine or SLIGRL-NH2, and vice versa. Moreover, we demonstrate that a targeted
silencing of itch-generating fibers does not reduce pain-associated behavior. However, we found that
silencing TRPV1+ or TRPA1+ neurons allows AITC or capsaicin respectively to evoke itch, implying
that certain peripheral afferents may normally indirectly inhibit algogens from eliciting itch. These
findings both support the presence of functionally distinct sets of fibers for producing histaminergic and
non-histaminergic itch behavior in adult mice, and suggest that the targeted silencing of activated
sensory fibers may represent a clinically useful anti-pruritic therapeutic approach.
Animal Models for Neurodegenerative Diseases
Prof. Chenjian Li
Abstract
In an aging society, neurodegenerative diseases became one of the most devastating impairment of
patients and a severe burden to the family. Among neurodegenerative diseases, my lab mainly focuses
on Parkinson's disease (PD) and Huntington's disease (HD). PD is the second largest neurodegenerative
disease, and HD is a relatively small but nevertheless important “model” disease. Both PD and HD
involve neurodegeneration in basal ganglia, a brain region of many critical functions, and yet still at the
beginning to be understood.
We first worked on establishing new methodology for transgenic animals for modeling diseases. We
have developed Bacterial Artificial Chromsome (BAC) mediated transgenic technology which is now
commonly used in this line of research. With this method, we have created animal models that
accurately recapitulated disease phenotypes of Parkinson’s disease (PD) and Huntington’s disease
(HD).
In the past decade, mouse genetics field has been overwhelmingly active and researchers including us
have established a variety of powerful genetic tools. However, rat as a genetic research organism was
not developed well. Although closely related in evolution, rats are different from mice, and are much
closer to human in many physiological aspects. We have successfully overcome the technical hurdles
of BAC transgenesis in rat, and have generated transgenic rats with phenotypes closely resembles that
of PD patients.
With these models, we have investigated important mechanisms of disease pathogenesis. At this
meeting, I will discuss questions concerning protein aggregation, mitochondrial deficits and kinase
signaling pathways, as important aspects of pathogenesis.
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Theoretical and physiological aspects of the basal ganglia and their disorders
Prof. Hagai Bergman
Abstract
Previous reinforcement-learning models of the basal ganglia networks have highlighted the role of
dopamine (basal ganglia critic) in encoding the mismatch between reward prediction and reality. These
models underscore the role of dopamine in modulating the efficacy of the cortico-striatal synapses and
modification of the state to action mapping. Far less attention has been paid to the fast effects of
dopamine (and other basal ganglia neuromodulators) and to the computational algorithms of the mainaxis (actor) of the basal ganglia network. For example, it is still debated whether limbic, cognitive and
motor aspects are processed in parallel or in series. Similarly, there is no consensus whether the ventral
striatum is part of the critic or the actor part of the basal ganglia.
I suggest that the computational goal of the basal ganglia is not to maximize cumulative (positive and
negative) reward. Rather, the basal ganglia aim at multi-objective optimization of independent gain and
cost functions. To do so, they process in parallel limbic, cognitive and motor information (e.g., in the
ventral striatum, caudate and putamen respectively). Unlike previously suggested single-variable
maximization processes, this multi-objective optimization process leads naturally to a softmax-like
behavioral policy. The direct effects of dopamine, acetylcholine, serotonin and histamine (basal ganglia
critics) on striatal excitability provide a fast and robust pseudo-temperature signal that immediately
modulates the ongoing behavior. The modulation of the efficacy of the cortico-striatal transmission and
the state-to-action mapping (behavioral policy) is a slow and subtle process that eventually leads to
optimization of the behavioral policy.
In my talk I will show that the resulting experience and temperature modulated softmax policy can serve
as a theoretical framework to account for the broad range of neuronal activities (as revealed by crosscorrelation studies of simultaneously recorded spiking activity of cortical and basal ganglia neurons),
behaviors and clinical states (e.g., Parkinson’s disease, schizophrenia) expressed and governed by the
basal ganglia networks.
Capturing Alternative Polyadenylation in the Alzheimer Brain
Shachar Barbash
Abstract
Alternative polyadenylation (APA) is a major regulator of gene expression, but was only explored for a
few genes in the Alzheimer`s disease (AD) brain. Here, we report a global high-resolution dataset for
APA changes in temporal gyrus tissues from AD patients and non-demented donors with or without AD
neuropathology. Using the SQUARE multiple 3’ primer-based library preparation, we achieved superior
resolution and found known and novel APA-modified RNA transcripts, validated by RT-PCR. The APA
differences classified cognitively declined patients with AD neuropathology from healthy controls better
than total transcript differences, and identified 30 APA variants that distinguish AD patients from both
healthy controls and individuals with AD pathology who did not show cognitive decline. The APA
differences indicated ATP and mitochondrial metabolism changes as potentially involved in delaying
the AD cognitive damage, indicating the value of APA variants as a resource to AD researchers.
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Transcriptional Networks Provide Insight Into The Neural Circuitry of Addiction
Dr. Ami Citri
Abstract
Addiction is a prominent neuropsychiatric disorder, responsible for an enormous burden on society.
Addiction is the result of maladaptive neuroplastic modifications of the brain’s natural reward circuitry,
induced by the repetitive experience of drugs of abuse. Rodent models of drug addiction are well studied
and provide substantial insight into the mechanisms underlying the long-term memory induced by drug
experience. Importantly, drugs of abuse induce robust and reliable behavioral responses in rodents, as
well as robust neuroplastic events in defined brain nuclei. Therefore, beyond providing a model for the
mechanisms underlying addiction, studying the experience induced by drugs of abuse provides a potent
and convenient model system to study experience-dependent neuroplasticity.
Using simple rodent models, we have identified clear and robust transcriptional programs induced in
the nucleus accumbens of mice following cocaine experience. These transcriptional responses evolve
following consecutive drug experiences, revealing a number of intriguing molecular events, which we
are actively investigating in the lab, and which we believe could underlie the persistent memory of drug
experience in addiction.
Based on our study of the transcriptional response, we have further developed a number of experimental
tools that enable higher resolution in the analysis of the neuronal circuits encoding cocaine experience.
We will describe our approaches and observations.
Racial in-group bias in human brain activity
Prof. Shihui Han
Abstract
I'll present our recent studies that examine neural, molecular and genetic associations of
racial in-group bias in empathy for other suffering. Our studies demonstrate that brain regions
such as the ACC/SMA respond more strongly to the suffering perceived in racial in-group compared to
out-group members. The racial in-group bias in brain activity is associated with oxytocin and oxytocin
receptor gene. The implications of these findings will be discussed.
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