SfN15_HotTopics_vFINAL

i
SOCIETY FOR NEUROSCIENCE
45th
ANNUAL MEETING
October 17–21, 2015
Information from lay-language summaries
is embargoed until the conclusion of the scientific presentation.
For more information contact:
October 17–21: Neuroscience 2015 Press Room, S 501ABC
McCormick Place
(312) 791-6730
Before/After: Media and Communications Department
(202) 962-4000
media@sfn.org

ii
The material contained in the News Releases and Hot Topics books
represents the research of the study authors and does not reflect the opinions
of the Society for Neuroscience, its Officers, or its Councilors.
Copyright © 2015 Society for Neuroscience
1121 14th
Street, NW, Suite 1010
Washington, DC 20005
(202) 962–4000
www.sfn.org

iii
Hot Topic Themes
ADDICTION............................................................................................................. 1
AGING....................................................................................................................... 6
ALZHEIMER’S......................................................................................................... 7
BRAIN DEVELOPMENT....................................................................................... 14
BRAIN-MACHINE CONNECTIONS, PROSTHETICS....................................... 16
CELL COMMUNICATION.................................................................................... 17
CELLULAR & MOLECULAR TECHNIQUES..................................................... 18
CHILDHOOD & COGNITIVE DEVELOPMENT................................................ 20
CIRCUITS, MAPPING, CONNECTOME.............................................................. 23
DECISION-MAKING............................................................................................. 27
DEGENERATIVE DISORDERS............................................................................ 28
DEPRESSION, MOOD DISORDERS.................................................................... 36
DEVELOPMENTAL DISORDERS........................................................................ 39
DIET & OBESITY................................................................................................... 41
EMOTIONS............................................................................................................. 42
EXERCISE.............................................................................................................. 43
GENETICS.............................................................................................................. 45
HEARING................................................................................................................ 48
HORMONES........................................................................................................... 51
IMAGING TECHNIQUES...................................................................................... 54
LANGUAGE........................................................................................................... 56
LEARNING & MEMORY...................................................................................... 59
MOVEMENT.......................................................................................................... 73
PARENTING & PREGNANCY.............................................................................. 75
PARKINSON’S DISEASE...................................................................................... 76
PSYCHIATRIC DISORDERS................................................................................ 80
SENSES & PERCEPTION...................................................................................... 82
SLEEP...................................................................................................................... 91
SPINAL CORD........................................................................................................ 95
STRESS & ANXIETY............................................................................................. 98
STROKE, BRAIN TRAUMA & INJURY............................................................ 100
VISION.................................................................................................................. 109

1
Addiction
THE EFFECT OF EXERCISE ON THE NEUROCHEMICAL CONSEQUENCES OF
METHAMPHETAMINE ABUSE
M. Murray, Z. Vlastos, K. Varley, A. N. Fricks-Gleason. Regis University, Denver, CO. mmurray004@regis.edu
Program Number: 317.03
Session Date/Time: Monday, Oct.19, 8:00 AM
Room Number: Hall A
Board Number: K8
Presentation Time: 8:00 AM - Noon
Session Title: Amphetamines and Cocaine
Our research suggests that aerobic exercise may be capable of restoring methamphetamine-induced brain injury.
Approximately 12 million Americans age 12 and older have tried methamphetamine. The abuse of methamphetamine
in the United States has increased markedly in the past 15 years, due in large part to the relative ease with which
the molecule can be synthesized illicitly and the long-lasting, intense euphoria that its administration produces. Use
is endemic in the Western states and growing in the Midwest. Overall, the economic cost of drug abuse is high.
Methamphetamine abuse alone costs the U.S. $23.4 billion annually due to crime, lost workplace productivity, foster
care, and other social problems stemming from abuse of the drug.
Psychostimulant abuse carries with it several potential health risks, including addiction, and methamphetamine abuse
carries the additional danger of permanent brain injury in the reward pathway. As a result, methamphetamine addicts
develop Parkinson’s disease at a higher rate than the general population. Additionally, methamphetamine abusers are
reported to suffer from a wide range of cognitive deficits that significantly impact their ability to engage in and benefit
from treatment. To date, no effective pharmacological treatment for methamphetamine abuse has been identified, and
the existing behavioral therapies are known to be marginally effective.
Exercise is known for its beneficial physiological effects and cognition-enhancing properties. There is a long history
of investigation of exercise as a potential therapy in the context of neurodegenerative disease, but only recently has it
begun to be investigated for the treatment of drug abuse and addiction. In a recent rodent study, exercise was shown
to mitigate methamphetamine-induced neurotoxicity. Importantly, in this study the rats were exercised both before
and after methamphetamine administration, so it is unclear whether this effect was the result of protection against
the initial neurotoxic insult, or promoted recovery after methamphetamine administration. Our aim is to specifically
examine the effects of exercise after methamphetamine administration as a more clinically relevant therapeutic option.
In the current study rats were given methamphetamine four times in one day, a protocol known to induce damage to
the reward pathway in the brain. Rats were then split into two groups, the exercise group and the sedentary group.
Exercised rats were allowed free access running wheels every day for three weeks. The sedentary group was housed
with locked, non-functional running wheels for the same period of time. Following this three-week period, the brains
of the rats were examined for markers of methamphetamine-induced neurotoxicity.
The overall goal of our research is to examine the potential beneficial role of exercise in reducing methamphetamine-
induced neurotoxicity in the reward pathway, the associated cognitive deficits, and propensity for relapse. We believe
this work will provide the preclinical evidence necessary to support future clinical investigation of this novel, non-
pharmacological treatment for methamphetamine abuse and addiction. Having now examined the effect of exercise
on the neurochemical consequences of methamphetamine use, the next step of this research will be to examine the
influence of exercise on methamphetamine-induced cognitive deficits and cue-induced relapse.

2
Addiction
NNOS-EXPRESSING INTERNEURONS: A MASTER SWITCH FOR NUCLEUS ACCUMBENS
PLASTICITY UNDERLYING COCAINE RELAPSE
A. W. Smith, J. L. Heinsbroek, M. D. Scofield, M. R. Lorang, P. W. Kalivas. Medical University of South Carolina,
Charleston, SC. (843)822-3045. smitaw@musc.edu
Session Date/Time: Saturday, Oct.17, 1:00 PM
Room Number: Hall A
Board Number: F41
Presentation Time: 1:00 - 5:00 PM
Session Title: Cocaine: Neural Mechanisms of Reinforcement and Relapse I
Our research identifies the importance of a very small population of understudied brain cells that controls relapse to
cocaine seeking. That is to say that specifically inhibiting these neurons is able to prevent rats from relapsing, and
stimulating them is able to drive drug-seeking behavior.
Cocaine addiction is a problem that has serious negative consequences on many levels, including rising healthcare
costs, and loss of workplace productivity. There is currently no FDA-approved treatment for cocaine addiction, and
relapse rates remain high following protracted abstinence accompanied by cognitive-behavioral therapy. The National
Institute on Drug Abuse reports that the number of cocaine overdose related deaths rose by 29% nationally between
2001 and 2013, with that number recently eclipsing 5000 deaths annually.
A key brain region that mediates relapse is called the nucleus accumbens (NA). The NA is commonly called the
“pleasure center” of the brain, and it serves as a gateway between internal, emotional systems, and motor systems
that allow us to interact with the external world. The NA receives a strong input from the prefrontal cortex (PFC),
which is a decision-making center of the neocortex. Thus, the PFC-NA connection is a major component in the brain
“deciding” to initiate a goal-directed behavior (such as drug seeking), and also how aggressively that goal is pursued.
This PFC to NA projection undergoes drastic changes during the progression of addiction, through a process called
synaptic plasticity.
The most promising pharmaceutical targets for new drugs to treat addiction are those that are shared across classes
of drugs (e.g. cocaine, heroin, nicotine). Our lab has recently identified that relapse to all three of these drugs is
accompanied by a very fast, temporary strengthening of synapses between the PFC and NA, and this strengthening
depends on an enzyme called MMP-9. In order to study this, we train rats/mice to press a lever to self-administer
IV cocaine, nicotine, or heroin. During this phase, each IV infusion of cocaine is paired to a light and an auditory
tone, and over 2 weeks of daily self-administration, this light and tone become conditioned stimuli that the animal
associates with the drug. After two weeks, the animal enters a withdrawal stage wherein they undergo extinction
training for two more weeks. During this phase, lever pressing does not result in any drug infusion, or the light or
tone cues. Relapse is then initiated by re-presenting the light and tone cues, which robustly causes the animal to seek
the drug. The human condition that this attempts to model is the drug addict who associates certain objects (e.g. a
crack pipe, syringe, straw etc.), with the drug, and even after rehabilitation, seeing these or similar objects can trigger
relapse.
The current studies focused on mechanisms of synaptic plasticity only in cocaine relapse. Within the NA,
approximately 1% of neurons create a gaseous neurotransmitter called nitric oxide, through an enzyme called neuronal
nitric oxide synthase (nNOS). We found that inhibiting nNOS stopped rats from relapsing, and also stops the MMP-
9 activity that underlies relapse. Then, by using a genetically modified mouse, we were able to selectively activate
nNOS-containing neurons through a technique called chemogenetics. We found that activating this 1% of neurons in
the NA was able to activate MMP-9 activity, strengthen synapses globally throughout the NA, and cause animals to
relapse. Future studies are needed to determine if this mechanism is indeed one that is shared across classes of drugs.
These results indicate that a very small population of neurons is able to control drug relapse, and targeting these
neurons specifically may be a viable therapeutic option for reducing relapse with minimal side effects.

3
Addiction
IS HIGH FRUCTOSE CORN SYRUPAS ADDICTIVE AS OXYCODONE? A STUDY OF DUAL
INTRAVENOUS AND INTRAORAL SELF-ADMINISTRATION, EXTINCTION AND REINSTATEMENT
IN RATS
M. Minhas, F. Leri. Univ Guelph, Guelph, Canada. minhasm@uoguelph.ca
Session Date/Time: Wednesday, Oct.21, 1:00 PM
Room Number: Hall A
Board Number: J17
Session Title: Hedonia, Feeding, and Addictive Drugs
Our research indicates that sugar and drugs differentially acquire control over motivated behaviour in the absence of
the reinforcers. We found that oxycodone cues initiate seeking behaviour, an effect not observed with high fructose
corn syrup. Additionally, brief re-exposure to one reinforcer does not induce seeking of the other. These studies further
clarify the similarities and differences in the behavioral regulation of sugar and drug reinforcement.
It is reported that highly palatable food can engender “addictive-like” patterns of consumption. Furthermore, there
is substantial evidence in animals that palatable food (i.e., high in fat and sugar) activates brain reward centers in
ways that closely resemble the action of drugs of abuse. These similarities suggest that “addiction” can develop to
food. The current study investigated the hypothesis that sugar can be addictive as drugs of abuse by studying the self-
administration of sugar and drugs in the same animals.
To model drug and sugar taking, we used self-administration to train animals to lever press for infusions of oxycodone
and high fructose corn syrup. Male rats were surgically implanted with both intra-oral (IO) and intravenous (IV)
cannulas through which they self-administered IO infusions of high fructose corn syrup (8, 25, 50%) and IV infusions
of oxycodone (0.05, 0.1, and 0.2 mg/kg/inf), across 16 alternating days for 3 hours/day. They then underwent a
4-day forced abstinence period in home cages. Abstinence was followed by re-exposing animals to the sugar and
drug-related environment in the absence of high fructose corn syrup and oxycodone. During this time animals lever
pressed for both high fructose corn syrup- and oxycodone-paired levers in the absence of associated cues. This
behavioural model is known to represent drug-seeking. We then tested, the impact of reinforcer paired cues on seeking
by exposing animals to cues that were previously paired during self-administration. Lastly, animals were briefly re-
exposed to oxycodone and/or high fructose corn syrup through experimenter-administered injections. This test is used
to assess the impact of an oxycodone or high fructose corn syrup “slip” which can then lead to relapse as measured
by seeking behaviour. Our research is the first to use intra-oral and intravenous self-administration to investigate the
similarities and differences in sugar- and drug-seeking behaviour. This data has not previously been presented or
published.
Initial findings indicate that during self-administration there was greater responding for high fructose corn syrup than
oxycodone, however the pattern of self-administration for both reinforcers was similar across time. In the absence
of the reinforcers and cues, lever pressing was similar in animals. Upon re-exposure to cues, oxycodone-paired cues
increased responding above baseline; an effect not observed with high fructose corn syrup. Lastly, experimenter-
administered injections of high fructose corn syrup and/or oxycodone reinstated responding that was specific to the
levers previously associated with their self-administration. These findings indicate that high fructose corn syrup and
oxycodone engender similar patterns of consumption and seeking in the same animal. Importantly, however, re-
exposure to one reinforcer does not induce seeking of the other suggesting that specific associations were formed with
each reinforcer.
The next step in this research is to dissociate the neurobiological mechanisms involved in drug and sugar
reinforcement. These studies are important as research on drug addiction is having an impact on designing
interventions to combat obesity and in the development of public health policy despite evidence to suggest that there
are important differences in how drugs and food control behaviour. These studies will give us a better understanding
about the validity of “food addiction” as a construct by clarifying the parallels and points of divergence in the
behavioral regulation of sugar and drug reinforcement.

4
Addiction
CHRONIC NICOTINE EXPOSURE DURING ADOLESCENCE ALTERS THE REWARDING
PROPERTIES OF THE CANNABINOID AGONIST CP 55,940 IN YOUNG ADULT MALE RATS
A. D. Hardin, M. J. Stone, Z. R. Harmony, G. J. Kaplan, C. A. Crawford. California State University, San Bernardino,
CA. (909) 537-7416. hardina@coyote.csusb.edu
Room Number: Hall A
Board Number: K11
Session Title: Adolescence and Addiction
Our data indicates that moderate doses of nicotine, when used in adolescence, increase the preference for low doses of
cannabinoids such as marijuana in adulthood.
Although cigarette use amongst teenagers has reportedly decreased, use of nicotine in general is still problematic in
this population. With the introduction of products like e-cigarettes and vape pens, we see that the reported declines in
cigarette use do not necessarily mean that nicotine use is decreasing, but more likely changing form. Previous research
has demonstrated that nicotine acts as a gateway drug in the teenage brain. The likelihood of moving onto harder
drugs has been shown to increase when nicotine is used regularly at that pivotal age when the brain is still developing.
Additional studies have led researchers to believe that a gateway effect exists on a neurochemical level where the use
of nicotine permanently alters reward systems and thereby increases the chances that the teenager will find harder
drugs more rewarding. Despite the fact that cigarette use has declined, nicotine use is still affecting the adolescent
population.
In order to examine the effects that nicotine use in adolescence has later on in life, we obtained preference scores
through a conditioned place preference paradigm that gave an indication of how rewarding a drug (or combination
of drugs) is. We injected male rats with one of four nicotine doses on a daily basis starting in adolescence (31 days
old, an age determined to be analogous to human adolescence), one dose being a placebo. Administration of nicotine
continued throughout the experiment up until test day.
At 60 days old, rats began a 14-day conditioning phase. The first day was a preconditioning day in which rats were
allowed to establish an initial preference for one of two environments. During the conditioning trials they learned to
associate a marijuana-like drug with the environment they did not prefer. This drug was administered at one of four
doses, one a placebo, for each rat to test how the two drugs work together at various doses. The preferred environment
was paired with saline. On the last day of this procedure (at 73 days old, an age indicated as being analogous to human
adulthood), rats were allowed free access to both environments so that preferences for both environments could be
measured. Because the drug-paired side was not the preferred one, changes in preference to that side indicated that the
combination of drugs was highly rewarding.
The results of this study indicated that nicotine use at a young age could affect how rewarding a drug like marijuana
could be in adulthood. These results serve to confirm suspicions of alterations in the rewarding value of one drug that
can be attributed to nicotine use in adolescence. Additional data is currently being analyzed for inclusion in this study.
In the future, a more in-depth examination of the underlying neurological changes may be carried out through use of
tissue sample data.
It should be mentioned that these results are uncommon for studies of laboratory animals and drugs that work like
marijuana. Laboratory animals have been found to dislike drugs of this nature on a much more consistent basis. The
preference shown for the combination of specific doses of nicotine and marijuana-like drugs in animals that generally
avoid it speaks to the powerful impact the two drugs can have together in humans who do not work so hard to avoid it.

5
Addiction
METHAMPHETAMINE-INDUCED ABERRANT NEUROGENESIS: PROTECTION BY EXERCISE
M. Toborek, H. Levine, M. Park. University of Miami School of Medicine, Miami, FL. (305)243-0230.
mtoborek@med.miami.edu
Room Number: Hall A
Board Number: K7
Session Title: Amphetamines and Cocaine
Our study indicates that voluntary exercise protects against abnormal neurogenesis induced by a common drug of
abuse, methamphetamine.
Amphetamines are the second (after cannabinoids) most often abused drugs in the US. Worldwide, approximately 35
million people use this illicit drug. Methamphetamine is relatively easily available, easy to use, and has a relatively
low price, combined with a high potential of addiction. Methamphetamine has very fast stimulatory effects on the
brain and causes the feeling of immediate and intense euphoria. These effects are only temporary, which prompts
frequent use of the drug in increasing doses. People who abuse methamphetamine long-term experience cognitive
dysfunction, anxiety, mood disturbances, and display violent behavior. In addition, they experience loss of memory.
Several of these effects can be linked to the function of the brain structure, called the hippocampus.
It is now generally accepted that neurons are produced in the adult brain, including the hippocampus, from parent
cells, called neural progenitor cells. The process is called neurogenesis. These newly formed neurons are important for
learning and memory. Indeed, their generation is shown to be affected in disease conditions associated with cognitive
impairment, depression, or anxiety. The major pool of these cells is located in proximity to small brain vessels,
making them susceptible to vascular changes. Because methamphetamine is characterized by substantial vascular
toxicity, we hypothesized that this effect may impair differentiation of neural progenitor cells to mature neurons.
There is currently no effective therapy for the treatment of methamphetamine addiction and/or toxicity; however,
recent studies provide preliminary evidence in support of beneficial effects of exercise-based interventions in reducing
depression and anxiety symptoms in abstinent methamphetamine-dependent individuals. These reports coincide
with our data that voluntary exercise stabilizes the brain vessels in an animal model of methamphetamine toxicity.
Therefore, in the present study we also evaluated if exercise can influence the impact of methamphetamine on
neurogenesis.
Mice were injected with methamphetamine three times per day for 5 days with an escalating dose regimen in 3 h
intervals, starting from 0.2 mg/kg, mimicking the pattern of drug abuse in humans. One set of mice was sacrificed 24
h post last injection of methamphetamine, and the remaining animals were either subjected to voluntary wheel running
(exercised mice) or remained in sedentary housing (the sedentary group). Methamphetamine administration resulted
in increased permeability of the vessels in the hippocampus and, at the same, was associated with abnormal neural
differentiation. Specifically, less neurons were formed and they exhibited abnormal morphology. These effects were
long-lasting and were preserved as long as two weeks after methamphetamine administration was discontinued.
Exercise protected against these effects by enhancing the integrity and stability of brain vessels. Importantly, exercise
stimulated neurogenesis and attenuated abnormal neurogenesis, bringing the number and morphology of newly
formed neurons to control levels. In addition, exercise protected against the methamphetamine-induced systemic
increase in inflammatory cytokine levels. These results suggest that exercise is a powerful approach to protect against
methamphetamine-induced neurotoxicity and abnormal formation of new neurons in adult brain by maintaining
the health of brain vessels and related micro-environmental changes in the hippocampus. These findings provide
promising evidence that exercise can be used to protect the brain against toxicity substances, including illicit drugs,
which affect normal brain functions.

6
Aging
HDAC3: AN EPIGENETIC KEY TO AMELIORATING SYNAPTIC PLASTICITY AND MEMORY
IMPAIRMENTS IN THE AGING BRAIN
J. L. Kwapis, Y. Alaghband, E. A. Kramár, D. P. Matheos, D. Rhee, A. J. Lopez, M. A. Wood. University of California,
Irvine, Irvine, CA. (414) 229-4979. jkwapis@uci.edu
Session Date/Time: Sunday, Oct.18, 1:00 PM
Room Number: Hall A
Board Number: X29
Session Title: Molecular Mechanisms of Memory Consolidation
Our research indicates that epigenetic mechanisms may contribute to age-related memory dysfunction. Further,
our work suggests that restoring these dysregulated epigenetic mechanisms can ameliorate age-related memory
impairments. This work is not yet published.
Aging is accompanied by numerous cognitive impairments, including difficulty forming long-term memories. This
is an increasingly important problem, as lifespans continue to lengthen and approximately 20% of the US population
is expected to be age 65 or older by the year 2030. Identifying the mechanisms that underlie age-related memory
impairments may lead to new treatment strategies to improve memory and prolong healthy cognitive aging.
Long-term memory formation requires gene expression, a process that may be disrupted with age. Epigenetic
mechanisms, which change gene expression by regulating chromatin structure rather than changing the DNA sequence
itself, may therefore contribute to age-related impairments in memory. One major epigenetic mechanism important
for memory is histone acetylation, in which acetyl groups are added or removed from histone tails by histone
acetyltransferases (HATs) or histone deacetylases (HDACs), respectively. Generally, HDAC-mediated removal of
acetyl groups from histone tails promotes a repressive chromatin structure that restricts gene expression. In particular,
histone deacetylase 3 (HDAC3) appears to be a key negative regulator of learning-induced gene expression and long-
term memory formation, as blocking HDAC3 produces persistent memory for hippocampus-dependent object location
memory following subthreshold training. To date, no one has tested whether HDAC3 contributes to age-related
impairments in long-term memory or synaptic plasticity.
In this study, we created focal genetic deletions of HDAC3 in the dorsal hippocampus of aging, 18-month-old mice.
We then trained these mice in a simple hippocampus-dependent memory task, object location memory, in which
mice learn the location of two identical objects in a familiar context. Object location memory is a form of memory
that quickly deteriorates in the aging human brain. We found that wildtype mice show age-related deficits in object
location memory, as expected. Deleting HDAC3 in the dorsal hippocampus ameliorated this memory impairment;
18-month-old mice with hippocampal HDAC3 deletions showed robust memory with the same training parameters.
We then demonstrated that age-related synaptic plasticity impairments were also ameliorated by selectively disrupting
HDAC3 activity in the dorsal hippocampus. As synaptic plasticity is generally agreed to be a cellular correlate of
memory formation, this indicates that age-related impairments in memory may occur through impaired synaptic
plasticity. Finally, we measured the mRNA levels of three different learning-induced genes (cFos, Arc, and Nr4a2)
in the dorsal hippocampus to identify the gene signature following learning in the aging brain. We found that Nr4a2
(an immediate early gene previously implicated in long-term memory) failed to normally express following learning
in aging wildtype mice. Nr4a2 expression, however, was restored in mice lacking HDAC3 in the hippocampus,
indicating that this is one potential mechanism through which HDAC3 deletion may ameliorate age-related memory
impairments.
Overall, these results suggest that HDAC3 may be dysregulated with age, contributing to a repressive chromatin
structure that impairs gene expression and therefore memory and synaptic plasticity in the aging brain. We are
currently working to understand how gene expression dynamics downstream of HDAC3 change with age, giving rise
to age-related impairments. Overall, the findings from this study suggest that HDAC3 may be one key mechanism that
could be targeted to improve memory during the aging process.

7
Alzheimer’s
EXPRESSION OF MICRO-RNA-34A IN LATE-ONSET ALZHEIMER’S DISEASE (LOAD) BRAIN
MECHANISTICALLY LINKS SYNAPTIC PLASTICITY AND ENERGY METABOLISM DYSFUNCTION
VIA SIMULTANEOUS REPRESSION OF TARGET GENES
S. N. Sarkar, S. Jun, S. Rellick, D. D. Quintana, J. W. Simpkins. West Virginia University, Morgantown, WV.
(817)675-1401. snsarkar@hsc.wvu.edu
Room Number: S401
Board Number: N/A
Session Title: Alzheimer’s Disease: Synaptic and Neuronal Dysfunction
Alzheimer’s disease (AD) is the most common form of dementia for which there is currently no disease modifying
treatments. The genetics of AD is complex and a number of study indicate that many important genes necessary for
energy metabolism and synapse activity are down regulated in AD. Also, functional imaging studies of AD subjects
reveal that the severity of decrease in brain metabolism correlates with increased dementia. Thus, the development
of new therapeutic strategies to treat AD requires the identification of novel molecular targets that are involved in
simultaneously dysregulating activity of multiple genes involved in brain energy metabolism and synaptic plasticity.
MicroRNAs (miRs) are important gene expression regulators. The binding of these short (~21-23 nucleotides)
non-protein-coding RNAs to its target mRNA results in either translational repression or degradation of the target.
Because, a single miR can target many gene transcripts and concurrently down regulate multiple biological pathways
by repressing mRNA translation, we sought to identify novel miRs that maximizes the number of target genes
involving AD.
We discovered that miR-34a compared to other miRs is over expressed in the temporal and frontal cortex but not
the cerebellum in AD and the level of expression correlated with AD neuropathology. Further overexpression of
miR-34a in the AD brain correlates with reduced expression of proteins important for synaptic plasticity and energy
metabolism. The forced overexpression of miR-34a in primary neurons severely reduced mitochondrial function and
reduced target protein levels necessary for brain metabolism. Moreover, we showed that secreted miR-34a exosomes
generated in neurons have the capacity to spread and deliver miR-34a among neurons thereby potentially spreading
the disease. Collectively, the results of these studies can expedite the discovery of AD modifying therapy.

8
Alzheimer’s
PASSIVE VACCINATION TARGETING PYROGLUTAMATE-3 Aβ REDUCES Aβ PLAQUE BURDEN
WITHOUT MICROHEMORRHAGE AND PARTIALLY RESCUES COGNITIVE DEFICITS IN AGED APP/
PS1DE9 MICE
H. Crehan, M. Kleinschmidt, E. Fitzpatrick, S. Chowdhury, K. Le, J. L. Frost, B. O’Nuallain, B. J. Caldarone, H.
Demuth, J. Rahfeld, I. Lues, S. Schilling, C. A. Lemere. Brigham & Women’s Hospital, Boston, MA. (617) 525-5263.
hcrehan@partners.org
Room Number: S403
Board Number: N/A
Session Title: Alzheimer’s Disease: Experimental Therapeutics
Our research demonstrates reduction in amyloid-β (Aβ) plaque burden and a partial cognitive rescue in aged APP/
PS1dE9 transgenic mice, Alzheimer’s disease animal model, following 4 months of weekly treatment with an anti-
pyroglutamate-3 Aβ IgG2a monoclonal antibody (mAb) called “m6”.
Alzheimer’s disease is the main cause of dementia in the elderly, caused by changes in the brain that are beyond
normal aging. A gradual build-up and misfolding of proteins, called Aβ protein and tau, in the brain damages nerve
cells called and their inter-connections, and incites neuroinflammatory responses, ultimately resulting in nerve cell
loss and cognitive decline. Pyroglutamate-3 Aβ is a particularly toxic, truncated and modified version of the Aβ
protein, a normal protein found in nerve cells. It is formed when two amino acids are trimmed off the beginning
(N-terminus) of Aβ to expose an amino acid called glutamate. After exposure to an enzyme called glutaminyl cyclase,
the N-terminus is modified, resulting in a stickier, harder-to-degrade, toxic pyroglutamate-3 Aβ protein.
Immunotherapy for Alzheimer’s disease is a method of stimulating the immune system to clear Aβ using antibodies.
These antibodies can be divided into different classes or isotypes and these isotypes differ in their biological
properties. Our collaborators at Probiodrug Ag (Halle, Germany) have developed several monoclonal antibodies
targeting pyroglutamate-3 Aβ that have different isotypes (including k6, IgG1 and m6, IgG2a mAbs). Here, we
passively immunized 12 month-old APP/PS1dE9 mice, an age at which these mice typically have many amyloid
plaques in brain and some cognitive deficits, to 16 months of age. We carried out behavioral testing in these mice
during the last month of treatment. Remarkably, we showed, for the first time, that mice treated with an anti-
pyroglutamate-3 Aβ mAb (m6, IgG2a mAb) were significantly better at learning and memory in the Water T-Maze
Test, compared to saline-treated APP/PS1dE9 mice. There were no differences in general locomotor activity
in the Open Field test; however, there was a trend for normalization of anxiety-like behavior in k6 IgG1 anti-
pyroglutamate-3 mAb compared to saline-treated mice. Tiny microhemorrhages have been observed following
treatment with some anti-Aβ mAbs in previous studies. However, after staining the mouse brain tissues, we found no
evidence for increased microhemorrhages after treatment with either isotype of anti-pyroglutamate-3 mAb. The plaque
burden in the hippocampus and cortex of these animals was significantly reduced in m6 IgG2a anti-pyroglutamate-3
Aβ mAb-treated mice compared to saline-treated control mice. Reduced amyloid levels were further confirmed
biochemically. In addition, we found that the reduced Aβ plaque load in the brains of the m6 IgG2a pyroglutamate-3
mAb-vaccinated mice correlated with an increase in immune cells such as microglia and macrophages in the brain,
specifically around the Aβ plaques, which likely contributed to Aβ lowering in brain as these cells are known to play a
role in engulfing debris, including Aβ deposited outside of cells.
Our study indicates that anti-Aβ antibody isotype and target play important roles in Aβ immunotherapy treatment.
The m6 IgG2a anti-pyroglutamate-3 mAb may be useful for clearing existing plaques, without introducing
microhemorrhages, and stabilizing cognition after the onset of Alzheimer’s disease. Further studies are underway
to better understand the specific role of pyroglutamate-3 Aβ in Alzheimer’s disease progression and mechanisms of
clearance using anti-pyroglutamate-3 Aβ monoclonal antibodies.

9
Alzheimer’s
A NOVEL MECHANISM FOR LOWERING ABETA
P. C. Mullen, C. Chen, E. Zeldich, L. E. Brown, J. A. Porco, C. R. Abraham. Boston University School of Medicine,
Boston, MA. pcmull09@yahoo.com
Room Number: N226
Board Number: N/A
Presentation Time: 10:30 - 10:45 AM
Session Title: Alzheimer’s Disease: Beyond Abeta and Tau
Our group has discovered a novel method to inhibit the production of a protein implicated in Alzheimer’s disease
(AD). This protein, called amyloid beta (or “Abeta”) is toxic to nerve cells and has been shown to cause the cognitive
deterioration and progressive dementia that occur in AD. It is widely thought that lowering Abeta levels, either
through clearance or inhibition of its production, should ameliorate or even prevent the progression to full blown AD.
We have discovered a class of small molecules that are capable of inhibiting Abeta production. Our approach toward
preventing Abeta production is highly unique in the context of AD treatment. To date, all Abeta-targeting therapeutics
have focused on clearing Abeta after it has formed. Further, all completed clinical trials targeting Abeta clearance to
date have failed. Abeta is a fragment of a larger protein named the amyloid precursor protein or “APP.” The joining
of two APP proteins (a process known as “dimerization”) initiates a poorly understood sequence of events that
ultimately leads to increased Abeta production. Knowing this, we performed a search for small drug molecules that
would inhibit APP dimerization. From nearly 80,000 molecules tested, a single “hit” APP-dimerization inhibitor was
identified. From this initial hit we were able to identify similar compounds that are even more potent Abeta blockers.
Given what is known about the activity of these compounds, we have further identified possible enzymes involved
in the pathway leading from APP dimerization to Abeta production. We are currently studying these Abeta-lowering
compounds in two ways. First, we are using the molecules as tools to help elucidate and characterize this Alzheimer’s-
causative pathway. This characterization has led to additional drug targets heretofore unknown in the context of AD.
Second, these molecules are being further studied and optimized as potential AD therapeutics. AD is the major form
of dementia among the elderly. With the average life expectancy steadily increasing, the number of people suffering
from AD is increasing similarly. At present, approximately 36 million people suffer with AD worldwide, and that
number is expected to increase to about 120 million by 2040. Cognitive functions, such as learning and memory,
are of fundamental biological importance. Diseases such as AD, which affect these functions, are among the most
challenging biomedical problems of our time, scientifically, emotionally, and financially. Despite decades of intense
research and billions of dollars spent on clinical trials, no disease-modifying treatment has been identified. Currently,
there are four FDA-approved drugs for AD. Two classes of compounds are currently in use: cholinesterase inhibitors
(e.g., donepezil, rivastigmine, galantamine) and a glutamate inhibitor (e.g., memantine). These drugs offer minor
improvement in patient cognition for a short period of time, but do not affect the underlying cause of the disease
or stop deterioration of functional abilities. By inhibiting Abeta formation we hope to have the first small molecule
disease-modifying drug to treat AD. A small molecule is easy to manufacture and orders of magnitude less expensive
than the antibodies used to clear Abeta.

10
Alzheimer’s
RISK OF AGGRAVATION OF NEURONAL DYSFUNCTION BY PASSIVE IMMUNOTHERAPY WITH
ANTI-Aβ ANTIBODIES
M. A. Busche, A. Keskin, C. Grienberger, U. Neumann, M. Staufenbiel, H. Förstl, A. Konnerth. Institute of
Neuroscience, Technical University Munich, Munich, Germany. aurel.busche@lrz.tum.de
Session Date/Time: Monday, Oct.19, 1:00 PM
Room Number: N426A
Board Number: N/A
Session Title: Structural and Signaling Changes in Aging and Alzheimer’s Disease
Our research provides a cellular explanation for the failure of immunotherapies for Alzheimer´s disease (AD) in
recent clinical trials.
AD is the most common cause of dementia in the elderly. The incidence of AD continues to rise as the population
ages, but preventive or curative treatments are still lacking. Substantial human genetic, neuropathological, and
biochemical evidence definitely indicates that the excessive accumulation and deposition of amyloid-β (Aβ) peptides
in the brain plays an essential role in the pathogenesis of the disease. Accordingly, the clearance of Aβ peptides
from the brain - especially, by using passive immunotherapy with Aβ antibodies - has become a leading therapeutic
goal in the treatment of AD. However, all recent clinical trials of immunotherapies have ended in failure. A better
understanding of the cellular mechanisms of the Aβ antibodies in the diseased brain may help to explain this
seemingly counterintuitive finding.
In this study, we used in mouse models of AD high-resolution two-photon calcium imaging, a microscopic technique
that allows to visualize the activity of many neurons in the brain of living animals in real-time. As expected from
previous studies, treatment with Aβ antibodies reduced the Aβ burden in the brains of the Alzheimer models.
However, the treatment was ineffective in repairing neuronal dysfunction, and even worsened it. Indeed, we found that
two different Aβ antibodies used for treatment of AD caused a massive increase in abnormal neuronal hyperactivity.
Furthermore, in some cases, the treatment even promoted abnormal neuronal synchrony, which may increase the risk
for epileptogenic activity.
These results suggest that Aβ antibodies can aggravate neuronal dysfunction despite the apparently beneficial effects
on Aβ burden in the brain. The next step of this research is to investigate the underlying mechanisms of our findings
and to evaluate whether other Aβ-lowering therapies have similar or different effects on neuronal dysfunction in the
intact brain in vivo.
The findings from this study provide a cellular mechanism for the failure of immunotherapies for AD in repairing
cognitive deficits and highlight the urgent need to incorporate functional in vivo assays into the toolbox of methods
for the development and evaluation of new treatment strategies for AD.

11
Alzheimer’s
TRANSLATING CD33 GENETICS TO AN ALZHEIMER’S DISEASE PROPHYLACTIC
S. Estus, M. Malik, J. Simpson, J. Turchan. Sanders-Brown Ctr Aging, Lexington, KY. (859) 323-3985 EXT 264.
sestus2@email.uky.edu
Session Date/Time: Tuesday, Oct.20, 8:00 AM
Room Number: S403
Board Number: N/A
Session Title: Alzheimer’s Disease: Risk Factors
Our research suggests that an antibody-based drug that has been used safely in humans may be help to enhance the
body’s immune response to fight against Alzheimer’s disease (AD).
AD is a modern day scourge that takes away a person’s self while challenging families financially. As we have an
aging population, effective methods to prevent, treat, or delay AD must be developed to avoid a public health crisis.
Along with other AD researchers, we are working to identify the mechanisms underlying genetic risk factors and then
exploiting these mechanisms to tackle the disease. Twin and family studies suggest that AD risk is largely genetic.
Recent large-scale genetic studies identified genetic variants called single nucleotide polymorphisms (SNPs) that
influence AD risk. Several of these SNPs were found in genes related to brain inflammation. Although we have long
known that AD brains have increased inflammation, the identification of these genetic risk factors demonstrates that
inflammation is not merely a result of AD but rather contributes to the cause of AD. Hence, we have focused our effort
on understanding how AD genetic risk factors impact the function of these genes at the molecular and cellular level.
A SNP near a gene called CD33 was one of the genetic variants found to influence AD risk. The CD33 gene consists
of seven exons that, when joined together, encode a protein that inhibits immune activation. In the brain, CD33
is expressed in cells called microglia, the resident immune cells. To elucidate the actions of the CD33 SNP, we
studied RNA isolated from autopsied human brain to identify RNA where the CD33 exons were not joined together
appropriately. We found CD33 isoforms that lacked exon 2 or retained sequence between exon 1 and 2. Both of
these CD33 variant RNAs are predicted to produce non-functional CD33 protein. When we quantified these mRNA
variants, we found that individuals with the AD-protective allele of the SNP produced a greater proportion of CD33 as
these nonfunctional CD33 isoforms and, therefore, less functional CD33.
Since an apparent loss of functional CD33 correlates with reduced AD risk, we interpret our findings as suggesting
that a more robust CD33 inhibitor may reduce AD risk further. Considering possible inhibitors, we noted that since
acute myeloid leukemia (AML) cells overexpress CD33, pharmaceutical companies have tried to target these cells
with antibodies against CD33. For example, a CD33 antibody called Lintuzumab was found to be safe in humans
but ineffective when tested in AML trials. Since antibody binding to a cell surface receptor like CD33 often leads
to internalization and destruction of the receptor, we tested Lintuzumab as a reagent to reduce CD33 on the cell
surface. We found that Lintuzumab is effective and potent in promoting CD33 degradation in human cell lines. We
are currently evaluating Lintuzumab effects on microglial cell line function, including phagocytosis and production of
inflammatory mediators called cytokines.
Overall, genetics suggest that reduced CD33 function is associated with reduced AD risk. Hence, CD33 inhibitors
may protect from AD. Our studies with Lintuzumab are just one of the approaches underway to inhibit AD. Given
the safety record for Lintuzumab and our findings here regarding potency and efficacy, this agent may prove useful
in future studies. Hence, elucidating the mechanisms underlying genetic protection from disease and developing
pharmacologic agents that mimic these protective effects may prove useful in our fight against AD.

12
Alzheimer’s
GENERATION OF ISOGENIC IPS CELLS TO ADDRESS THE EFFECTS P25/CDK5 ACTIVITY ON AD
PATHOLOGY
J. Seo, Y. Lin, R. Madabhushi, L. Tsai. Massachusetts Institute of Technology, Cambridge, MA. (617)324-1648.
jinsoo.roneto@gmail.com
Room Number: Hall A
Board Number: C18
Our study shows that neuronal cells derived from induced pluripotent stem cells (iPSCs) from patients with
Alzheimer’s disease (AD) recapitulate pathological phenotypes of the disease. By utilizing genome editing technique,
we generate isogenic lines, the ones that differ from the patient’s cells only by not expressing p25, a cyclin-dependent
kinase activator, and investigate the beneficial effects of p25 inhibition on AD.
AD is a progressive neurodegenerative disease characterized by profound memory loss, disruptions in thinking and
reasoning, and changes in personality and behavior. As of now, AD is the sixth-leading cause of death in the United
States and more than five million Americans suffer from the disease. Moreover, the prevalence of the disease is
estimated to be increased by 40% in the next ten years due to the aging American population. Although the disorder
was first identified over 100 years ago, there is still no effective treatment or cure for the disease.
Previously, researchers found abnormally increased levels of certain protein, called p25, in post-mortem brain samples
from AD patients. And many studies revealed the deleterious role of p25, which causes aberrant activation of Cdk5
leading to multiple pathological phenotypes including neuroinflammation and cell death in brain. To precisely address
the roles of p25 in AD, we have generated transgenic mice in which endogenous p25 expression is suppressed,
and found that the blockade of p25 generation attenuated various pathological phenotypes such as amyloid plaque
formation and cognitive deficits in the brain of an AD mouse model.
In this study, we made further investigation on the effects of p25 inhibition on AD pathology in human systems
because of the lack of tauopathy phenotypes in most of AD mouse models harboring mutations in amyloid beta
precursor protein (APP) or presenilin 1 (PSEN1) locus, and the biochemical and physiological differences between
mouse models and humans. For this purpose, we took advantage of iPSCs derived from fibroblasts of AD patients
harboring mutations on PSEN1 locus. We first differentiated iPSCs to neural progenitor cells (NPCs), and observed
more DNA damage and increased levels of histone deacetylase 2 known to suppress expression of genes required
for learning and memory in NPCs harboring PSEN1 mutations compared to controls. Also, our epigenetic profiling
data from these lines suggest reduced transcriptional activity in cell cycle-related genes, but more active transcription
in genes involved in differentiation. To address whether inhibition of p25 generation is beneficial, we utilized the
CRISPR/Cas9 genome editing tool for PSEN1 mutant iPSCs to create isogenic lines, in which endogenous p25
generation is blocked. We also created control isogeneic iPSCs in which PSEN1 mutations are corrected.
The pathological phenotypes observed in NPCs suggest that neuronal cells derived from patients’ iPSCs are useful for
a better understanding of the underlying mechanisms of AD. With multiple pairs of isogenic lines, we are currently
investigating the role of p25 on the disease and beneficial effects of inhibiting p25 generation by differentiating them
into other cell types such as NPCs, neurons or gilal cells and characterizing them in aspect of Aβ generation, synaptic
function and neuroinflammation. By performing transcriptosome analyses, we will also address whether PSEN1
mutations have an effect on gene transcription in the whole-genome and whether inhibition of p25 attenuates such a
change.
Although, many of animal models for the disease have contributed greatly to our understanding of disease
mechanisms, the medications that have made it to clinical trials based on the animal studies have so far failed. Using
human model system with a proper control, the findings from this study will provide better understanding of the
mechanisms that drive AD progression and idea for developing novel therapeutics.

13
Alzheimer’s
DYSFUNCTIONAL TUBULAR ENDOPLASMIC RETICULUM IN ALZHEIMER’S PATHOGENESIS
R. Yan, M. Sharoar, Q. Shi, Y. Ge, J. Zhou, W. He, X. Hu, G. Perry, X. Zhu. Case Western Reserve University School
of Medicine, Cleveland, OH. (216) 445-2690. yanr@ccf.org
Room Number: N226
Board Number: N/A
Abnormally clustered tubular endoplasmic reticulum (ER) is identified as a pathological trigger, which can disrupt
mitochondrial integrity and induce formation of dystrophic neurites (DNs) in brains of Alzheimer’s disease (AD)
patients. Pathological features in Alzheimer’s brains include mitochondrial dysfunction and DNs in areas surrounding
amyloid plaques. We hypothesize that simply removing amyloid plaques or tau aggregates will not be sufficient to
improve cognitive function in AD patients if DNs are persistent. This conjecture is consistent with repeated failures in
AD clinical trials, as cognitive function is not significantly improved. This study provides the first evidence that shows
abnormal changes in tubular ER organization in brain cells (neurons) causing pathological changes closely related to
cognitive functions in human. Our results suggest that prevention of such abnormal tubular ER clustering in elderly
people is likely an alternative strategy for treating and improving cognitive function in AD patients.
In AD brains, pathological hallmarks include neuritic plaques and neurofibrillary tangles. Neuritic plaques refer to
core amyloid deposition surrounded by reactive glial cells and DNs. Intriguing questions regarding how DNs are
formed and what the pathological consequences of DN formation are remain to be answered. In our earlier study, we
discovered that a protein called reticulon 3 (RTN3) is abundantly enriched within DNs. More interestingly, transgenic
mice overexpressing RTN3 under the control of prion promoter (Tg-RTN3) spontaneously develop DNs, which are
also
called RTN3-immunoreactive dystrophic neurites (RIDNs), in Tg-RTN3 hippocampi in an age-dependent manner.
Such RIDNs can also naturally occur in aging wild-type mouse hippocampi, excluding possible artificial formation
of RIDNs in this transgenic mouse model. More significantly, our functional and morphological studies demonstrated
that the presence of RIDNs clearly disrupts normal dendritic structures and that these impairments can cause
reduction of long-term potentiation (LTP) as well as impairments in learning and memory. Moreover, the density of
RIDNs correlates with impaired cognitive function, implicating it as a contributing factor in aging and AD cognitive
dysfunction.
In our recent studies, using this Tg-RTN3 mouse model, we discovered that DNs contain both RTN3 and REEPs,
topologically similar proteins that can shape tubular endoplasmic reticulum (ER). Importantly, ultrastructural
examinations of such DNs revealed gradual accumulation of tubular ER in axonal termini, and such abnormal
tubular ER inclusion is found in areas surrounding amyloid plaques in biopsy samples from AD brains. Functionally,
abnormally clustered tubular ER induces enhanced mitochondrial fission in the early stages of DN formation and
eventual mitochondrial degeneration at later stages. Furthermore, such DNs are abrogated when RTN3 is ablated in
aging and AD mouse models.
Tubular ER is a part of smooth ER. While the precise function of tubular ER in neurons remains to be established,
recent emerging evidence suggests that it likely mediates vesicle transport and/or organelle contacts,
controls cellular communications, and regulates mitochondrial fusion and fission. This study provides the first
evidence that altered tubular ER organization in cells can causes pathological consequences. Such changes in
hippocampal neurons are linked to cognitive failure in AD.

14
Brain Development
BIRTH: AN OVERLOOKED EVENT IN BRAIN DEVELOPMENT?
A. Castillo-Ruiz, M. Mosley, N. G. Forger. Georgia State University, Atlanta, GA. (517) 402-9284.
acastilloruiz@gsu.edu
Room Number: Hall A
Board Number: S1
Session Title: Parental and Gestational Influences on Stress Vulnerability
Our research indicates that birth is an important event for brain development and that deviations from the natural
(vaginal) mode of birth may alter brain development and behavior.
For the newborn, vaginal birth entails a dramatic entry to the world as this event is accompanied by hormonal
changes, mechanical pressure, a switch to air breathing, and a transition from the womb’s sterile environment to one
teeming with microorganisms. In preparation for postnatal life, organs such as the lungs, heart, and gut go through
physiological adjustments right before birth; whether developmental processes in the brain are similarly triggered by
birth has not been studied. Mice offer a great opportunity to study birth as their reproductive biology has features that
are shared with all placental mammals, including humans.
We recently found that many brain regions show increased cell death around the time of birth in mice, and that on the
day of birth, mice born by Cesarean section had decreased cell death across several brain regions compared to those
born vaginally. These findings could have important implications because the pruning of cells is an important event
that reshapes neural circuits early in development. With the advent of modern medicine, Cesarean births are becoming
a widespread practice around the world. In fact, in the US they account for more than 30% of births per year.
Remarkably, little is known about the effects of Cesarean birth on brain development, although recent studies have
linked Cesarean birth with greater risk for developing disorders such as asthma, type 1 diabetes and celiac disease,
later in life.
In this study, we sought to systematically examine how birth influences cell pruning in the brain (cell death) by
manipulating birth mode in mice, and by collecting brains of female and male offspring before and after birth, up to
weaning age, carefully matching pups for time of delivery. We also measured physical development and behavior.
While birth mode did not affect measures of development such as body weight or eye-opening in juvenile mice, we
observed an increase in body weight in Cesarean born mice at weaning age, which is consistent with clinical reports of
higher body mass index in humans born by Cesarean section. In addition, in a test of behavioral development, which
involves separation from the mother early in life, we found that Cesarean born pups made softer cries than those born
vaginally. Interestingly, it has been shown that the louder an infant mouse cries, the more attention it receives from the
mother.
We are currently processing the brains of these mice for detection of cell death, as well as ‘microglia’, a cell type that
may be actively contributing to cell death. Microglia are the brain’s resident immune cells, and can be activated by
chemicals (cytokines) produced by the peripheral immune system. It is known that before and during birth cytokine
levels increase in fetal tissues, but less is known about what happens postnatally. In a pilot study, we recently
identified fluctuations in levels of key cytokines sampled at regular time intervals before and after birth. Our future
work will also investigate if these cytokines mediate the effects of birth on cell death.
Taken together our work on cell death, behavior, and cytokine levels suggests that birth may trigger important events
in brain development. Deviations from the natural mode of birth may interfere with development of the brain which
can result in altered behavior.

15
Brain Development
EXPLORING THE ROLE OF SRGAP2AAND ITS HUMAN-SPECIFIC PARALOG SRGAP2C DURING
SYNAPTIC DEVELOPMENT OF CORTICAL CIRCUITS
E. Schmidt, J. Kupferman, D. Iascone, C. Charrier, F. Polleux. Columbia University, New York, NY.
ers2204@cumc.columbia.edu
Program Number: DP03.01
Room Number: Hall A
Board Number: DP01
Session Title: Dynamic Posters--Sunday Afternoon
Our research shows how a gene that is only present in the human genome, called SRGAP2C, affects the way neurons
connect to each other and how it changes their response to the input they receive. We discovered that SRGAP2C does
this by affecting the function of the ancestral copy of this gene, called SRGAP2A, which is found in all mammals.
This work provides novel insights into how genes that emerged during the course of human evolution have helped
shape the structure, organization and function of the human brain.
What makes us human? An intriguing and fundamental question that has kept philosophers, artists, and scientists
engaged for many centuries. A particular hallmark that characterizes modern humans is the emergence of higher
cognitive functions that allowed for abstract thinking, language, and complex reasoning, all of which have been
dependent, in part, on the evolution of the mammalian neocortex.
Compared to other mammals, including primates, a characteristic feature of the human neocortex is the extended
period of maturation that is believed to be fundamental for our increased capacity to learn. In addition, the human
brain shows a significant increase in the number of connections established between specific groups of neurons, for
example cortical neurons. However, evolutionary changes that have led to this prolonged synaptic maturation and
increased connectivity are by no means trivial. Potential problems include generating an imbalance between excitatory
and inhibitory connectivity that might have dramatic consequences for neuronal circuit function. Indeed, such
imbalances have been hypothesized to underlie various neuropsychiatric disorders, such as autism and schizophrenia.
Understanding the mechanisms that control neuronal connectivity and maturation, and how these mechanisms evolved
to shape the human brain, is therefore crucial to understand neurodevelopmental and neuropsychiatric disorders.
In the present study, we focus on the human-specific gene called SRGAP2C. While all mammals have a copy of the
ancestral SRGAP2A gene, only in the human lineage this gene was duplicated and altered, resulting in the human-
specific variant SRGAP2C. Previously published work from our lab (Charrier et al. 2012) has shown how expression
of SRGAP2C in mouse cortical neurons increases the number of connections these neurons receive and the time
it takes for neuronal connections to mature. Interestingly, both these features are characteristic of human neurons.
More recent data from our lab demonstrate that these changes affect both excitatory and inhibitory connections and
preserves the balance between them. This is one of the first molecular mechanisms to be discovered that coordinates
both excitatory and inhibitory connectivity and suggests that SRGAP2A and SRGAP2C are involved in regulating
synaptic maturation and connectivity while preserving the balance between excitation and inhibition. We will also
present new data showing that SRGAP2A and SRGAP2C are also directly involved in regulating how neurons
respond to neuronal activity. In addition, using fluorescently tagged versions of both SRGAP2A and SRGAP2C, we
show that SRGAP2C directly alters the levels and localization of SRGAP2A.
Using recent advances to map and visualize neuronal circuits, our current efforts are aimed at unraveling how
SRGAP2A and the human-specific SRGAP2C shape neuronal networks and cortical function in the context of human
brain evolution. Together, our work aims to contribute to the exciting and fundamental question of how neuronal
connectivity is shaped during development and how human-specific genes can modify neuronal circuit architecture to
enable the emergence of higher cognitive functions.

16
Brain-Machine Connections, Prosthetics
A BLUETOOTH WIRELESS BRAIN-MACHINE INTERFACE FOR GENERAL PURPOSE COMPUTER
USE
P. Nuyujukian, C. Pandarinath, C. Blabe, L. Hochberg, K. Shenoy, J. Henderson. Stanford University, Stanford, CA.
sfn14.npl.stanford@herag.com
Room Number: N226
Board Number: N/A
Session Title: Controlling Prostheses with Brain Machine Interfaces
We report the first demonstration of an intracortically-controlled tablet computer. Millions of people have paralysis
from spinal cord injury, stroke, or neurodegenerative disease. For some, this disability precludes speaking or
typing and can hinder access to computers and mobile devices. This can limit options for employment and impede
communication with friends and family. For these individuals, assistive technology such as eye- or head-tracking
devices often become important tools to restore the ability to communicate and interact with electronic systems.
However, use of these systems is often limited due to eye fatigue and inaccuracy, and no single technology works
optimally for every individual. Brain-computer interfaces (BCIs) have the potential to be faster and easier to use
than current assistive devices. BCIs record activity from the brain and electronically translate it into useful control
signals for assistive devices without relying on physical movements. The signals extracted from a BCI could be
used to control a broad range of assistive technologies. As an example, a computer system could be controlled by
an individual’s “intent” to move one’s own hand. In this abstract, we report an early demonstration of a wireless
brain-controlled tablet computer. We show that BCIs may be viable tools for controlling and interacting with
general-purpose computing platforms. In prior studies (Gilja*, Pandarinath*, et al. Nature Medicine (in press) and
Nuyujukian*, Pandarinath*, et al., SFN 2014), we detailed the development of a high-performance intracortical BCI
as part of the BrainGate2 pilot clinical trial (http://braingate.org). This study builds upon that work with participant
T6, a 52 year-old woman diagnosed with amyotrophic lateral sclerosis (ALS). Two years prior to the results reported
here, she was neurosurgically implanted with a 100-channel electrode array on the left side of her brain in regions
responsible for movement. The BCI recorded neural activity from her brain and translated it into continuous two-
dimensional control signals (X and Y direction) and a click signal (Simeral, et al. JNE 2011 and Bacher, et al. NNR
2014). We used these “point-and-click” control signals to emulate a Bluetooth wireless mouse and paired it with an
unmodified, off-the-shelf tablet computer running the Android operating system (Google Nexus 9). Participant T6
was able to control the tablet through the BCI, enabling her to to send email, browse the web, watch videos, and
play games. These findings demonstrate further proof-of-principle that intracortical BCIs may be useful assistive
technologies for people with paralysis. Next steps for this work include replication with additional participants
and further improvements to the interface. Certain useful features of general-purpose cursor control are not yet
implemented. The system currently only provides an instantaneous click signal, but not click-and-drag functionality
or multi-touch maneuvers. These additional capabilities will unlock the full user interface common to general-purpose
computers and mobile devices. This work was enabled by the decades of preceding basic systems neuroscience
research and actively leverages recent and ongoing findings from basic science. The findings reported in this study are
a first step towards developing a fully-capable brain-controlled communication and computer interface for restoring
function for people with paralysis.

17
Cell Communication
METHAMPHETAMINE REGULATES TRAFFICKING OF THE NEURONAL GLUTAMATE
TRANSPORTER, EAAT3
S. M. Underhill, P. D. Hullihen, S. G. Amara. NIH/NIMH, Bethesda, MD. (301) 402-9211. smunderhill@yahoo.com
Session Date/Time: Monday, Oct.19, 1:00 PM
Room Number: Hall A
Board Number: B30
Session Title: Glutamate Transporters
Amphetamine (AMPH) and methamphetamine (METH) are addictive stimulant drugs that affect behavior through
modulation of brain neurotransmitters, primarily dopamine and glutamate. Although AMPH and METH are almost
identical in structure, they have different behavioral actions, medicinal uses, and addictive potentials. AMPH
and METH both act to increase extracellular dopamine concentrations by modulating the dopamine transporter,
DAT, a neuronal membrane protein that mediates the reuptake of dopamine from the extracellular space during
neurotransmission. AMPH and METH enter dopamine neurons through the DAT and enhance dopamine levels
through several mechanisms, one of which involves the removal of the DAT from the cell surface, which decreases
dopamine clearance and leads to a buildup of dopamine in critical circuits within the brain. We have recently shown
that AMPH also has the ability to regulate the major excitatory neurotransmitter, glutamate, by altering the surface
distribution of glutamate transporter, EAAT3. In order to address whether METH also affects the clearance of
glutamate uptake by EAAT3, we treated cultured dopamine neurons with AMPH or METH and observed a dramatic
decrease in both DAT and EAAT3 at the cell surface. However, when the effects of METH on other neurons within
the brain were compared with those of AMPH a striking difference emerged: AMPH only affected cells that expressed
DAT, whereas METH had broad effects on glutamate transport in many types of neurons that were not dependent on
the presence of the DAT.
These findings indicate that unlike AMPH, METH has the capacity to alter clearance of glutamate by modulating the
density of surface glutamate transporter in a manner that does not depend on DAT expression. These data imply that
METH acts not only on dopamine neurons but also has the capacity to alter glutamate signaling in a wider variety of
neurons within the brain, which could contribute to the different behavioral and neurochemical profiles of METH and
AMPH.

18
Cellular & Molecular Techniques
IN VIVO DEEP TWO-PHOTON BRAIN IMAGING WITH A RED-SHIFTED FLUOROMETRIC CA2+
INDICATOR
C. H. Tischbirek, A. Birkner, H. Jia, B. Sakmann, A. Konnerth. Institute of Neuroscience, TU Munich, Munich,
Germany. carsten.tischbirek@lrz.tum.de
Session Date/Time: Wednesday, Oct.21, 8:00 AM
Room Number: Hall A
Board Number: CC72
Session Title: In Vivo Imaging Methods
We present a versatile method to image the activity of individual neurons with improved depth penetration in the
intact brain of living animals.
When neurons are active, Ca2+ ions rapidly flow into them. This Ca2+ influx is, for example, crucial for cells to
effectively communicate with other neurons. In cells filled with a fluorescent Ca2+ indicator, changes of Ca2+
concentrations can be optically monitored with high speed, spatial resolution and sensitivity using specialized
microscopes. More than three decades of research into this topic have led to a great number of Ca2+-indicators and a
large variety of technical approaches to record cellular activity with them. In this study, we used the newly developed
synthetic dye Cal-590 (AAT Bioquest, Sunnyvale, CA, USA) in combination with a microscopic method called two-
photon imaging to record neuronal activity down to depths of 900 µm below the surface of the brain.
The problem with all optical techniques is that light cannot pass through brain tissue without being scattered. Here,
we took advantage of the fact that light with longer wavelengths is scattered less and can therefore pass better through
the brain tissue. Thus, an important property of Cal-590 is that the light that optimally excites the dye, as well as the
light that Cal-590 emits, have longer wavelengths than most dyes commonly used before, resulting in a better depth
penetration. While similar long-wavelength dyes have been developed before, Cal-590 is sufficiently bright, optically
stable and responds to changing Ca2+ concentrations fast enough to efficiently report neuronal activity from deep
within the brain.
Why is an imaging depth of around 900 µm noteworthy, considering that other methods like magnetic resonance
imaging (MRI) are able to image through complete human bodies? The difference is a combination of spatial
resolution and speed. Within the brain of living animals, two-photon imaging allows the functional analysis of single
cells as well as small structures like the processes of individual brain cells, called dendrites, and even tiny processes
on the dendrites, called dendritic spines. Additionally, our microscopes can record up to 1000 images per second,
which is fast enough to monitor the cellular Ca2+ dynamics in great detail. Furthermore, the mouse cortex is roughly
1 mm thick and consists of six functionally distinct layers. With the established fluorescent dyes, it was generally
possible to record activity with single-cell resolution down to layer 4. Now, with Cal-590 we can reliably image the
activity of neurons in all layers, even in the deep regions of layer 5 and 6, which are furthest away from the brain
surface. Since this was not possible before, our method might help to analyze the role of these layers within the
complex information processing machinery of the mammalian cortex.
Additionally, Cal-590 can be used for multi-color imaging experiments. In this study, we imaged Cal-590 together
with another Ca2+-indicator, which has shorter excitation and emission wavelengths. Since both dyes are spectrally
different from each other, the emission light of both indicators can be separated and recorded with two detectors.
With the two dyes loaded into different neurons, this approach allows the simultaneous analysis of the activity of
two distinct neuronal populations. As both dyes can be loaded either in single cells or entire cell populations, a great
number of combinations of new experiment can be thought of with the aim to better understand the activity of neurons
and neuronal networks within the brain.
Thus, the method described in our study creates new ways to analyze neuronal activity in previously inaccessible
regions deep within the brain and multi-color functional imaging experiments, in which neurons are labeled with
spectrally different dyes.

19
Cellular & Molecular Techniques
RATIONAL DESIGN OF ULTRAFAST, HIGH-AFFINITY RED CALCIUM INDICATOR FOR
MONITORING NEURONALACTIVITY
M. Inoue, A. Takeuchi, S. Horigane, H. Fujii, S. Kamijo, S. Takemoto-Kimura, M. Ohkura, K. Gengyo-Ando, M.
Kano, J. Nakai, K. Kitamura, H. Bito. Dept. of Neurochemistry, The University of Tokyo, Tokyo, Japan. CREST-JST,
Tokyo, Japan. m-inoue@m.u-tokyo.ac.jp
Session Date/Time: Sunday, Oct.18, 8:00 AM
Room Number: Hall A
Board Number: BB72
Session Title: Genetic Techniques
New research results presented in this meeting by Inoue et al. report a groundbreaking technology to rationally
engineer of a new class of molecular spies that can record neuronal activities (i.e. listen to Morse codes of neurons), in
multicolor, from parallel ensembles of active neurons simultaneously.
Orchestrated information processing in constellations of active neurons are at the basis of how the brain works.
However, only a minority of neurons are active during any given brain task. So, to understand which neurons
participate in such endeavors, and decipher how their collective activity code for the resulting behavioral output,
simultaneous recording from hundreds of neurons are necessary. Since Ca2+
ions rapidly rush into neurons when these
receive crucial information from its neighbors, spying molecules that fluoresce upon Ca2+
rises have been widely
used to listen to the whispers transmitted across neurons. However, the need to deliver Ca2+
dyes, via tiny glass tubes
or with a chemically harsh protocol, have strongly limited their use. Genetically encoded calcium indicator (GECI),
a recent invention, largely circumvent these constraints and potentially enable long-term, repetitive and unbiased
functional imaging.
To directly interrogate the relationship between two distinct neural constellations of activities, however, requires a
multicolor recording. Despite recent progress in green GECI, the development of red GECI that can monitor neural
information with high fidelity in vivo has lagged behind. Furthermore, previous versions of GECI were too slow in
their response speed to accurately resolve neurons’ information code critical for elucidating brain functions such as
memory.
To address these issues, we recently designed a sensitive fast red Ca2+
indicator, R-CaMP2, which can image
neuronal as well as synaptic activities in vivo. One major breakthrough was the use of a Ca2+
/CaM-sensing domain
(ckkap sequence), originally found in a protein which our group had intensively worked with, the CaMKK-α/β. We
successfully replaced the M13 calmodulin-binding sequence that was previously used in all GECI derivatives (from
either green or other any colors) with the ckkap sequence, and then mutated it for further improvements. Thus, we first
created R-CaMP2, a red GECI with a three-fold faster signal response properties than the previous best red GECI. In
intact brain tissues, these features allowed resolving precise information transfer rate between single neurons in the
20-40 Hz range, with similar efficacy as with previously reported sensitive green GECIs. Combining R-CaMP2 and
conventional green Ca2+
dyes, we successfully achieved dual-color monitoring of neuronal activities of distinct cell
types, excitatory and inhibitory in the mouse cortex (Inoue et al Nature Methods 2015).
In our presentation in this meeting, we further improved R-CaMP2 performance to an unprecedented resolution, based
on rational mutagenesis of the ckkap sequence of R-CaMP2. Through screening, we identified a new R-CaMP variant
with a two-fold on-rate amelioration compared to R-CaMP2, with little trade-offs regarding other desirable properties
of R-CaMP2. In sections of brain tissues, fast information transfer of neurons’ firing activity over 50 Hz were directly
resolved through imaging. This new protein is therefore the fastest calcium probe ever developed and the first to allow
reliable detection of neural impulses at a speed that far exceeds video-rates.
These next generation red GECIs will provide enormous advantage in measuring activities of fast-acting neurons
that critically regulate the function of the cerebral cortex. Simultaneous multicolor imaging of diverse sets of neural
activities in a living mammalian brain will push our current frontiers in understanding key mechanisms of brain cells’
intercommunication, the dysregulation of which is at the cause of several mental disorders and memory impairment.
The dissemination of this powerful technology is expected to help uncover novel targets for brain disease therapy of
the future.

20
Childhood & Cognitive Development
FATHER: AN ESSENTIAL ELEMENT THE IMPACT OF PRECONCEPTION PATERNAL EXPERIENCE
ON OFFSPRING NEURODEVELOPMENT AND BEHAVIOUR
A. F. Harker, S. Raza, K. Williamson, B. Kolb, R. Gibb. University of Lethbridge, Lethbridge, Canada.
(403) 393-1394. allonna.harker@uleth.ca
Room Number: Hall A
Board Number: R19
Session Title: Parental and Gestational Influences on Stress Vulnerability
Our research indicates that a father’s experience prior to conception, whether negative or positive, can significantly
impact brain development and behavioral outcomes of offspring that may persist throughout the lifespan. Findings
from this research project are currently in multiple states of publication, one manuscript has been accepted for
publication, another has been submitted and approval is pending, and yet another is in the preparation stage of
publication.
In the past two decades there has been a lot of research examining the influence of mother experience on early
development and later behavior in offspring. We now know that events that mothers experience while pregnant have
a powerful effect and these effects often endure throughout the lifespan. Recent work on maternal experience in
the preconception period has demonstrated that events prior to conception also have the ability to impact offspring
development. As a society we have focused on the relationship between mother and baby and yet have invested very
little in advancing our understanding of the role of fathers and their experience on their offspring. Work in our lab has
explored the effects of both positive and negative paternal experiences on their offspring.
The goal of the research described was to examine the effect of two independent (and quite opposite) preconception
father experiences on subsequent brain development and behavior of male and female offspring. As research has
demonstrated that maternal prenatal stress and prenatal environmental enrichment have been shown to have opposing
effects on brain development and behavioural outcomes in offspring, we decided to explore the impact on offspring of
these two experiences provided to fathers during the preconception period. Our first experiment examined the negative
impact of father stress prior to conception on offspring development. For our second experiment we predicted that
preconception father enrichment would alter brain development and positively impact behavior of offspring. Both
experiments followed the same experimental design. Male Long Evans rats were exposed to either a stressing
paradigm or a complex environment for 27 days prior to mating. Global DNA methylation levels, brain anatomy, and
behavioral assessments were conducted. DNA methylation levels are a measure of gene expression that takes place
without modification to the genetic code itself.
The impact of father stress on global methylation levels at postnatal day 21 (P21) showed an increase in methylation
in the hippocampus of both male and female offspring, reflecting a decrease in gene expression, similar to what has
been observed in prenatal (mother) stress. Conversely, the impact of father enrichment on offspring at P21 showed
a decrease in global methylation levels in the hippocampus, thereby reflecting an increase in gene expression in this
area. This finding is consistent with research examining gene expression in adult rats after enrichment, and may
help to explain discoveries of enhanced brain cell growth and increased learning observed in rats living in complex
housing. Offspring of both stressed fathers and enriched fathers were tested on two early behavioral tasks, negative
geotaxis and open field. Negative geotaxis, a measure used to assess early developmental progress in offspring,
revealed that there was delayed acquisition of the task in father stress offspring, whereas offspring of enriched fathers
showed no deficits in this task. Open field, a measure of exploratory activity and anxiety revealed that male offspring
of father stress exhibited maladaptive behavior, contrary to male offspring of enriched fathers who demonstrated an
increase in exploration and reduced anxiety.
This study demonstrates that both father experiences, stress and enrichment, have the ability to significantly alter
offspring developmental trajectories in either a negative or positive manner, respectively, as hypothesized.

21
EARLY LIFE STRESS ACCELERATES BEHAVIORALAND NEURAL MATURATION OF THE
HIPPOCAMPUS
K. G. Bath, G. Manzano-Nieves, H. Goodwill. Brown University, Providence, RI. (212) 746-3169.
kevin_bath@brown.edu
Room Number: Hall A
Board Number: AA33
Session Title: Developmental Regulators of Stressful Experiences
The results of our research indicate that early life stress (ELS) leads to precocious behavioral development and
accelerates maturation of key circuits in the brain. These novel results challenge the traditional view that stress retards
(or delays) brain and behavioral development.
In a mouse model, we found that ELS suppresses brain growth while simultaneously accelerating neural and
behavioral maturation. Such effects may represent an adaptation to promote earlier independence and egress from a
stressful environment, with potential long-term effects on brain function and risk for disorder. These studies provide
new insights into ways in the brain adapts to stress incurred early in life and may provide novel inroads for treating
stress-associated pathology rooted in early life experiences.
Prior research has shown that nearly 64% of children will experience at least one significant stressor early in their
life, while ~30% will experience 3 or more. ELS can vary in its form, ranging from the loss of primary care-giver to
physical and psychological abuse. These negative early life experiences are associated with a wide array of negative
outcomes, including increased risk for substance abuse, obesity, cognitive dysfunction, and affective pathology. A
single stressor experienced during childhood increases the lifetime risk of affective pathology (anxiety or depression)
by ~30%, while having three or more adverse early experiences more than doubles the lifetime risk. These results
suggest that ELS profoundly alters brain and behavioral development.
In animal models and humans, ELS has been linked with decreased brain volume, an earlier silencing of the birth
of new brain cells, and poorer cognitive and emotional functioning. This combination of results has led to the
predominant view that ELS slows or impairs the growth of the brain leading to delayed or incomplete development.
However, recent work by several labs have found that ELS can result in what appears to be more mature patterns
of behavior or brain activation following ELS. This has prompted us to re-evaluate the effects of ELS to include
measures of neural maturation.
In our study, we used a mouse model of ELS in which stress was induced by restricting a mothers access to resources
that are necessary to take care of the young (nesting material). This resulted in a fragmentation of maternal care,
ultimately inducing measurable stress in the infant mice. The young mice showed elevations in stress hormone levels
and decreased weight gain. We collected measures to assess neural growth (birth of new cells) as well as multiple
measures of neural and behavioral maturation across early development. Consistent with previous work, ELS led
to an earlier suppression of measures of growth. However, measures of maturation (the arrival of types of cells that
appear late in development and changes in the connectivity of brain cells) were accelerated in ELS compared with
typically reared mice. The acceleration in maturation could also be observed behaviorally. Mice were trained to
associate a location (testing box) with a mild electric shock. Mice demonstrate their learned aversion to the testing
box by engaging in freezing behavior (immobility). We have previously identified a discrete period in development,
when freezing behavior is temporarily suppressed. In mice exposed to ELS, suppressed freezing occurred nearly a
week earlier than in typically reared animals, indicating an earlier onset of this behavior. We are currently undertaking
studies to understand the molecular mechanisms underlying accelerated maturation and assessing the effects of ELS
on the development of multiple sub-regions of the brain to test if this is a general process or unique to specific parts of
the brain.

22
NEUROIMMUNE CONSEQUENCES OF POSTNATAL ETHANOL EXPOSURE AND THE POTENTIAL
ANTI-INFLAMMATORY AND PRO-COGNITIVE BENEFITS OF IBUPROFEN TREATMENT
M. J. Goodfellow, Y. Shin, D. Lindquist. The Ohio State University, Columbus, OH.
goodfellow.10@buckeyemail.osu.edu
Session Date/Time: Tuesday, Oct.20, 1:00 PM
Room Number: Hall A
Board Number: I35
Session Title: Alcohol: Effects of Prenatal Exposure
Is it possible to protect the brain from the damaging effects of alcohol in the offspring of women who drink while
pregnant? Our research suggests that ibuprofen treatment could ameliorate some of the cognitive deficits associated
with alcohol exposure during fetal brain development.
Fetal alcohol spectrum disorders (FASD) pose a significant public health problem in the United States. According to
the Center for Disease Control (CDC), 7.6% of pregnant women report using alcohol and 1.4% admit binge drinking
during the past 30 days. As a result, it is estimated that FASD afflicts 2-5% of American children. Many of these
children experience pervasive deficits in cognitive function, including but not limited to attention, memory, and
low academic achievement. These persistent cognitive deficits contribute to a higher prevalence of mental health
problems, unemployment, and criminal activity in individuals with FASD in later life. The combination of increased
healthcare costs and diminished productivity in individuals with fetal alcohol syndrome alone (the most severe form
of FASD) is $3.6 billion annually; the economic impact of the full spectrum is even greater.
In order to understand and treat FASD, we must first uncover the mechanism(s) by which alcohol exerts its toxic
effects on the developing brain. Previous research indicates that fetal alcohol exposure can produce massive cell death
in a number of brain regions, as well as impair the ability of surviving cells to effectively communicate with one
another. An emerging theory is that alcohol stimulates inflammation in the body and brain, which contributes to the
damage of otherwise healthy tissue. Ibuprofen, an over-the-counter anti-inflammatory drug that is commonly given to
pre-term infants under medical supervision, has been shown to prevent birth defects in FASD animal models. It is not
clear, however, whether it can also prevent brain damage.
In the current study, we investigated the ability of ibuprofen to counteract memory impairments in a FASD rat
model. During a human 3rd trimester-equivalent period, when the hippocampus_a brain region that is critical for
the formation of long-term memories_undergoes rapid growth and development, rats were given six binge doses of
alcohol. Following each alcohol dose, animals were treated with ibuprofen or saline. As predicted, alcohol increased
inflammation in the hippocampus of saline-treated rats, while ibuprofen diminished the inflammatory response.
During adolescence, animals were trained in a challenging learning task and tested for memory retention 48 hours
later. While still preliminary, current data suggests that, relative to animals that never received alcohol, long-term
memory is impaired in FASD rats given saline and restored in rats given ibuprofen.
Results indicate that inflammation arising from alcohol exposure during the 3rd trimester may exert long-lasting
effects on memory. Future research will explore how early life alcohol exposure changes the brain’s immune system
across development and how such changes might affect memory formation and storage. We hypothesize the FASD rat
brain will show persistent alterations in immune function_if correct, administration of anti-inflammatory medication
during adolescence and/or adulthood, long after fetal alcohol exposure, could improve general cognition and memory.
While it is not advised that women combine alcohol and ibuprofen during pregnancy, findings from this study support
further research into the ability of anti-inflammatory medication to mitigate memory impairments in children and
adults diagnosed with FASD. The results also add to previous work on early-life inflammation, such as that induced
by infection or physical trauma, and its damaging effects on brain development and cognitive function.

23
Circuits, Mapping, Connectome
MOLECULARLY DEFINED ASTROCYTE SUBPOPULATIONS IN ADULT CNS AND THEIR RESPONSE
TO NEURODEGENERATIVE DISEASE INJURY
S. J. Miller, T. Philips, M. Robinson, R. Sattler, J. D. Rothstein. Johns Hopkins School of Medicine, Baltimore, MD.
(215) 850-8482. smill150@jhmi.edu
Session Date/Time: Sunday, Oct.18, 8:00 AM
Room Number: Hall A
Board Number: C55
Session Title: Astrocytes: Profiling and Modulation
Astrocytes are the most abundant cell type in the CNS, reflecting their important responsibilities and range of
subtypes. Their fundamental roles in brain health are to support the survival of neurons and other non-neuronal cells
in the CNS. Little is known about subtypes of adult astrocytes- other than the first descriptions of gray matter versus
white matter astrocytes more than 100 years ago. In recent years, gray matter astrocytes have been implicated as major
contributors to neurodegenerative disease. For example, in neurological diseases such as ALS and Huntington’s they
become dysregulated and contribute to disease progression. It has become clear that studying astrocyte subpopulations
in both health and disease could help further our understanding of these complex diseases.
Using a series of molecular tools, for the first time we have now identified and characterized a distinct subpopulation
of cortical and spinal cord gray matter astrocytes, which are appear to be affected during disease progression in a
mouse model of Amyloid Lateral Sclerosis (ALS).
A major caveat scientists face in the study of astrocyte subpopulations is the lack of biomarkers to identify these
different cell populations in the CNS. Identification of subpopulations is currently based on their neuroanatomical
location, but this has limitations, as it does not provide us with insight into their biological relevance or a way to
identify subtle changes.
Recently, our group generated a novel mouse model in which a particular astrocyte subpopulation is labeled in the
CNS. Using this mouse model we were able to isolate the astrocyte subpopulation and subsequently profile it for
candidate biomarkers. After extensive analyses and validation, we created a list of unique biomarkers that we could
potentially use as a robust tool to define the subpopulation.
Next, we investigated if these biomarkers could define astrocyte subpopulations in the human brain. To address this
question we obtained post-mortem brain tissue to investigate our biomarkers of interest. The results were two-fold: we
were not only able to validate our candidate biomarkers as a research tool, but we could then use them to show for the
first time that astrocyte subpopulations do indeed exist in the human brain.
Now that we have demonstrated the existence of the astrocyte subpopulation in cortex and spinal cord in both the
mouse and human CNS, we are attempting to understand the physiological relevance of this unique astrocyte group.
To expand our investigations we are using cutting-edge research technology, including multiphoton imaging to
visualize the subpopulation deep in the mouse brain over a period of months.
Finally, we want to investigate how this astrocyte subpopulation plays a role in neurodegenerative disease. We have
generated a novel ALS mouse model in which our astrocyte subpopulation is uniquely labeled. Our preliminary
findings provide evidence that this subpopulation is selectively affected in ALS and may contribute to disease
progression.
With our research efforts we have began to uncover an astrocyte subpopulation in the CNS. From our transgenic
mouse model we have been able to discover biomarkers to identify these unique cell groups in mouse and human
tissue aiding future subpopulation investigations in both health and disease. Lastly, our preliminary findings display a
dramatic response in this astrocyte group in the disease progression of an ALS mouse model.
Taken all of these findings, our future studies are aimed at exploring the basic biology of this novel astrocyte
subpopulation in hopes to gain insight into its role in health and disease. The impact of this research may lead to us
and other medical scientists to new therapeutics to help treat various neurological disorders, including ALS.

24
Circuits, Mapping, Connectome
MAPPING SPATIAL PATTERNS OF WHOLE BRAIN MRI USING SIMULTANEOUSLY RECORDED
SINGLE NEURONS
D. C. Godlove, B. E. Russ, S. Park, C. S. Mpamaugo, F. Q. Ye, D. B. McMahon, D. A. Leopold. NIMH/NIH,
Bethesda, MD. (615) 232-4821. david.godlove@nih.gov
Session Date/Time: Tuesday, Oct.20, 8:00 AM
Room Number: Hall A
Board Number: O6
Session Title: Mapping Connectivity and Function of Extrastriate Cortex
Our research reveals maps linking the activity of individual neurons with activity measured throughout the brain. This
provides a new way to understand how networks of neurons cooperate to process information.
To understand brains in action, scientists must study the interplay between single cells and large networks of neurons.
Some neurons send signals to their next-door neighbors just a fraction of a millimeter away, while others pass
signals to distant neurons in other parts of the brain. These different scales of brain circuitry pose serious questions
and challenges to scientists. Scientists must consider both the complexity of small-scale, microscopic, circuits, and
the interaction of these circuits with each other across the entire brain. Tools used to study brain activity tend to be
suited to one of these jobs or the other. For instance, one standard technique that involves recording electrical activity
from individual neurons cannot easily be used to measure activity widely across the brain. Other techniques such as
functional magnetic resonance imaging (or fMRI) can provide a view of the activity of millions of neurons throughout
the brain by measuring changes in blood flow, but these lack the microscopic precision needed to measure individual
neurons. Combining results across scales and techniques is therefore critical to obtaining a holistic understanding of
brain functioning.
Here we combined two conventional techniques to provide the best of both worlds: a microscopic portrait of a family
of neurons and a simultaneous big-picture view of fMRI activity throughout the brain. We trained 3 monkeys to rest
quietly while we recorded electrical activity from neurons in areas of their brains related to vision. At the same time,
we used fMRI to measure larger-scale activity changes throughout the brain. We then compared these two measures to
see whether patterns of activity were shared more by some brain regions than others. For each point in the brain, we
determined how similar the fMRI activity and the neuron’s activity were by computing a correlation between the two.
In this way, we built three dimensional maps linking each neuron’s activity to the fMRI activity measured throughout
the brain.
The results revealed a wide variety of different maps from a family of neurons that were all situated within half a
millimeter of one another - much smaller than the smallest unit of our fMRI measurement. Because the neurons were
in areas related to vision, several of the neurons yielded maps showing high similarity with other visual areas. In many
cases the areas of similarity were quite specific, and, interestingly, they differed from cell to cell. Many neurons were
related to brain regions that were unexpected from the known anatomy such as the frontal cortex, the thalamus, and
the cerebellum. These findings hint at differences in the functions carried out by adjacent neurons. It is possible to
characterize neurons into different groups by measuring their activity while monkeys look at pictures, watch movies,
or play simple games. Moving forward, we will characterize neurons using strategies such as these to see if neurons
involved in different aspects of information processing are correlated with activity in different brain regions.
These findings show that neighboring neurons can participate in widely different brain networks. The data also
suggest that neurons cooperate within groups that are more diverse and complex than previously thought. By
continuing to analyze neurons in the context of whole-brain activity we will gain new insight into the ways in which
brains processes information.

SfN15_HotTopics_vFINAL

Recommended

Recommended

More Related Content

Similar to SfN15_HotTopics_vFINAL

Similar to SfN15_HotTopics_vFINAL (20)

SfN15_HotTopics_vFINAL