NNS 2015 Abstract Book

Each year, traumatic Brain Injury (TBI) impacts millions of people

worldwide. Despite the increased resources dedicated to understanding

the complex series of physiological events that follow a TBI, effective

diagnostic and treatment options are lacking. Following a TBI, there is a

rapid, innate neuroinflammatory and inflammatory response. This re-

sponse includes activation of astrocytes and microglial cells in the

central nervous system (CNS), as well as expansion, activation and

infiltration of peripheral immune cells into the CNS. Our recent data, as

well as data from a few select other groups, have demonstrated that

following a TBI, there is evidence for a transition from an innate to an

adaptive immune response. This response appears to involve both the

liver and the spleen. This evidence for an adaptive immune response to

a TBI will be presented, as will our data highlighting the innate immune

response to TBI. In addition, data will be shown to illustrate that tar-

geting the transition from an innate to an adaptive immune response

provides neuroprotection following a TBI. The broad impact of such

findings will be further contextualized to allow for a discussion of the

potential impact on the short- and long-term consequences of targeting

the switch to an adaptive immune response for the treatment of TBI.

Keywords: Peripheral immune system, Liver, Spleen, CD74, MHC,

Invariant Chain

S13-02

NEUROGENIC IMMUNE DEFICIENCY AFTER SPINAL

CORD INJURY: MECHANISMS OF ACTION AND THER-

APEUTIC OPPORTUNITIES

Phillip Popovich

, Yan Wang

, Zhen Guan

, Jan Schwab

, Masaki

Ueno

, Yutaka Yoshida

Ohio State Univ., Dept. of Neuroscience, Columbus, USA

Cincinnati Children’s Hospital Medical Center, Division of Devel-

opmental Biology, Cincinnati, USA

Most who suffer a traumatic spinal cord injury (SCI) above spinal level

T5 develop autonomic dysreflexia (AD), a pathological condition char-

acterized by severe episodic paroxysmal hypertension. Untreated, AD

can cause pulmonary embolism, stroke or even death. Data from our lab

indicate that maladaptive plasticity in the spinal cord circuitry respon-

sible for causing AD also causes chronic immune suppression. In SCI

mice, the onset and frequency of AD correlates with the magnitude of

immune suppression. We predicted that as large segments of spinal cord

lose supraspinal input, the periodic activation of viscera-sympathetic

reflexes (e.g., due to bladder/bowel filling) will cause uncontrolled ac-

tivation of sympathetic motor neurons with heightened release of cate-

cholamines and glucocorticoids (GCs) into blood and lymphoid tissues.

Data indicate that GC and catecholamine-dependent signaling synergizes

to elicit apoptosis in leukocytes and that remaining immune cells are

functionally impaired. Retrograde trans-synaptic labeling from the

spleen of SCI mice reveals the formation of new and complex intraspinal

circuitry, presumably due to ongoing plasticity and synaptogenesis be-

tween primary sensory afferents, interneurons and sympathetic pregan-

glionic neurons. Moreover, the receptive field for activating this new

circuitry expands beyond the thoracic spinal segment that controls sec-

ondary lymphoid tissues in naı¨ve/uninjured mice. Thus, after SCI, an

uncontrolled ‘‘supercharged’’ autonomic circuit develops that recapitu-

lates convulsive neuropathology (‘‘autonomic spinal epilepsy’’) and

causes immune suppression. New preliminary data indicate that this

aberrant circuitry can be ‘‘silenced’’ and immune cell ablation reversed

by injecting inhibitory Designer Receptors Exclusively Activated by

Designer Drugs (DREADDs) into the spinal cord. Neurogenic immune

ablation may explain why people with high-level SCI are more suscep-

tible to infection – a leading cause of morbidity and mortality in this

patient population. Overcoming this deficit will reduce mortality, sig-

nificantly improve quality of life and also recovery of neurological

function after SCI. Supported in part by NIH-NINDS R01NS083942

(PGP), Dept. of Defense (W81XWH-13-1-0356).

Keywords: Autonomic Dysreflexia, hypertension, maladaptive

plasticity, Spinal Cord Injury, immune Suppression

S13-03

INTESTINAL BARRIER DYSFUNCTION AFTER TRAU-

MATIC BRAIN INJURY

Vishal Bansal

UCSD, Dept. of Surgery, San Diego, USA

The physio-logic connection be-tween the brain and the gut has recently

been coined the ‘‘neuro-enteric axis.’’ In this regard, in-ves-tigators have

established the unique in-ter-play and com-mu-nication be-tween parts of

the brain, namely the dorsal motor nucleus of the vagus nerve, the vagus

nerve and the in-testine itself. Our laboratory has demon-strated that

severe TBI causes sig-nifi-cant in-testinal dysfunc-tion. Inter-estingly, by

electrically stimulating the vagus nerve, we have shown post-TBI in-

testinal injury to be sig-nifi-cantly mitigated. When the para-digm was

reversed, vagus nerve stimulation actually impro-ved blood brain barrier

leakage and neu-ronal degene-ration fol-lowing severe TBI. How vagus

nerve stimulation may affect the neuro-enteric axis in unknown. It is

likely not purely secondary to the known anti-in-flam-matory effects of

the vagus nerve. These modulators and signals may very well be from gut

derived neuro-endo-crine hormones.

Keywords: intestinal barrier dysfunction, neuroendocrine hormone,

vagus nerve

S14 Purines - Forgotten Mediators in CNS Injury

S14-01

ROLE OF THE 2

-CAMP-ADENOSINE PATHWAY IN

TRAUMATIC BRAIN INJURY

Edwin Jackson

, Patrick Kochanek

University of Pittsburgh, Pharmacology and Chemical Biology,

Pittsburgh, USA

University of Pittsburgh, Critical Care Medicine, Pittsburgh, USA

Using mass spectrometry, we recently discovered that some tissues

generate a positional isomer of 3

-cAMP, namely 2

-cAMP. Ad-

ditionally, we established that: 1) the biosynthesis of 2

-cAMP is

stimulated by cellular injury; 2) 2

-cAMP derives from the breakdown

of mRNA; 3) 2

-cAMP is exported to the extracellular compartment;

and 4) extracellular 2

-cAMP is metabolized to 2

-AMP and 3

-AMP,

which are subsequently metabolized to extracellular adenosine. We call

this biochemical sequence (intracellular 2

-cAMP

extracellular

-cAMP

-AMP/3

-AMP

adenosine) the ‘‘2

-cAMP-adeno-

sine pathway.’’ Emerging evidence suggests that intracellular 2

cAMP promotes opening of brain mitochondrial permeability transition

pores and that extracellular adenosine is a key neuroprotective autacoid.

Thus we hypothesize that the 2

-cAMP-adenosine pathway may be an

important mechanism for protection against neurotrauma. In support of

this concept, we find that neurons, oligodendrocytes, astrocytes, and

microglia convert 2

-cAMP mostly to 2

-AMP (with oligodendrocytes

being most efficient) and 2

-AMP to adenosine (with microglia being

most efficient), and knockout of 2

-cyclic nucleotide 3

-phosphodies-

terase (CNPase) attenuates the ability of oligodendrocytes to metabolize

-cAMP to 2

-AMP. Microdialysis experiments in mice demonstrate

that traumatic brain injury (TBI; controlled cortical impact) activates the

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