Page 38 - NNS 2014 Program & Abstract Book

T1-11
EARLY HINDLIMB UNLOADING PRODUCES MALADAP-
TIVE PLASTICITY THAT LIMITS FUNCTIONAL RE-
COVERY AFTER SPINAL CORD INJURY (SCI)
Morioka, K.1,2, Tazoe, T.2,3, Ma, X.1, Guandique, C.F.1, VanCitters,
L.1, Huie, J.R.1 , Bresnahan, J.C.1, Beattie, M.S.1, Tanaka, S.4, Ferguson,
A.R.1 , Ogata, T.2
1Brain and Spinal Injury Center (BASIC), Dept Neurological Surgery,
UCSF, San Francisco, USA
2Research Institute, National Rehabilitation Center for Persons with
the Disabilities, Saitama, Japan
3Dept Physical Medicine and Rehabilitation, University of Pittsburgh,
Pittsburgh, USA
4Dept Orthopaedic Surgery, The University of Tokyo, Tokyo, Japan
Partial weight bearing gait training for SCI induces adaptive plasticity
and/or inhibits maladaptive spinal cord plasticity to promote func-
tional recovery and re-organization of spinal reflex circuits. Weight-
less conditions such as prolonged bed rest in chronic SCI are thought
to facilitate maladaptive spinal cord plasticity, leading to exaggerated
withdrawal reflexes that can interfere with locomotor recovery.
Hence, it has been suggested that appropriate shaping of loading-
related spinal plasticity contributes to recovery in chronic SCI.
However, the specific mechanisms by which loading and unloading
shape spinal plasticity early after SCI remain poorly understood. We
investigated hind-limb unloading (HU) early after SCI using adult
female SD rats subjected to mild bilateral SCI (50 kdyn IH device) at
T9. Groups were 1) chronic HU by tail suspension, and 2) normal
loading controls. The HU group was returned to normal loading
conditions at 2 wks and all animals were observed for 8 wks post-SCI.
Assessments included: 1) Locomotor recovery using the BBB and
kinematics, 2) reflex modulation using H-reflex testing of the plan-
taris muscle at 8 wks, 3), tissue biochemistry, and 4) unbiased high-
resolution robotic confocal microscopy for plasticity-related changes.
HU early after SCI impaired locomotor recovery and produced over-
excitation of spinal reflex circuits. Biochemical and confocal micro-
scopic studies into the substrates of this plasticity are ongoing. Our
findings suggest that complete limb unloading early after SCI pro-
duces maladaptive spinal cord plasticity that impairs functional re-
covery. Our data suggest that loading-related spinal plasticity early
after SCI plays an essential role in functional recovery.
Key words
loading, maladaptive spinal plasticity, recovery of function, synaptic
plasticity
T1-12
INCREASED NODOSE GANGLION EXPRESSION OF CCK,
CCK-1R, AND TRPV1 AND THE PATHOPHYSIOLOGY OF
VAGAL AFFERENT DYSFUNCTION
Swartz, E.M.1, Deiter, G.M.2, Stocker, S.D.2, Holmes, G.M.1
1Neural and Behavioral Sciences, Penn State University College of
Medicine, Hershey, USA
2Cellular and Molecular Physiology, Penn State University College of
Medicine, Hershey, USA
Spinal cord injury (SCI) causes immediate changes to gastrointestinal
(GI) tract physiology. Parasympathetic control from the esophagus to
the proximal colon is modulated by vago-vagal circuits which remain
anatomically intact following SCI. Our previous reports indicate that
SCI reduces gastric reflexes and vagal afferent sensitivity to GI peptides
such as cholecystokinin (CCK). Furthermore, mesenteric hypoperfusion
initiates a GI inflammatory response. Evidence in other models of GI
dysfunction suggests that inflammatory mechanisms co-activate the
transient receptor potential vanilloid type 1 receptor (TRPV1) that, in
turn, contributes to the symptomatology of GI dysregulation. We tested
the hypothesis that acute SCI induces molecular and neurophysiological
alterations in gastric vagal afferents, cell bodies of which reside in the
nodose ganglion, through the increased expression of TRPV1 and CCK
and reduction in expression of CCK-1 receptor (CCK-1r). We used qRT-
PCR to quantify the levels of CCK, CCK-1r, and TRPV1 in the no-
dose ganglia and inflammatory markers in the proximal colon at 1-day,
3-days, and 7-days post-SCI. Neurophysiological recordings were used
to quantify the sensitivity of gastric vagal afferents to ligands of CCK-1r
and TRPV1. Our data show a significant elevation of inflammatory
markers within the proximal colon. Nodose ganglion expression of CCK
and CCK-1r was significantly elevated as was expression of TRPV1. In
Inactin-anesthetized rats, SCI resulted in the predicted reduction of mean
arterial blood pressure. Low doses of CCK-8s provoked similar peak and
mean vagal afferent firing, while preliminary data suggest an increased
sensitivity to the TRPV1 agonist capsaicin following SCI. Our data are
similar to the altered neurochemical phenotype of nodose ganglion
neurons following vagal axotomy. The increase in CCK-1r may repre-
sent diminished receptor trafficking and needs further study. We con-
clude that an increase in inflammatory mediators in our model of SCI
provokes TRPV1-mediated changes in vagal afferent signaling. Support:
NS 49177, NS 87834.
Key words
cholecystokinin, gastrointestinal, nodose ganglion, TRPV1, vagus
T1-13
PERIPHERAL NOCICEPTIVE INPUT OVERDRIVES AMPA
RECEPTOR ACTIVITY TO PRODUCE MALADAPTIVE
PLASTICITY AFTER SPINAL CORD INJURY (SCI)
Huie, J.R.1, Stuck, E.D.1, Lee, K.H.2, Irvine, K.A.1, Bresnahan, J.C.1,
Beattie, M.S.1 , Grau, J.W.2, Ferguson, A.R.1
1University of California, San Francisco, United States
2Texas A&M University, College Station, United States
Human SCI patients typically present with concomitant injury from
the traumatic event, which likely sends a barrage of nociceptive input
to the injured cord. Little is known about the effect of nociceptive
input from concomitant injuries on plasticity in the injured spinal
cord. Prior work has shown that intermittent nociceptive stimulation
(INS) delivered below a complete SCI in rats produces hyperexcit-
ability and undermines spinal training through unknown mechanisms.
The dysregulation/overexpression of AMPA receptors following
neural insult can lead to saturation of synaptic plasticity, ex-
citotoxicity, and cell death. The current experiments assess the role of
AMPA receptors in the impairing effects of INS in the injured cord.
Rats with complete T2 spinal transections were given 6 min of INS to
the tail (or unstimulated restraint), after which cords were harvested at
20 min or 2 hr post-stimulation. Western blot analysis revealed that
INS rapidly increases GluA1 phosphorylation and plasma membrane
expression, while reducing GluA2. Automated confocal image anal-
ysis of motor neurons revealed that INS increases GluA1 expression at
extrasynaptic and synaptic sites in a sustained manner. GluA2 initially
decreased extrasynaptically, and later decreased at synapses in re-
sponse to INS. As GluA2 is the AMPA receptor subunit that mitigates
calcium permeability, postsynaptic reduction suggests that Ca2 +
permeable AMPA receptors (CP-AMPARs) may dictate functional
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