Northwestern University, Chicago, IL

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Northwestern University, Chicago, IL

Hitoshi Kita -Primate Testing - 2006

Grant Number: 5P50NS047085-040003
Project Title: SYNAPTIC CONTROLOF PALLIDAL ACTIVITY
PI Information: PROFESSOR HITOSHI KITA

Abstract:
The globus pallidus is located at the strategically important locus of the basal ganglia connections and is considered to play a key role in the physiology and pathophysiology of the basal ganglia. Our recent results and those of others suggested that the pallidal neurons change their firing rate and pattern under various pathophysiological conditions. One dramatic observation made by us and others was that a chemical blockade of the subthalamic nucleus (STN) induced a very slow oscillatory activity, an alternating occurrence of long active and long silent periods, in pallidal neurons. Our main working hypothesis is that the slow oscillation of the pallidum might be due to alterations in the synaptic inputs and the membrane properties of the pallidal neurons. The goal of proposed study is to characterize the synaptic inputs and the membrane properties of the pallidum under normal conditions and after removal of the STN. The whole-cell recording technique in rat brain slice preparations and the unitary recording combined with local drug application techniques in awake-monkeys will be used to address the following two specific aims. Aim-1 will test the hypothesis that high-frequency unitary activity observed in pallidal neurons in normal awake-animals is due to the concerted activation of sustained glutamatergic and sustained GABAergic synaptic inputs. Aim-2 will test the hypothesis that the removal of the glutamatergic STN-pallidal inputs alter the firing rate and the pattern of pallidal neurons not only by the removal of glutamatergic inputs but also by inducing plastic changes of synaptic inputs and membrane properties. The significance of the proposed study is that the results obtained will 1) advance our knowledge of the physiological properties of the pallidum and 2) reveal changes that might occur in the pallidum of patients suffering from basal ganglia diseases. These finding might contribute to the formation of new, less invasive, therapeutic strategies for basal ganglia diseases.

Thesaurus Terms:
brain electrical activity, gamma aminobutyrate, glutamate, lenticular nucleus, neural transmission, neurologic manifestation, synapse
GABA receptor, Parkinson's disease, basal ganglia, biophysics, experimental brain lesion, glutamate receptor, ion channel blocker, membrane channel, membrane potential, neural plasticity, neuropharmacology, neuroregulation, subthalamus, wakefulness
Macaca, immunocytochemistry, laboratory rat, polymerase chain reaction, tissue /cell preparation

Institution:
NORTHWESTERN UNIVERSITY
EVANSTON, IL 602081110
Fiscal Year: 2006
Department:
Project Start:
Project End:
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG: ZNS1

The Journal of Neuroscience, January 3, 2007, 27(1):75-83

Serotonin Modulates Pallidal Neuronal Activity in the Awake Monkey
 
Hitoshi Kita,1 Satomi Chiken,1,2 Yoshihisa Tachibana,2 and Atsushi Nambu2
 
1Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee Memphis, Memphis, Tennessee 38163, and 2Division of System Neurophysiology, National Institute for Physiological Sciences, and Department of Physiological Science, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan

Preparation of animals.
This study was performed in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the National Institute of Physiological Sciences Guide for the Use and Care of Laboratory Animals in Research. The monkey preparation methods used in the present study were very similar to those reported previously (Nambu et al., 2000 ; Kita et al., 2004 , 2005a ). Each of three Japanese macaques (Macaca fuscata) was trained to sit quietly in a monkey chair. Before surgery, each monkey was anesthetized with sodium pentobarbital (25 mg/kg, i.v.) and ketamine hydrochloride (10 mg/kg, i.m.) and was placed in a homemade acrylic stereotaxic frame. Then, magnetic resonance images of the head were taken. The monkeys received surgery to install headgear for holding their heads painlessly to a metal stereotaxic frame attached to the chair. Still under the anesthesia, the skull of the monkey was widely exposed. Small stainless steel screws were attached to the skull as anchors, and the exposed skull and screws were covered with acrylic resin. Two stainless steel pipes were mounted in parallel over the frontal and occipital areas of the skull. The monkey was then removed from the chair, allowed to recover in the animal housing facility, and was cared for.

A few days after the initial surgery, a second surgery was performed to implant stimulus electrodes in the hand region of the primary motor cortex (M1) and the supplementary motor cortex (SMA). For the second surgery, the monkey was anesthetized with ketamine hydrochloride (10 mg/kg, i.m.) and xylazine hydrochloride (12 mg/kg, i.m.) and was seated in a monkey chair with its head fixed to a stereotaxic frame. To access the M1 and SMA, a hole was drilled in the skull. After the monkey recovered from the anesthesia, and while it was still in the chair, a glass-coated Elgiloy (Elgin, IL) alloy microelectrode (0.51.5 M at 1 kHz) was inserted perpendicularly to the cortical surface. Extracellular unit activity was recorded in 11.5 mm intervals of depth across the M1 and SMA, and the neuronal responses to somatosensory stimuli (skin touch and passive joint movement) were examined. After extracellular unit recording, intracortical microstimulation using a train of 12 cathodal pulses (200 s duration at 333 Hz) with currents of <50 A was delivered, and the movements evoked in the various body parts were observed.

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Rats, mice, birds, amphibians and other animals have been excluded from coverage by the Animal Welfare Act. Therefore research facility reports do not include these animals. As a result of this situation, a blank report, or one with few animals listed, does not mean that a facility has not performed experiments on non-reportable animals. A blank form does mean that the facility in question has not used covered animals (primates, dogs, cats, rabbits, guinea pigs, hamsters, pigs, sheep, goats, etc.). Rats and mice alone are believed to comprise over 90% of the animals used in experimentation. Therefore the majority of animals used at research facilities are not even counted.

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