Fos expression following activation of the ventral pallidum in normal rats and in a model of Parkinson's Disease: implications for limbic system and basal ganglia interactions.
The circuit-related consequences of activating the ventral pallidum (VP) are not well known, and lacking in particular is how these effects are altered in various neuropathological states. To help to address these paucities, this study investigated the brain regions affected by VP activation by quantifying neurons that stain for Fos-like immunoreactivity (ir). Fos-ir was assessed after intra-pallidal injections of the excitatory amino acid agonist, NMDA, or the GABA(A) antagonist, bicuculline in normal rats and in those rendered Parkinsonian-like by lesioning dopaminergic neurons with the neurotoxin, 6-OHDA. We hypothesized that activation of the VP will alter the activity state of brain regions associated with both the basal ganglia and limbic system, and that this influence would be modified in the Parkinsonian state. Blocking tonically activated GABA(A) receptors with bicuculline (50 ng/0.5 microl) elevated Fos-ir in the VP to 423% above the contralateral, vehicle-injected side. Likewise, intra-VP NMDA (0.23 microg or 0.45 microg/0.5 microl), dose-dependently increased the number of pallidal neurons expressing Fos-ir by 224 and 526%, respectively. At higher NMDA doses, the density of Fos-ir neurons was not elevated above control levels. This inverted U-shaped profile was mirrored by a VP output structure, the medial subthalamic nucleus (mSTN). The mSTN showed a 289% increase in Fos-ir neurons with intra-VP injections of 0.45 microg NMDA, and this response was halved following intra-VP injections of 0.9 microg NMDA. Of the 12 other brain regions measured, three showed VP NMDA-induced enhancements in Fos-ir: the frontal cortex, entopeduncular nucleus and substantia nigra pars reticulata, all regions associated with the basal ganglia. In a second study, we evaluated the NMDA activation profile in a rat model of Parkinson's Disease (PD) which was created by a unilateral injection of 6-OHDA into the rostral substantia nigra pars compacta. Comparisons of responses to intra-VP NMDA between the hemispheres ipsilateral and contralateral to the lesion revealed that Fos-ir cells in the pedunculopontine nucleus was reduced by 62%, whereas Fos-ir for the basolateral amygdala and STN was reduced by 32 and 42%, respectively. These findings support the concept that the VP can influence both the basal ganglia and the limbic system, and that that the nature of this influence is modified in an animal model of PD. As the VP regulates motivation and cognition, adaptations in this system may contribute to the mood and mnemonic disorders that can accompany PD.
Turner
Michael S
MS
M.D./Ph.D. Program and the Neuroscience Graduate Program, Loyola University Chicago, Medical Center, Maywood, IL, USA.
Gray
Thackery S
TS
Mickiewicz
Amanda L
AL
Napier
T Celeste
TC
D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001640:Bicuculline / Q000008:administration & dosage / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology; D018756:GABA Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008845:Microinjections; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016761:Oncogene Proteins v-fos / Q000378:metabolism*; D016627:Oxidopamine / Q000008:administration & dosage / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013565:Sympatholytics / Q000008:administration & dosage / Q000633:toxicity
D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D016761:Oncogene Proteins v-fos; D013565:Sympatholytics; D016202:N-Methylaspartate; D016627:Oxidopamine; D001640:Bicuculline