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

Abstract

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.

The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors

“…VP neurons are sensitive to NMDA or AMPA, and most (82%) are sensitive to both (Turner et al, 2001). Intra-VP infusions of low to moderate doses of NMDA (0.23 or 0.45 μg) increases Fos-like immunoreactivity within the VP as much as five fold (Turner et al, 2008). Metabotropic glutamate receptor subunit proteins are also observed within the VP (Shigemoto et al, 1992; Herrold et al, 2011, 2013).…”

“…In rats, intra-VP injections of 45 μg/0.5 μl NMDA or 50 ng/0.5 μl bicuculline increases Fos-IR in the dorsomedial STN, while Fos activation is not seen in the lateral STN (Turner et al, 2008). Given that VP outputs are largely GABAergic, the increased activity in this VP projection target may reflect indirectly mediated disinhibitory effects of VP activation, but if so, it is noteworthy that the polysynaptic pathways follow the direct projections of VP outputs.…”

“…The VPdl also sends a light GABAergic projection to the EPN (Zahm et al, 1996; Maurice et al, 1997; Bevan et al, 1997) and intra-VP injections of NMDA or bicuculline increase Fos-IR in the EPN (Turner et al 2008). These VP to EPN projections are largely separate from GP projections, but exhibit some overlap (Bevan et al, 1997).…”

“…Yet, EPN dendrites are not organized in a similar manner as STN neurons, and receive comparatively less VP input than the STN, suggesting more topographic influence from the GP. Nevertheless, intra-VP NMDA robustly increases Fos-IR in the EPN as well as its ontogenetically linked region, the SNr (Turner et al, 2008), and both are targets associated with projections from the VPdl.…”

“…Intra-VP injections of NMDA increase Fos-like staining in the frontal cortex (Turner et al, 2008) and intra-VP injections of the GABA-A agonist, muscimol suppresses firing of cortical neurons (Rigdon and Pirch, 1984; Pirch et al, 1991). In contrast, cortically projecting cholinergic neurons within the VP are not regulated by intra-VP kappa or delta opiate agonists; mu activation does reduce acetylcholine turnover in the frontal cortex (but notably, this is not blocked by a mu antagonist) ( Table 1 ).…”