Consequences of Dopaminergic Denervation on the Metabolic Activity of the Cortical Neurons Projecting to the Subthalamic Nucleus in the Rat

Abstract

Parkinsonian symptoms are currently thought to be related to hyperactivity of the subthalamic nucleus (STN). Because the STN is known to receive many inputs including glutamatergic cortical afferent fibers, we sought to determine whether the activity of this pathway is altered after dopaminergic denervation to estimate its contribution to the impairment of STN activity. A precise mapping of the origin of the corticosubthalamic projection was first performed using retrograde and anterograde tracing methods. Cortical neurons projecting to the STN were found to originate in layer V of the motor, anterior cingulate, and dorsal insular cortices, and the most anterior tip of the frontal lobe, leading to different functional corticosubthalamic inputs. The metabolic activity of the neurons projecting to the STN, first identified by retrograde tracing, was then evaluated by in situ hybridization of the first subunit of cytochrome oxidase (COI), a marker of metabolic activity, in unilateral 6-hydroxydopamine-lesioned rats. Measurements of COI mRNA expression showed a 38 and 41.5% decrease after dopaminergic denervation in the neurons projecting to the STN located in the motor and dorsal insular areas, respectively, whereas neuronal activity was mildly changed in neurons of the anterior cingulate cortex. The modified activity of STN neurons in parkinsonism may thus result in part from complex interactions between glutamatergic hyperactive fibers originating in the thalamus and the pedunculopontine nucleus and hypoactive fibers originating in the cerebral cortex.

Progressive Motor Cortex Functional Reorganization Following 6-Hydroxydopamine Lesioning in Rats

“…Indeed, vibrissa and forelimb areas interact to define their border (Maggiolini et al, 2008). Overall, our findings support previous evidence for reduced cortical activation in 6-OHDAhemilesioned rats as revealed by reduced metabolic activity (Orieux et al, 2002) and immediate-early gene expression (Steiner and Kitai, 2000) in the frontal cortex. Two previous ICMS studies in 6-OHDA-hemilesioned rats failed to detect functional changes in the ipsilateral forelimb area, not providing information on M1 function in the unlesioned hemisphere (Metz et al, 2004;Brown et al, 2009).…”

Rhythmic Bursting in the Cortico-Subthalamo-Pallidal Network during Spontaneous Genetically Determined Spike and Wave Discharges

“…The depth of intracellular recordings, between 1491 and 2025 m from the cortical surface, suggested that CSth neurons were located in the deep part of layer V (Hall and Lindholm, 1974), a laminar localization that is consistent with previous findings obtained from anterograde and retrograde labeling of rat CSth neurons (Orieux et al, 2002). CSth neurons were identified electrophysiologically by antidromic activation after electrical stimulation of the ipsilateral STN ( Fig.…”

Phase relationships support a role for coordinated activity in the indirect pathway in organizing slow oscillations in basal ganglia output after loss of dopamine

“…Other inputs in addition to the GP, such as those from cortex, pedunculopontine and parafascicular nuclei (Orieux et al, 2000(Orieux et al, ,2002Breit et al, 2001; but see Ni et al, 2000b) could also be affected by loss of dopamine and play a role in modulating STN firing patterns after dopamine cell lesion. Cortical input to the basal ganglia appears critical as cortical ablation dramatically reduces the incidence of slow oscillations in the GP and STN after dopamine lesion in the anesthetized rat (Magill et al, 2001).…”

“…Phase relationships derived from STN spike-triggered cortical LFP waveform averages indicate that STN spiking is greatest during the trough of the LFPs recorded from within the cortex which coincides with the intervals of increased cortical spiking activity (Goldberg et al, 2004;Parr-Brownlie et al, 2006). Thus, phase relationships support a scenario in which increased oscillatory inhibitory input from the GP converges with antiphase excitatory input from cortex to contribute to changes in STN firing patterns after loss of dopamine.Other inputs in addition to the GP, such as those from cortex, pedunculopontine and parafascicular nuclei (Orieux et al, 2000(Orieux et al, ,2002Breit et al, 2001; but see Ni et al, 2000b) could also be affected by loss of dopamine and play a role in modulating STN firing patterns after dopamine cell lesion. Cortical input to the basal ganglia appears critical as cortical ablation dramatically reduces the incidence of slow oscillations in the GP and STN after dopamine lesion in the anesthetized rat (Magill et al, 2001).…”