Frequency-Specific Optogenetic Deep Brain Stimulation of Subthalamic Nucleus Improves Parkinsonian Motor Behaviors.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapy for the motor symptoms of Parkinson's disease (PD). However, the neural elements mediating symptom relief are unclear. A previous study concluded that direct optogenetic activation of STN neurons was neither necessary nor sufficient for relief of parkinsonian symptoms. However, the kinetics of the channelrhodopsin-2 (ChR2) used for cell-specific activation are too slow to follow the high rates required for effective DBS, and thus the contribution of activation of STN neurons to the therapeutic effects of DBS remains unclear. We quantified the behavioral and neuronal effects of optogenetic STN DBS in female rats following unilateral 6-hydroxydopamine (6-OHDA) lesion using an ultrafast opsin (Chronos). Optogenetic STN DBS at 130 pulses per second (pps) reduced pathologic circling and ameliorated deficits in forelimb stepping similarly to electrical DBS, while optogenetic STN DBS with ChR2 did not produce behavioral effects. As with electrical DBS, optogenetic STN DBS exhibited a strong dependence on stimulation rate; high rates produced symptom relief while low rates were ineffective. High-rate optogenetic DBS generated both increases and decreases in firing rates of single neurons in STN, globus pallidus externa (GPe), and substantia nigra pars reticular (SNr), and disrupted ß band oscillatory activity in STN and SNr. High-rate optogenetic STN DBS can indeed ameliorate parkinsonian motor symptoms through reduction of abnormal oscillatory activity in the STN-associated neural circuit, and these results highlight that the kinetic properties of opsins have a strong influence on the effects of optogenetic stimulation.SIGNIFICANCE STATEMENT Whether STN local cells contribute to the therapeutic effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) remains unclear. We re-examined the role of STN local cells in mediating the symptom-relieving effects of STN DBS using cell type-specific optogenetic stimulation with a much faster opsin, Chronos. Direct optogenetic stimulation of STN neurons was effective in treating the symptoms of parkinsonism in the 6-hydroxydopamine (6-OHDA) lesion rat. These results highlight that the kinetic properties of opsins can have a strong influence on the effects of optogenetic activation/inhibition and must be considered when employing optogenetic to study high-rate neural stimulation.

Parietal stimulation reverses age-related decline in exploration, learning, and decision-making.

Aging can compromise decision-making and learning, potentially due to reduced exploratory behaviors crucial for novel problem-solving. We posit that invigorating exploration could mitigate these declines. Supporting this hypothesis, we found that older mice mirrored human aging, displaying less exploration and learning during decision-making, but optogenetic stimulation of their posterior parietal cortex boosted initial exploration, subsequently improving learning. Thus, enhancing exploration-driven learning could be a key to countering cognitive aging.

Electrodeposited platinum-iridium coating improves in vivo recording performance of chronically implanted microelectrode arrays.

Reliable single unit neuron recordings from chronically implanted microelectrode arrays (MEAs) are essential tools in the field of neural engineering. However, following implantation, MEAs undergo a foreign body response that functionally isolates them from the brain and reduces the useful longevity of the array. We tested a novel electrodeposited platinum-iridium coating (EPIC) on penetrating recording MEAs to determine if it improved recording performance. We chronically implanted the arrays in rats and used electrophysiological and histological measurements to compare quantitatively the single unit recording performance of coated vs. uncoated electrodes over a 12-week period. The coated electrodes had substantially lower impedance at 1 kHz and reduced noise, increased signal-to-noise ratio, and increased number of discernible units per electrode as compared to uncoated electrodes. Post-mortem immunohistochemistry showed no significant differences in the immune response between coated and uncoated electrodes. Overall, the EPIC arrays provided superior recording performance than uncoated arrays, likely due to lower electrode impedance and reduced noise.