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Deep brain stimulation (DBS) provides symptomatic relief in a growing number of neurological indications, but local synaptic dynamics in response to electrical stimulation that may relate to its mechanism of action have not been fully characterized.The objectives of this study were to (1) study local synaptic dynamics during high frequency extracellular stimulation of the subthalamic nucleus (STN), and (2) compare STN synaptic dynamics with those of the neighboring substantia nigra pars reticulata (SNr).Two microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for Parkinson's disease (PD). Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode.Inhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .013). There were no differences between STN and SNr inhibitory fEP dynamics at low stimulation frequencies (p .999). However, inhibitory neuronal responses were sustained over time in STN during high frequency stimulation but not in SNr (p .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003).Persistent inhibitory input to the STN suggests a local synaptic mechanism for the suppression of subthalamic firing during high frequency stimulation. Moreover, differences in the resiliency versus vulnerability of inhibitory inputs to the STN and SNr suggest a projection source- and frequency-specificity for this mechanism. The feasibility of targeting electrophysiologically-identified neural structures may provide insight into how DBS achieves frequency-specific modulation of neuronal projections.

For all animals, undisturbed periods of rest are essential for undergoing recuperative processes. How neural interactions create brain states capable of dissociating an animal from its external world to promote quiescence remains a fundamental question. Here, we show how coherent network oscillations can create neural filters that favor a quiescent brain state over a state that promotes navigation. Circadian regulation and excitability of the Drosophila sleep homeostat (dFSB) generate nighttime specific slow-wave coherence between neural networks mediating sleep need (R5) and networks gating locomotion (helicon cells). Optogenetically mimicking coherent activity reveals that temporally fine-tuned R5 oscillations promote a quiescent state and reduce responsiveness to visual stimuli by hierarchically overruling locomotion-promoting helicon cells. We uncover that R5 and helicon bidirectionally regulate behavioral responsiveness by providing antagonistic inputs to head direction targets (EPG). Thus, coherent oscillations can form the mechanistic basis of neural filters by temporally associating antagonistic inputs and therefore reducing the functional connectivity between locomotion gating and navigational networks.

Rigorous analysis of synaptic transmission in the central nervous system requires access to presynaptic terminals. However, cortical terminals have been largely inaccessible to presynaptic patch-clamp recording, due to their small size. Using improved patch-clamp techniques in brain slices, we recorded from mossy fiber terminals in the CA3 region of the hippocampus, which have a diameter of 2-5 microm. The major steps of improvement were the enhanced visibility provided by high-numerical aperture objectives and infrared illumination, the development of vibratomes with minimal vertical blade vibrations and the use of sucrose-based solutions for storage and cutting. Based on these improvements, we describe a protocol that allows us to routinely record from hippocampal mossy fiber boutons. Presynaptic recordings can be obtained in slices from both rats and mice. Presynaptic recordings can be also obtained in slices from transgenic mice in which terminals are labeled with enhanced green fluorescent protein.