Abstract Deep brain stimulation (DBS) is a promising neuromodulation therapy, but the neurophysiological mechanisms of DBS remain unclear. In awake mice, we performed high-speed membrane voltage fluorescence imaging of individual hippocampal CA1 neurons during DBS delivered at 40 Hz or 140 Hz, free of electrical interference. DBS powerfully depolarized somatic membrane potentials without suppressing spike rate, especially at 140 Hz. Further, DBS paced membrane voltage and spike timing at the stimulation frequency and reduced timed spiking output in response to hippocampal network theta-rhythmic (3–12 Hz) activity patterns. To determine whether DBS directly impacts cellular processing of inputs, we optogenetically evoked theta-rhythmic membrane depolarization at the soma. We found that DBS-evoked membrane depolarization was correlated with DBS-mediated suppression of neuronal responses to optogenetic inputs. These results demonstrate that DBS produces powerful membrane depolarization that interferes with the ability of individual neurons to respond to inputs, creating an informational lesion.
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Stimulation‐induced entrainment of hippocampal network activity: Identifying optimal input frequencies
The hippocampus contains rich oscillatory activity, with continuous ebbs and flows of rhythmic currents that constrain its ability to integrate inputs. During associative learning, the hippocampus must integrate inputs from a range of sources carrying information about events and the contexts in which they occur. Under these circumstances, temporal coordination of activity between sender and receiver is likely essential for successful communication. Previously, it has been shown that the coordination of rhythmic activity between the lateral entorhinal cortex (LEC) and the CA1 region of the hippocampus is tightly correlated with the onset of learning in an associative learning task. We aimed to examine whether rhythmic inputs from the LEC in specific frequency ranges were sufficient to enhance the temporal coordination of activity in downstream CA1. In urethane‐anesthetized rats, we applied extracellular low‐intensity alternating current stimulation across the length of the LEC. Using this method, we aimed to phase‐bias ongoing neuronal activity in LEC at a range of different frequencies (from 1.25 to 55 Hz). Rhythmic stimulation of LEC at both 35 and 50 Hz increased the proportion of CA1 neurons significantly entrained to the phase of the applied stimulation current. A subset of stimulation frequencies modified CA1 spiking relationships to the phase of local ongoing CA1 oscillations, with each stimulation frequency exerting a unique influence upon downstream CA1, often in frequency ranges outside the target stimulation frequency. These results suggest there are optimal frequencies for LEC–CA1 communication, and that different profiles of LEC rhythms likely have distinct outcomes upon CA1 processing.
more » « less- NSF-PAR ID:
- 10392824
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Hippocampus
- Volume:
- 33
- Issue:
- 2
- ISSN:
- 1050-9631
- Page Range / eLocation ID:
- p. 85-95
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Despite its evident importance to learning theory and models, the manner in which the lateral perforant path (LPP) transforms signals from entorhinal cortex to hippocampus is not well understood. The present studies measured synaptic responses in the dentate gyrus (DG) of adult mouse hippocampal slices during different patterns of LPP stimulation. Theta (5 Hz) stimulation produced a modest within‐train facilitation that was markedly enhanced at the level of DG output. Gamma (50 Hz) activation resulted in a singular pattern with initial synaptic facilitation being followed by a progressively greater depression. DG output was absent after only two pulses. Reducing release probability with low extracellular calcium instated frequency facilitation to gamma stimulation while long‐term potentiation, which increases release by LPP terminals, enhanced within‐train depression. Relatedly, per terminal concentrations of VGLUT2, a vesicular glutamate transporter associated with high release probability, were much greater in the LPP than in CA3–CA1 connections. Attempts to circumvent the potent gamma filter using a series of short (three‐pulse) 50 Hz trains spaced by 200 ms were only partially successful: composite responses were substantially reduced after the first burst, an effect opposite to that recorded in field CA1. The interaction between bursts was surprisingly persistent (>1.0 s). Low calcium improved throughput during theta/gamma activation but buffering of postsynaptic calcium did not. In all, presynaptic specializations relating to release probability produce an unusual but potent type of frequency filtering in the LPP. Patterned burst input engages a different type of filter with substrates that are also likely to be located presynaptically.
image Key points The lateral perforant path (LPP)–dentate gyrus (DG) synapse operates as a low‐pass filter, where responses to a train of 50 Hz, γ frequency activation are greatly suppressed.
Activation with brief bursts of γ frequency information engages a secondary filter that persists for prolonged periods (lasting seconds).
Both forms of LPP frequency filtering are influenced by presynaptic, as opposed to postsynaptic, processes; this contrasts with other hippocampal synapses.
LPP frequency filtering is modified by the unique presynaptic long‐term potentiation at this synapse.
Computational simulations indicate that presynaptic factors associated with release probability and vesicle recycling may underlie the potent LPP–DG frequency filtering.
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