Biology subjects

Mishler, J.

Publications and source records attributed to Mishler, J..

4 recordsLinked to original sources

bioRxiv2025

Differential glutamatergic and GABAergic responses drive divergent prefrontal cortex neural outcomes to low and high frequency stimulation

BackgroundRepetitive brain stimulation is hypothesized to bidirectionally modulate excitability, with low-frequency trains decreasing and high-frequency (>5 Hz) trains increasing activity. Most insights on the neuroplastic effects of repetitive stimulation protocols stem from non-invasive human studies (TMS/EEG) or data from rodent slice physiology. Here, we developed a rodent experimental preparation enabling simultaneous imaging of cellular activity during stimulation in vivo to understand the mechanisms by which brain stimulation modulates excitability of prefrontal cortex. MethodsRepetitive trains of intracortical stimulation were applied to the medial prefrontal cortex using current parameters mapped to human rTMS electric-field estimates. Calcium imaging of glutamatergic (CamKII) and GABAergic (mDLX) neurons was performed before, during, and after stimulation in awake rodents (n=9 females). Protocols included low-frequency (1 Hz, 1000 pulses) and high-frequency (10 Hz, 3000 pulses), with sham stimulation as a control. ResultsGlutamatergic neurons were differentially modulated by stimulation frequency, with 10 Hz increasing and 1 Hz decreasing activity. Post-stimulation, 1 Hz suppressed both glutamatergic and GABAergic activity, whereas 10 Hz selectively suppressed GABAergic neurons. ConclusionsThese findings provide direct evidence that clinical brain stimulation protocols induce long-term modulation of cortical excitability, with low-frequency stimulation broadly suppressing activity and high-frequency stimulation preferentially inhibiting GABAergic neurons after stimulation.

neuroscience↗

bioRxiv2024

Intermittent Theta Burst Stimulation Drives Bi-Directional Changes in Excitability in Prefrontal Cortex

Intermittent Theta Burst Stimulation (iTBS) is a patterned stimulation protocol FDA-cleared to treat depression, yet its outcomes are variable and mechanistically unclear. Here, using a combination of calcium imaging, histology, optogenetics and behavior, we show that one parameter of iTBS, the inter-train interval (ITI) between stimulation trains, plays a critical role in modulating GABAergic (and especially parvalbumin) neuronal activity, modulating subsequent neuronal plasticity and antidepressant effects. Shorter ITI stimulation protocols (4-10Ssinter-train intervals) activate GABA neurons, limiting resulting changes in cortical excitability and plasticity compared to extended interval TBS protocols (eTBS, with a 20s ITI). eTBS also drives the largest changes in synaptic / spine plasticity and leads to rapid and durable antidepressant-like effects after only a single stimulation session. Optogenetic activation of GABAergic neurons during eTBS blocks synaptic plasticity and rapid antidepressant effects. Together, these findings reveal a temporal control principle for TBS-induced cortical plasticity and provides a physiology-based strategy to improve TBS efficacy. HighlightsO_LIInter-train interval (ITI) controls excitatory-inhibitory balance during theta burst stimulation C_LIO_LIShort ITIs strongly activate PV interneurons limiting longer-term changes in glutamatergic excitatory plasticity C_LIO_LIExtended ITI (20s in particular) reduces inhibitory activity while maintaining sufficient activation of glutamatergic neurons to promote post-stimulation plasticity C_LIO_LIeTBS produces rapid and durable antidepressant-like effects that are blocked by GABAergic co-activation C_LI Graphical AbstractInter-train interval (ITI) determines the balance between excitation and inhibition during theta burst stimulation (TBS), an FDA-cleared treatment for depression. (A) Short ITIs (4s) drive concurrent glutamatergic and GABAergic activation, with inhibitory dominance during stimulation and suppressed long-term modulation of excitability. Extending the ITI to 20s (eTBS) reduces GABAergic recruitment during stimulation, promoting sustained long-term glutamatergic modulation resulting cortical disinhibition, leading to rapid and durable antidepressant-like effects (B). Optogenetic activation of GABAergic interneurons during eTBS abolishes synaptic and antidepressant effects, demonstrating that reduced inhibitory recruitment during eTBS is required for the rapid and durable behavioral effects observed with that protocol. O_FIG O_LINKSMALLFIG WIDTH=182 HEIGHT=200 SRC="FIGDIR/small/608693v3_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@15a7decorg.highwire.dtl.DTLVardef@1220forg.highwire.dtl.DTLVardef@63258forg.highwire.dtl.DTLVardef@13707e7_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Local field potentials and single unit dynamics in motor cortex of unconstrained macaques during different behavioral states

Different sleep states have been shown to be vital for a variety of brain function, including learning, memory, and skill consolidation. However, our understanding of neural dynamics during sleep and the role of prominent LFP frequency bands remain incomplete. To elucidate such dynamics and changes between different behavioral states we collected multichannel LFP and spike data in primary motor cortex of unconstrained macaques for up to 24 hours using the Neurochip3. Each 8 second bin of time was classified into awake and moving (Move), awake and at rest (Rest), REM sleep (REM), or non-REM sleep (NREM) by using dimensionality reduction and clustering on the average spectral density and the acceleration of the head. LFP power showed high delta during NREM, high theta during REM, and high beta when the animal was awake. Cross-frequency phase-amplitude coupling typically showed higher coupling for deeper sleep between all pairs of frequency bands. Two notable exceptions were high delta-high gamma and theta-high gamma coupling during Move, and high theta-beta coupling during REM. Sorted single units showed decreased firing rate with deeper sleep, though with higher "bursty" patterns during NREM compared to other states. Spike-LFP synchrony showed high delta synchrony during Move, and higher coupling with all other frequency bands with deeper sleep. These results altogether are consistent with previous findings showing reactivation of cortical circuitry during sleep, which may be moderated by delta band LFP.

neuroscience↗

bioRxiv2022

Responses of cortical neurons to intracortical microstimulation in awake primates

Intracortical microstimulation (ICMS) is commonly used in many experimental and clinical paradigms; however, its effects on the activation of neurons are still not completely understood. To document the responses of cortical neurons in non-human primates to stimulation, we recorded single unit activity while delivering single-pulse stimulation via Utah arrays implanted in primary motor cortex of three macaque monkeys. Stimuli between 5-50 A delivered to single channels reliably evoked spikes in neurons recorded throughout the array with delays of up to 12 milliseconds. ICMS pulses also induced a period of inhibition lasting up to 150 ms that typically followed the initial excitatory response. Higher current amplitudes led to a greater probability of evoking a spike and extended the duration of inhibition. The likelihood of evoking a spike in a neuron was dependent on the spontaneous firing rate as well as the delay between its most recent spike time and stimulus onset. Tonic repetitive stimulation between 2 and 20 Hz often modulated both the probability of evoking spikes and the duration of inhibition, although high frequency stimulation in particular was more likely to change both responses. On a trial-by-trial basis, whether a stimulus evoked a spike did not affect the subsequent inhibitory response; however, their changes over time were frequently positively or negatively correlated. Our results document the complex dynamics of cortical neural responses to electrical stimulation that need to be considered when utilizing ICMS for scientific and clinical applications. Significance statementIntracortical microstimulation (ICMS) is commonly used to probe the cortex, and previous studies have characterized the responses of single neurons to ICMS. However, these studies typically explored the averaged effects of ICMS throughout each experimental session, rather than by a trial-by-trial basis for each stimulation pulse. By shifting the approach, we explored the dependence of neural responses to ICMS on the spontaneous neural activity as well as the dynamics of responses over time due to repetitive stimulation. Our results highlight how the responses of neurons to ICMS are likely the result of interactions between local excitatory and inhibitory cortical circuits. These results will help inform the design of ICMS for both basic research and clinically relevant stimulation protocols.

neuroscience↗