Biology subjects

Lamsifer, S. I.

Publications and source records attributed to Lamsifer, S. I..

4 recordsLinked to original sources

bioRxiv2025

Interneuron theta phase locking controls seizure susceptibility

The timing of neuronal activity is highly precise and often organized by brain-wide oscillations. Many neurons modulate their firing rates at specific phases of theta (known as theta phase locking), creating discrete windows for information processing. Disrupted theta phase locking has been found across several neurological and psychiatric disorders (e.g., epilepsy), but gaps in technology have prevented its causal influence from being tested. Here, we developed PhaSER, a closed-loop optogenetic system designed to control the phase locking of specific interneurons, and demonstrate a causal role for inhibitory phase locking in seizure susceptibility. We first found that parvalbumin (PV+) and somatostatin (SOM+) expressing interneurons in the dentate gyrus (DG) show distinct theta phase locking profiles and are differentially impacted in a mouse model of chronic temporal lobe epilepsy. In healthy mice, PV+ interneurons have extremely consistent phase-locked firing near the trough of CA1 theta, aligned with excitatory inputs to DG. However, in epileptic mice, PV+ interneuron activity is dispersed across the theta cycle, suggesting that altered inhibitory phase locking could be a causal mediator of seizure susceptibility in epilepsy. To test this hypothesis, we applied PhaSER to directly control the phase locking of DG interneurons during an acute test of seizure susceptibility. In epileptic mice, re-aligning DG PV+ interneuron theta phase locking reduced seizure susceptibility, while in healthy mice, disrupting normal phase locking of PV+ interneurons increased seizure susceptibility. Together, this provides the first causal evidence that inhibitory theta phase locking can directly control network function by shifting seizure susceptibility in the healthy and epileptic brain.

neuroscience↗

bioRxiv2024

Simultaneous dual-color calcium imaging in freely-behaving mice

Miniaturized fluorescence microscopes (miniscopes) enable imaging of calcium events from a large population of neurons in freely behaving animals. Traditionally, miniscopes have only been able to record from a single fluorescence wavelength. Here, we present a new open-source dual-channel Miniscope that simultaneously records two wavelengths in freely behaving animals. To enable simultaneous acquisition of two fluorescent wavelengths, we incorporated two CMOS sensors into a single Miniscope. To validate our dual-channel Miniscope, we imaged hippocampal CA1 region that co-expressed a dynamic calcium indicator (GCaMP) and a static nuclear signal (tdTomato) while mice ran on a linear track. Our results suggest that, even when neurons were registered across days using tdTomato signals, hippocampal spatial coding changes over time. In conclusion, our novel dual-channel Miniscope enables imaging of two fluorescence wavelengths with minimal crosstalk between the two channels, opening the doors to a multitude of new experimental possibilities. TeaserNovel open-source dual-channel Miniscope that simultaneously records two wavelengths with minimal crosstalk in freely behaving animals.

neuroscience↗

bioRxiv2024

Distinct changes to hippocampal and medial entorhinal circuits emerge across the progression of cognitive deficits in epilepsy

Temporal lobe epilepsy (TLE) causes pervasive and progressive memory impairments, yet the specific circuit changes that drive these deficits remain unclear. To investigate how hippocampal-entorhinal dysfunction contributes to progressive memory deficits in epilepsy, we performed simultaneous in vivo electrophysiology in hippocampus (HPC) and medial entorhinal cortex (MEC) of control and epileptic mice 3 or 8 weeks after pilocarpine-induced status epilepticus (Pilo-SE). We found that HPC synchronization deficits (including reduced theta power, coherence, and altered interneuron spike timing) emerged within 3 weeks of Pilo-SE, aligning with early-onset, relatively subtle memory deficits. In contrast, abnormal synchronization within MEC and between HPC-MEC emerged later, by 8 weeks after Pilo-SE, when spatial memory impairment was more severe. Furthermore, a distinct subpopulation of MEC layer 3 excitatory neurons (active at theta troughs) was specifically impaired in epileptic mice. Together, these findings suggest that hippocampal-entorhinal circuit dysfunction accumulates and shifts as cognitive impairment progresses in TLE.

neuroscience↗

bioRxiv2023

Manipulating single-unit theta phase-locking with PhaSER: An open-source tool for real-time phase estimation and manipulation

The precise timing of neuronal spiking relative to the brains endogenous oscillations (i.e., phase-locking or spike-phase coupling) has long been hypothesized to coordinate cognitive processes and maintain excitatory-inhibitory homeostasis. Indeed, disruptions in theta phase-locking have been described in models of neurological diseases with associated cognitive deficits and seizures, such as Alzheimers disease, temporal lobe epilepsy, and autism spectrum disorders. However, due to technical limitations, determining if phase-locking causally contributes to these disease phenotypes has not been possible until recently. To fill this gap and allow for the flexible manipulation of single-unit phase-locking to on-going endogenous oscillations, we developed PhaSER, an open-source tool that allows for phase-specific manipulations. PhaSER can deliver optogenetic stimulation at defined phases of theta in order to shift the preferred firing phase of neurons relative to theta in real-time. Here, we describe and validate this tool in a subpopulation of inhibitory neurons that express somatostatin (SOM) in the CA1 and dentate gyrus (DG) regions of the dorsal hippocampus. We show that PhaSER is able to accurately deliver a photo-manipulation that activates opsin+ SOM neurons at specified phases of theta in real-time in awake, behaving mice. Further, we show that this manipulation is sufficient to alter the preferred firing phase of opsin+ SOM neurons without altering the referenced theta power or phase. All software and hardware requirements to implement real-time phase manipulations during behavior are available online (https://github.com/ShumanLab/PhaSER).

neuroscience↗