Biology subjects

Vetere, L. M.

Publications and source records attributed to Vetere, L. M..

6 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↗

bioRxiv2025

Medial entorhinal-hippocampal desynchronization parallels the emergence of memory impairment in a mouse model of Alzheimer's disease pathology

Alzheimers disease (AD) is a neurodegenerative disease characterized by progressive impairments in episodic and spatial memory, as well as circuit and network-level dysfunction. While functional impairments in medial entorhinal cortex (MEC) and hippocampus (HPC) have been observed in patients and rodent models of AD, it remains unclear how communication between these regions breaks down in disease, and what specific physiological changes are associated with the onset of memory impairment. We used silicon probes to simultaneously record neural activity in MEC and hippocampus before or after the onset of spatial memory impairment in the 3xTg mouse model of AD pathology. We found that reduced hippocampal theta power, reduced MEC-CA1 theta coherence, and altered phase locking of MEC and hippocampal neurons all coincided with the emergence of spatial memory impairment in 3xTg mice. Together, these findings indicate that disrupted temporal coordination of neural activity in the MEC-hippocampal system parallels the emergence of memory impairment in a model of AD pathology. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/633171v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@11606a5org.highwire.dtl.DTLVardef@10e5d0borg.highwire.dtl.DTLVardef@1feabe1org.highwire.dtl.DTLVardef@c646ed_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG HighlightsO_LISpatial memory impairments in 3xTg mice emerge between 6 and 8 months of age C_LIO_LIMemory deficits emerge alongside reduced HPC theta power and reduced CA1-MEC theta coherence C_LIO_LIMemory deficits emerge alongside disrupted timing of MEC and HPC neural activity C_LIO_LIInterneuron loss in MEC and interneuron desynchronization in HPC occur prior to memory impairment C_LI

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

Chronotate: An open-source tool for manual timestamping and quantification of animal behavior

A core necessity to behavioral neuroscience research is the ability to accurately measure performance on behavioral assays, such as the novel object location and novel object recognition tasks. These tasks are widely used in neuroscience research and measure a rodents instinct for investigating novel features as a proxy to test their memory of a previous experience. Automated tools for scoring behavioral videos can be cost prohibitive and often have difficulty distinguishing between active investigation of an object and simply being in close proximity to an object. As such, many experimenters continue to rely on hand scoring interactions using stopwatches which makes it difficult to review scoring after-the-fact and results in the loss of temporal information. Here, we introduce Chronotate, a free, open-source tool to aid in manually scoring novel object behavior videos. The software consists of an interactive video player with keyboard integration for marking timestamps of behavioral events during video playback, making it simple to quickly score and review bouts of rodent-object interaction. In addition, Chronotate outputs detailed interaction bout data, allowing for nuanced behavioral performance analyses. Using this detailed temporal information, we demonstrate that novel object location performance peaks within the first 3 seconds of interaction time and preference for the novel location becomes reduced across the test session. Thus, Chronotate can be used to determine the temporal structure of interactions on this task and can provide new insight into the memory processes that drive this behavior. Chronotate is available for download at: https://github.com/ShumanLab/Chronotate.

neuroscience↗

bioRxiv2023

Progressive excitability changes in the medial entorhinal cortex in the 3xTg mouse model of Alzheimer's disease pathology

Alzheimers disease (AD) is a chronic neurodegenerative disorder that is characterized by memory loss and progressive cognitive impairments. In mouse models of AD pathology, studies have found neuronal and synaptic deficits in the hippocampus, but less is known about what happens in the medial entorhinal cortex (MEC), which is the primary spatial input to the hippocampus and an early site of AD pathology. Here, we measured the neuronal intrinsic excitability and synaptic activity in MEC layer II (MECII) stellate cells, MECII pyramidal cells, and MEC layer III (MECIII) excitatory neurons at early (3 months) and late (10 months) time points in the 3xTg mouse model of AD pathology. At 3 months of age, prior to the onset of memory impairments, we found early hyperexcitability in MECII stellate and pyramidal cells intrinsic properties, but this was balanced by a relative reduction in synaptic excitation (E) compared to inhibition (I), suggesting intact homeostatic mechanisms regulating activity in MECII. Conversely, MECIII neurons had reduced intrinsic excitability at this early time point with no change in the synaptic E/I ratio. By 10 months of age, after the onset of memory deficits, neuronal excitability of MECII pyramidal cells and MECIII excitatory neurons was largely normalized in 3xTg mice. However, MECII stellate cells remained hyperexcitable and this was further exacerbated by an increased synaptic E/I ratio. This observed combination of increased intrinsically and synaptically generated excitability suggests a breakdown in homeostatic mechanisms specifically in MECII stellate cells at this post-symptomatic time point. Together, these data suggest that the breakdown in homeostatic excitability mechanisms in MECII stellate cells may contribute to the emergence of memory deficits in AD.

neuroscience↗

bioRxiv2019

ezTrack: An open-source video analysis pipeline for the investigation of animal behavior

Tracking small animal behavior by video is one of the most common tasks in the fields of neuroscience and psychology. Although commercial software exists for the execution of this task, commercial software often presents enormous cost to the researcher, and can also entail purchasing specific hardware setups that are not only expensive but lack adaptability. Moreover, the inaccessibility of the code underlying this software renders them inflexible. Alternatively, available open source options frequently require extensive model training and can be challenging for those inexperienced with programming. Here we present an open source and platform independent set of behavior analysis pipelines using interactive Python (iPython/Jupyter Notebook) that researchers with no prior programming experience can use. Two modules are described. One module can be used for the positional analysis of an individual animal across a session (i.e., location tracking), amenable to a wide range of behavioral tasks including conditioned place preference, water maze, light-dark box, open field, and elevated plus maze, to name but a few. A second module is described for the analysis of conditioned freezing behavior. For both modules, a range of interactive plots and visualizations are available to confirm that chosen parameters produce results that conform to the users approval. In addition, batch processing tools for the fast analysis of multiple videos is provided, and frame-by-frame output makes aligning the data with neural recording data simple. Lastly, options for cropping video frames to mitigate the influence of fiberoptic/electrophysiology cables, analyzing specified portions of time in a video, and defining regions of interest, can be implemented with ease.

neuroscience↗