Biology subjects

Adam, C. D.

Publications and source records attributed to Adam, C. D..

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↗

bioRxiv2024

Chemogenetic Breakdown of the Dentate Gate Causes Seizures and Spatial Memory Deficits

The dentate gyrus has often been posited to act as a gate that dampens highly active afferent input into the hippocampus. Effective gating is thought to prevent seizure initiation and propagation in the hippocampus and support learning and memory processes. Pathological changes to DG circuitry that occur in temporal lobe epilepsy (TLE) can increase DG excitability and impair its gating ability which can contribute to seizures and cognitive deficits. There is evidence that TLE pathologies and seizures may independently contribute to learning and memory deficits in TLE through distinct mechanisms. These two factors are difficult to untangle since TLE pathologies can drive seizures, and seizures can worsen TLE pathologies. Here we assessed whether chemogenetically increasing dentate granule cell (DGC) excitability was enough to break down the dentate gate in the absence of TLE pathologies. We found that increasing excitability specifically in DGCs caused seizures in non-epileptic mice. Importantly, due to the modulatory nature of DREADD effects, seizures were driven by intrinsic circuit activity rather than direct activation of DGCs. These seizures resulted in a spatial memory deficit when induced after training in the spatial object recognition task and showed stereotypical patterns of activity in miniscope calcium recordings. Our results provide direct support for the dentate gate hypothesis since seizures could be induced in non-epileptic animals by artificially degrading the dentate gate with chemogenetics in the absence of epilepsy pathologies.

neuroscience↗

bioRxiv2024

Disrupted Hippocampal Theta-Gamma Coupling and Spike-Field Coherence Following Experimental Traumatic Brain Injury

Traumatic brain injury (TBI) often results in persistent learning and memory deficits, likely due to disrupted hippocampal circuitry underlying these processes. Precise temporal control of hippocampal neuronal activity is thought to be important for memory encoding and retrieval and is supported by oscillations that dynamically organize single unit firing. Using high-density laminar electrophysiology, we found a loss of oscillatory power across CA1 lamina, with a profound, layer-specific reduction in theta-gamma phase amplitude coupling in injured rats. Interneurons from injured animals were less strongly entrained to theta and gamma oscillations, but both interneurons and pyramidal cells from injured animals became more strongly entrained to theta during periods of high theta power. During quiet immobility, sharp-wave ripple amplitudes were lower in injured animals compared to shams. These results reveal physiological deficits across brain states that may contribute to TBI-associated learning and memory impairments and elucidate potential targets for future neuromodulation therapies.

neuroscience↗

bioRxiv2022

Hippocampal Interneuronal Dysfunction and Hyperexcitability in Porcine Model of Concussion

Cognitive impairment is a common symptom following mild traumatic brain injury (mTBI or concussion) and can persist for years in some individuals. Hippocampal slice preparations following closed-head, rotational acceleration injury in swine have previously demonstrated reduced axonal function and hippocampal circuitry disruption. However, electrophysiological changes in hippocampal neurons and their subtypes in a large animal mTBI model have not been examined. Using in vivo electrophysiology techniques, we examined laminar oscillatory field potentials and single unit activity in the hippocampal network 7 days post-injury in anesthetized minipigs. Concussion altered the electrophysiological properties of pyramidal cells and interneurons differently in area CA1. While the firing rate, spike width and amplitude of CA1 interneurons were significantly decreased post-mTBI, these parameters were unchanged in CA1 pyramidal neurons. In addition, CA1 pyramidal neurons in TBI animals were less entrained to hippocampal gamma (40 - 80 Hz) oscillations. Stimulation of the Schaffer collaterals also revealed hyperexcitability across the CA1 lamina post-mTBI. Computational simulations suggest that reported changes in interneuronal physiology may be due to alterations in voltage-gated sodium channels. These data demonstrate that a single concussion can lead to significant neuronal and circuit level changes in the hippocampus, which may contribute to cognitive dysfunction following mTBI.

neuroscience↗

bioRxiv2018

Multichannel Silicon Probes for Laminar Cortical and Hippocampal Recordings in Large Animals.

Decoding laminar information across deep brain structures and cortical regions is necessary in order to understand the spatiotemporal ensembles that represent cognition and memory. Large animal models are essential for translational research due to their gyrencephalic neuroanatomy and significant white matter composition. One of the major obstacles to applying the approaches currently utilized in lower order animals are technical limitations in silicon probes, specifically a lack of long-length probes with appropriate stiffness to penetrate to deeper structures with minimal damage to the neural interface. We tested various solutions and designs of multichannel silicon probes developed for large animal electrophysiology by recording neurophysiological signals from deep laminar structures in an acute preparation and in chronically implanted awake behaving Yucatan pigs. Electrophysiological parameters of single units and local field potentials were analyzed to evaluate performance over time of given silicon probes in chronic implantations. The cross-sectional area of silicon probes was found to be a crucial determinant of silicon probes single unit performance over time, potentially due to reduction of damage to the neural interface. EDGE-style probes had the highest yields during intra-hippocampal recordings in pigs, making them the most suitable for chronic implantations and awake behavioral experimentation. Novel CAMB 64-channel EDGE-style probes with linear and poly-2 site arrangement tested acutely had optimal single unit separation and a denser sampling of the laminar structure, identifying them as potential candidates for chronic implantations with less cortical damage above the active portion of the probe. This study provides an analysis of multichannel silicon probes designed for large animal laminar electrophysiology of deep brain structures, and suggests that current designs are reaching the physical thresholds necessary for long-term (~ 1 month) recordings from laminar deep structures with single-unit resolution.

neuroscience↗

bioRxiv2017

Electrophysiological Signature Reveals Laminar Structure of the Porcine Hippocampus

The hippocampus is integral to working and episodic memory, and is a central region of interest in diseases affecting these processes. Pig models are widely used in translational research, and may provide an excellent bridge between rodents and non-human primates for CNS disease models due to their gyrencephalic neuroanatomy and significant white matter composition. However, the laminar structure of the pig hippocampus has not been well characterized. Therefore, we histologically characterized the dorsal hippocampus of Yucatan miniature pigs and quantified the cytoarchitecture of the hippocampal layers. We then utilized stereotaxis combined with single unit electrophysiological mapping to precisely place multichannel laminar silicon probes into the dorsal hippocampus without the need for image guidance. We used in vivo electrophysiological recordings of simultaneous laminar field potentials and single unit activity in multiple layers of the dorsal hippocampus to physiologically identify and quantify these layers under anesthesia. Consistent with previous reports, we found the porcine hippocampus to have the expected archicortical laminar structure with some anatomical and histological features comparable to the rodent and others to the primate hippocampus. Importantly, we found these distinct features to be reflected in the laminar electrophysiology. This characterization, as well as our electrophysiology-based methodology targeting the porcine hippocampal lamina combined with high channel count silicon probes will allow for analysis of spike-field interactions during normal and disease states in both anesthetized and future awake behaving neurophysiology in this large animal.\n\nSignificance StatementThe hippocampus is central to working and episodic memory and is critically affected by diverse disease processes. In order to investigate hippocampal electrophysiology in translational large animal models, we developed an imaging-free stereotaxis and intraoperative electrophysiology methodology with custom silicon probes to precisely localize probe placement within the hippocampal laminar structure. We report for the first time the profile of single units and local field potentials in the pig dorsal hippocampus and relate them to a histological description. This characterization forms the basis for accessible translational pig models to study diseases of the central nervous system affecting hippocampal circuitry in the large animal gyrencephalic brain, as well as the groundwork for potential awake behaving neurophysiology of the porcine hippocampus.\n\nFunding SourcesThe Department of Veterans Affairs, IK2-RX001479, I01-RX001097. The National Institutes of Health, NINDS R01-NS-101108-01, T32-NS043126. CURE Foundation, Taking Flight Award. DoD ERP CDMRP, W81XWH-16-1-0675.

neuroscience↗