Biology subjects

West, P. J.

Publications and source records attributed to West, P. J..

5 recordsLinked to original sources

bioRxiv2025

ASSESSMENT OF CELL-TYPE-SPECIFIC EXCITATORY SYNAPTIC STRENGTH IN THE DORSOLATERAL STRIATUM OF GOAL-DIRECTED AND HABITUAL COCAINE-SEEKING BEHAVIOR

With repeated exposure to addictive drugs, there is a shift from drug abuse to drug addiction that is mediated by the transition from goal-directed to habitual control. It is well known that the development of habitual control over behavior relies upon cell-type-specific synaptic changes in both D1 and D2 medium spiny neurons (MSNs) in dorsal striatum. Specifically, habitual behavior is mediated by increased synaptic strength in D2 MSNs in dorsolateral striatum (DLS), suggesting similar cell-type-specific synaptic changes may underlie the development of habitual cocaine-seeking behavior. However, cell-type-specific synaptic changes have not been evaluated in DLS in this context. Therefore, we trained rats to self-administer cocaine in a cocaine self-administration paradigm that allows for differentiation of goal-directed vs. habitual cocaine-seeking behavior. Moreover, we used a viral vector under a D2-specific promoter to fluorescently label D2 MSNs with eYFP in DLS. Evoked excitatory postsynaptic currents (EPSCs) were used to determine AMPA:NMDA receptor ratio and the rectification index. Surprisingly, we did not observe any significant differences in these measures in DLS of cocaine-seeking rats, regardless of whether cocaine seeking was under habitual control. Interestingly, preliminary observations revealed significant changes in the paired pulse ratio (PPR), suggesting that presynaptic mechanisms may be involved in the development of habitual control over cocaine seeking. Overall, however, these results suggest there are no changes in postsynaptic strength of D2 MSNs in the DLS of rats with an extended history of cocaine self-administration and regardless of whether the cocaine seeking is under goal-directed or habitual control. Significance StatementThe study of drug abuse and drug addiction represents a critical area of research with significant public health implications. Importantly, the underlying neurobiology of the transition between drug abuse and drug addiction is not well understood and insights to this transition may aid in the development of novel treatment options. Behaviorally, the shift from goal-directed to habitual control is thought to underly this transition. Much is known about the neurobiology of goal-directed and habitual behavior, however the transition in the context of drug-seeking is not well defined. We observed no significant differences in measures of synaptic strength, suggesting such postsynaptic neuroplasticity in the dorsolateral striatum is not involved in this transition.

neuroscience↗

bioRxiv2025

DynamoSort: Using machine learning approaches for the automatic classification of seizure dynamotypes

ObjectiveEpilepsy is characterised by unprovoked and recurring seizures, which can be electrically measured using electroencephalograms (EEG). To better understand the underlying mechanisms of seizures, researchers are exploring their temporal dynamics through the lens of dynamical systems modelling. Seizure initiation and termination patterns of spiking amplitude and frequency can be sorted into "dynamotypes", which may be able to serve as biomarkers for intervention. However, manual classification of these dynamotypes requires trained raters and is prone to variability. To address this, we developed DynamoSort, a machine-learning algorithm for automatic seizure onset and offset classification. MethodsWe used approximately 2100 seizures from an intra-amygdala kainic acid (IAK) mouse model of mesial temporal lobe epilepsy, categorized by five trained raters. MATLABs classification learner application was used to create an ensemble model to score and label dynamotypes of individual seizures based on spiking and frequency features. ResultsDynamotype classification of real EEG data lacks a definitive ground truth, with mean inter-rater agreement at 73.4% for onset and 64.2% for offset types. Despite this, DynamoSort achieved a mean area under the curve (AUC) of 0.81 for onset and a mean AUC of 0.75 for offset types. Machine-human agreement was not significantly different from human-to-human agreement. To address the lack of ground truth in ratings, DynamoSort assigns probabilistic scores (-20 to 20), to indicate similarity to each seizure dynamotype based on spiking features, allowing for a characterization of seizure dynamics on a spectrum rather than the traditional qualitative taxonomy. SignificanceAutomating the classification of dynamotypes is a critical step for their inclusion as a biomarker in clinical and research applications. DynamoSort is a straightforward, open-access tool that uses automatic labelling and probabilistic scoring to quantify subtle changes in seizure onset and offset dynamics. Key PointsO_LIDynamotypes are a promising seizure categorization system, but is prone to interrater variability and lacks a ground truth. C_LIO_LIMachine learning can be used to automatically classify seizure onsets and offsets into appropriate dynamotypes based on spike features. C_LIO_LIAgreement between DynamoSort and human raters rivals typical agreement rates in trained human raters. C_LIO_LIDynamoSort uses probabilistic scoring to quantify subtle changes in seizure onset and offset, allowing for a quantitative characterisation. C_LI

neuroscience↗

bioRxiv2021

Evaluation of spontaneous seizure activity, sex-dependent differences, behavioral comorbidities, and alterations in CA1 neuron firing properties in a mouse model of Dravet Syndrome

Dravet syndrome (DS) is a rare childhood epilepsy disorder resulting in spontaneous, recurrent seizures (SRS) and behavioral co-morbidities. To facilitate the discovery and development of anti-seizure drugs for DS, the contract site of the NINDS Epilepsy Therapy Screening Program (ETSP) has continued to evaluate a mouse model of DS. Scn1aA1783V/WT mice exhibited increased hyperactivity, thigmotaxis, and deficits in nest-building behavior. Ex-vivo brain slice electrophysiology experiments revealed increased excitability of hippocampal CA1 neurons specifically due to increased action potential firing frequency in response to brief depolarizations and decreased frequency of spontaneous GABAergic synaptic events. A video-EEG study revealed mice had on average, 1 seizure per day, with males seizing significantly more frequently than females. Increased proportion of seizure activity occurred during the dark phase of the light/dark cycle in both sexes. While clobazam, a drug commonly prescribed to patients with DS, had no effect on SRS activity at the tested doses, the seizure history and frequency observed in this study aids in determining the sample sizes and experimental timeline needed for adequately powered preclinical drug studies. Overall, this study provides a broad description of the Scn1aA1783V/WT mouse and highlights the utility of this model in therapy discovery.

pharmacology and toxicology↗

bioRxiv2020

Spontaneous recurrent seizures in an intra-amygdala kainate microinjection model of temporal lobe epilepsy are differentially sensitive to antiseizure drugs

The discovery and development of novel antiseizure drugs (ASDs) that are effective in controlling pharmacoresistant spontaneous recurrent seizures (SRSs) continues to represent a significant unmet clinical need. The Epilepsy Therapy Screening Program (ETSP) has undertaken efforts to address this need by adopting animal models that represent the salient features of human pharmacoresistant epilepsy and employing these models for preclinical testing of investigational ASDs. One such model that has garnered increased interest in recent years is the mouse variant of the Intra-Amygdala Kainate (IAK) microinjection model of mesial temporal lobe epilepsy (MTLE). In establishing a version of this model, several methodological variables were evaluated for their effect(s) on pertinent quantitative endpoints. Although administration of a benzodiazepine 40 minutes after kainate (KA) induced status epilepticus (SE) is commonly used to improve survival, data presented here demonstrates similar outcomes (mortality, hippocampal damage, latency periods, and 90-day SRS natural history) between mice given midazolam and those that were not. Using a version of this model that did not interrupt SE with a benzodiazepine, a 90-day natural history study was performed and survival, latency periods, SRS frequencies and durations, and SRS clustering data were quantified. Finally, an important step towards model adoption is to assess the sensitivities or resistances of SRSs to a panel of approved and clinically used ASDs. Accordingly, the following ASDs were evaluated for their effects on SRSs in these mice: phenytoin (20 mg/kg, b.i.d.), carbamazepine (30 mg/kg, t.i.d.), valproate (240 mg/kg, t.i.d.), diazepam (4 mg/kg, b.i.d.), and phenobarbital (25 and 50 mg/kg, b.i.d.). Valproate, diazepam, and phenobarbital significantly attenuated SRS frequency relative to vehicle controls at doses devoid of observable adverse behavioral effects. Only diazepam significantly increased seizure freedom. Neither phenytoin nor carbamazepine significantly altered SRS frequency or freedom under these experimental conditions. These data demonstrate that SRSs in this IAK model of MTLE are pharmacoresistant to two representative sodium channel-inhibiting ASDs (phenytoin and carbamazepine) but not to GABA receptor modulating ASDs (diazepam and phenobarbital) or a mixed-mechanism ASD (valproate). Accordingly, this model is being incorporated into the NINDS-funded ETSP testing platform for treatment resistant epilepsy. HighlightsO_LIAn intra-amygdala kainate model of TLE was evaluated for pharmacoresistant seizures C_LIO_LIAdministration of midazolam during status epilepticus did not affect mortality C_LIO_LIModel characteristics were evaluated over a 90-day natural history study C_LIO_LISpontaneous seizures were resistant to phenytoin and carbamazepine C_LIO_LISpontaneous seizures were sensitive to valproic acid, diazepam, and phenobarbital C_LI

neuroscience↗

bioRxiv2020

Development of an Antiseizure Drug Screening Platform for Dravet Syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program

ObjectiveDravet syndrome (DS) is a rare, but catastrophic genetic epilepsy, with 80% of patients with carrying a mutation in the SCN1A gene. Currently, no anti-seizure drug (ASD) exists that adequately controls seizures. Patients with DS often present clinically with a febrile seizure and generalized tonic-clonic seizures that continue throughout life. To facilitate the development of ASDs for DS, the contract site of the NINDS Epilepsy Therapy Screening Program (ETSP) has evaluated a mouse model of DS using the conditional knock-in Scn1aA1783V/WT mouse. MethodsSurvival rates and temperature thresholds for Scn1aA1783V/WT were determined. Prototype ASDs were administered via intraperitoneal injections at the time-to-peak effect, which was previously determined, prior to the induction of hyperthermia-induced seizures. Protection was determined if ASDs significantly increased the temperature at which Scn1aA1783V/WT mice seized. ResultsApproximately 50% of Scn1aA1783V/WT survive to adulthood and all have hyperthermia-induce seizures. The results suggest that hyperthermia-induced seizures in this model of DS are highly refractory to a battery of ASDs. Exceptions were clobazam, tiagabine, and the combination of clobazam and valproic acid with add-on stiripentol, which elevated seizure thresholds SignificanceOverall, the data demonstrate the proposed model for DS is suitable for screening novel compounds for the ability to block hyperthermia-induced seizures and heterozygous mice can be evaluated repeatedly over the course of several weeks, allowing for higher throughput screening. Key Points O_LIScn1aA1783V/WT mice have a 50% survival rate and all have hyperthermia-induced seizures. C_LIO_LICommon DS treatments such as CLB and combinatorial therapy of CLB, VPA, and STP increase temperature thresholds in Scn1aA1783V/WT mice. C_LIO_LISodium channel blockers, such as CBZ and LTG, decrease temperature thresholds of Scn1aA1783V/WT mice as predicted. C_LIO_LIScn1aA1783V/WT mice are highly pharmacoresitant to common ASDs C_LIO_LIThe Scn1aA1783V/WT may be a useful preclinical drug screening platform for the treatment of DS. C_LI

pharmacology and toxicology↗