Biology subjects

Linsenbardt, D.

Publications and source records attributed to Linsenbardt, D..

4 recordsLinked to original sources

bioRxiv2025

Unsupervised Phenotyping Reveals Disrupted Neural Firing Characteristics in the Anterior Thalamus and Surrounding Brain Regions Following Third-Trimester Equivalent Alcohol Exposure in Mice

Acute, binge-like alcohol exposure during the third-trimester-equivalent period (TTAE) produces apoptotic neurodegeneration in brain regions critical for spatial learning and memory, including the anterior thalamic nuclei (ATN), which are necessary for contextual learning and memory. To investigate the neural mechanisms underlying spatial cognition deficits following developmental alcohol exposure, we performed high-density electrophysiological recordings in and around the ATN of behaving mice, sampling 7,490 neurons across multiple, predominantly thalamic depths. To model acute binge-like TTAE, C57BL/6J mice received two injections of 2.5 g/kg ethanol (or saline) on postnatal day (PND) 7. In young adulthood (>PND 60), mice were implanted with silicon or multi-wire electrode arrays and allowed to explore a circular arena (40 cm diameter) under dim red light with two wall-mounted LED cues that rotated pseudo-randomly. Spike timing and waveform features were extracted from each putative single unit. Across the recorded population, firing rates were generally reduced following TTAE, although responses were heterogeneous. To characterize this variability, neuronal features were embedded using uniform manifold approximation and projection (UMAP). Logistic regression classified saline- and TTAE-exposed neurons based on electrophysiological properties and UMAP coordinates, achieving 80% accuracy. Cluster-based comparisons showed weak correspondence between physiological similarity and treatment response, suggesting TTAE effects are driven primarily by anatomical location. This study presents the first large-scale in vivo electrophysiological recordings in a freely behaving mouse model of fetal alcohol spectrum disorders, revealing divergent circuit adaptations marked by hippocampal hyperexcitability and thalamic dysfunction.

neuroscience↗

bioRxiv2024

Maternal Alcohol Drinking Patterns Predict Offspring Neurobehavioral Outcomes

SIGNIFICANCEThe timing, rate, and quantity of gestational alcohol consumption, collectively referred to here as Maternal Drinking Patterns (MDPs), are of known importance to fetal developmental outcomes. Though studies in rodents exist that have investigated the impact of gestational alcohol drinking characteristics, few have sought to determine the impact of MDPs on offspring behavioral outcomes. METHODSWe first used specialized equipment to record the precise amount and timing of binge alcohol consumption in pregnant mouse dams, and then characterized MDPs using Principle Component Analysis (PCA). We focused these analyses on the first fifteen minutes of every gestational drinking session when dams consumed the majority of each sessions alcohol (a phenomenon known as front-loading), as well as the entire 2 hour session across all days of gestation. We next tested offspring in open field and rotarod assays and evaluated these behavioral results in the context of MDPs. RESULTSMale alcohol exposed mice exhibited longer latencies to fall on the rotarod compared to their controls, which we attribute to a delayed decrease in body weight-gain not observed in females. This effect was found to be associated with MDPs within the first fifteen minutes of drinking, but not other MDPs. Female alcohol exposed mice had significantly reduced total locomotor activity in the open field compared to controls, and this effect was also associated with MDPs but only of the entire drinking session. Surprisingly, total gestational alcohol consumption alone was not associated with any particular behavioral outcome. Furthermore, we replicated robust behavioral data demonstrating development of allodynia in alcohol exposed mice where it did not develop in controls. CONCLUSIONSTo our knowledge, this report represents the highest resolution assessment of alcohol drinking throughout gestation, and one of few to have identified relationships between specific alcohol MDPs and neurobehavioral outcomes in offspring. Specifically, based on characteristics of the PCA groups, we found evidence that the rate of alcohol front-loading leads to developmental delays in males, whereas an interaction of front-loading rate and duration, overall persistence, and total amount consumed lead to a female-only decrease in locomotor activity. Beyond these results, we provide a method for precise and accessible tracking of such data.

neuroscience↗

bioRxiv2024

Knockout of AMPA receptor binding protein Neuron-Specific Gene 2 (NSG2) enhances associative learning and cognitive flexibility

The vast majority of gene mutations and/or gene knockouts result in either no observable changes, or significant deficits in molecular, cellular, or organismal function. However, in a small number of cases, mutant animal models display enhancements in specific behaviors such as learning and memory. To date, most gene deletions shown to enhance cognitive ability generally affect a limited number of pathways such as NMDA receptor- and translation-dependent plasticity, or GABA receptor- and potassium channel-mediated inhibition. While endolysosomal trafficking of AMPA receptors is a critical mediator of synaptic plasticity, mutations in genes that affect AMPAR trafficking either have no effect or are deleterious for synaptic plasticity, learning and memory. NSG2 is one of the three-member family of Neuron-specific genes (NSG1-3), which have been shown to regulate endolysosomal trafficking of a number of proteins critical for neuronal function, including AMPAR subunits (GluA1-2). Based on these findings and the largely universal expression throughout mammalian brain, we predicted that genetic knockout of NSG2 would result in significant impairments across multiple behavioral modalities including motor, affective, and learning/memory paradigms. However, in the current study we show that loss of NSG2 had highly selective effects on associative learning and memory, leaving motor and affective behaviors intact. For instance, NSG2 KO animals performed equivalent to wild-type C57Bl/6n mice on rotarod and Catwalk motor tasks, and did not display alterations in anxiety-like behavior on open field and elevated zero maze tasks. However, NSG2 KO animals demonstrated enhanced recall in the Morris water maze, accelerated reversal learning in a touch-screen task, and accelerated acquisition and recall on a Trace Fear Conditioning task. Together, these data point to a specific involvement of NSG2 on multiple types of associative learning, and expand the repertoire of pathways that can be targeted for cognitive enhancement.

neuroscience↗

bioRxiv2019

Alcohol preferring P rats exhibit aversion resistant drinking of alcohol adulterated with quinine

Understanding why some people continue to drink alcohol despite negative consequences and others do not is a central problem in the study of alcohol use disorder (AUD). In this study, we used alcohol preferring P rats (a strain bred to prefer to drink alcohol, a model for genetic risk for AUD) and Wistars (control) to examine drinking despite negative consequences in the form of an aversive bitter taste stimuli produced by quinine. Animals were trained to consume 10% ethanol in a simple Pavlovian conditioning task that paired alcohol access with an auditory stimulus. When the alcohol was adulterated with quinine (0.1 g/L), P rats continued to consume alcohol+quinine at the same rate as unadulterated alcohol, despite a demonstrated aversion to quinine adulterated alcohol when given a choice between adulterated and unadulterated alcohol in the home cage. Conversely, Wistars decreased consumption of quinine adulterated alcohol in the task, but continued to try the alcohol+quinine solution at similar rates to unadulterated alcohol. These results indicate that following about 8 weeks of alcohol consumption P rats exhibit aversion resistant drinking. This model could be used in future work to explore how biological basis of alcohol consumption and genetic risk for excessive drinking lead to drinking that is resistant to devaluation.

neuroscience↗