Biology subjects

Linsenbardt, D. N.

Publications and source records attributed to Linsenbardt, D. N..

9 recordsLinked to original sources

bioRxiv2026

Remotely Presenting Alcohol-predicting Cues Avoids Confound of Experimenter as First Cue and Reveals Sex-specific Behaviors that Predict the Rate and Amount of Alcohol Consumption

Understanding the neurobiological systems that regulate alcohol cue-induced craving is of utmost importance for the development of novel intervention strategies for alcohol use disorders (AUDs). However, although a human experimenter is required to conduct alcohol self-administration studies in the lab, the cues associated with the experimenter are seldom if ever factored into the experimental design. Thus, although we have learned much to date about alcohol cue-induced behavior and neurobiology, and in particular about discrete cues presented many times throughout a single daily alcohol self-administration session, we know relatively little about how responses to alcohol availability cues might predict subsequent alcohol consumption. For the current experiment, mice were exposed daily to auditory cues that preceded 2 hours of alcohol or water access using drinking-in-the-dark (DID) methods. An additional control group experienced cues but were not otherwise manipulated. Importantly, cues were initiated remotely from outside the animal facility, avoiding the experimenter being the first cue predicting ethanol availability. Head direction, location in the home cage, and movement velocity were the primary variables on interest. Surprisingly, during the cue period, there were no significant differences between groups in any of these measures, despite meaningful alterations over days. However, we observed many significant correlations between behaviors and drinking variables. First, we observed significant positive associations between ambulatory velocity during cues and subsequent total alcohol (R2=0.14; p<0.0001) and total water (R2=0.12; p=0.0002) consumption, but only in females. We also observed a significant positive relationship (R2=0.25; p<0.0001) between the amount of time oriented toward the sipper port during the auditory cues and the average rate of subsequent alcohol consumption (i.e. front-loading), but only in females. In males, head direction was found to be positively associated with subsequent total water consumption (R2=-0.21; p<0.0001), but not alcohol (R2=-0.01; p=0.2267). We also observed a significant negative relationship (R2=-0.15; p<0.0001) between proximity to the sipper during the cue period and subsequent total 2-hour alcohol intake in males. Although these associations were modest in strength, they suggest potential sex-specific behavioral predictors of alcohol consumption that are regulated by different neural dynamics.

animal behavior and cognition↗

bioRxiv2026

Epileptiform Discharges Drive High-frequency Oscillations Within the Retrosplenial Cortex of Mice with Third Trimester Alcohol Exposure

Fetal Alcohol Spectrum Disorders (FASDs) are associated with alterations in learning and memory that persist throughout the lifespan. Thus, determining the neural mechanisms driving these alterations has the potential to identify novel therapeutic targets for improving memory in those with FASD. Given the newly realized role of the Retrosplenial cortex (RSC) for learning and memory, as well as the profound neural apoptosis that exposure to alcohol during development causes to this brain region, we recorded electrophysiological activity from mice exposed to alcohol during the third trimester-equivalent developmental time period. We observed a large number of Epileptiform Discharges (EDs) in alcohol-exposed subjects compared to controls, which were found to drive with High-frequency Oscillations (HFOs). Furthermore, many features of HFOs (amplitude/duration/etc.) were found to be directly proportional to the temporal distance from ED onset. These findings identify EDs for the first time as a critical feature in a preclinical model of FASD, and suggest their relationship to RSC HFOs may be a key mechanism driving memory alterations.

neuroscience↗

bioRxiv2024

Neural basis of cognitive control signals in anterior cingulate cortex during delay discounting

Cognitive control involves allocating cognitive effort according to internal needs and task demands. The anterior cingulate cortex (ACC) is hypothesized to play a central role in this process. We investigated the neural basis of cognitive control in the ACC of rats performing an adjusting-amount delay discounting task, with a 4s or 8s delay between lever choice and reward. A reinforcement learning model indicated that decision making on this task can be guided by either a value tracking strategy, requiring a resource-based form of cognitive control or a delay-lever biased strategy requiring a resistance-based form of cognitive control. This was then tested in vivo by multiple single unit recordings and local field potentials acquired from male rats performing the task. On this task, the behavioral manifestation of resistance-based control is an excessive focus on delayed lever choices which was observed during a substantial portion of 4s but not 8s delay sessions. On a neural level, this was associated with an increase in Theta (6-12Hz) oscillations prior to delay choices which was present exclusively on 4s delay sessions. By contrast, evidence of a resource-based control signal was found in spike trains that closely tracked lever value prior to choice, and was far more prevalent on 8s delay sessions. These data provide candidate neural signatures of resource-based versus resistance-based forms of cognitive control. While mediated by distinct neural mechanisms, either form could be engaged by individual subjects under different task conditions.

neuroscience↗

bioRxiv2024

Repeated Binge Alcohol Drinking Leads to Reductions in Corticostriatal Theta Coherence in Female but not Male Mice

Decreased functional connectivity between the striatum and frontal cortex is observed in individuals with alcohol use disorder (AUD), and predicts the probability of relapse in abstinent individuals with AUD. To further our understanding of how repeated alcohol (ethanol; EtOH) consumption impacts the corticostriatal circuit, extracellular electrophysiological recordings (local field potentials; LFPs) were gathered from the nucleus accumbens (NAc) and prefrontal cortex (PFC) of C57BL/6J mice voluntarily consuming EtOH or water using a drinking-in-the-dark (DID) procedure. Following a three-day acclimation period wherein only water access was provided during DID, mice were given 15 consecutive days of access to EtOH. Each session consisted of a 30-minute baseline period where water was available and was followed immediately by a 2-hour period where sippers containing water were replaced with new sippers containing either unsweetened 20% (v/v) EtOH (days 4-18; DID) or water (days 1-3; acclimation). Our analyses focused primarily on theta coherence during bouts of drinking, as differences in this band are associated with several behavioral markers of AUD. Both sexes displayed decreases in theta coherence during the first day of binge EtOH consumption. However, only females displayed further decreases in theta coherence on the 14th day of EtOH access. No differences in theta coherence were observed between the first and final bout on any EtOH drinking days. These results provide additional support for decreases in the functional coupling of corticostriatal circuits as a consequence of alcohol consumption and suggests that female mice are uniquely vulnerable to these effects following repeated EtOH drinking.

neuroscience↗

bioRxiv2023

Flexible coding schemes in dorsomedial prefrontal cortex underlie decision-making during delay discounting

Determining how an agent decides between a small, immediate versus a larger, delayed reward has provided insight into the psychological and neural basis of decision-making. The tendency to excessively discount the value of delayed rewards is thought to reflect deficits in brain regions critical for impulse control such as the prefrontal cortex (PFC). This study tested the hypothesis that dorsomedial PFC (dmPFC) is critically involved in flexibly managing neural representations of strategies that limit impulsive choices. Optogenetic silencing of neurons in the rat dmPFC increased impulsive choices at an 8 sec, but not 4 sec, delay. Neural recordings from dmPFC ensembles revealed that, at the 8-sec delay, the encoding landscape transitions to reflect a deliberative-like process rather than the schema-like processes observed at the 4-sec delay. These findings show that changes in the encoding landscape reflect changes in task demands and that dmPFC is uniquely involved in decisions requiring deliberation.

neuroscience↗

bioRxiv2023

Repetitive Spreading Depolarization induces the activation of cell differentiation, synaptic plasticity and neuroprotective pathways.

Spreading depolarization (SD) is a slowly propagating wave of profound depolarization that sweeps through cortical tissue. While much emphasis has been placed on the damaging consequences of SD, there is uncertainty surrounding the potential activation of beneficial pathways such as cell survival and plasticity. The present study used unbiased assessments of gene expression to evaluate that compensatory and repair mechanisms could be recruited following SD, regardless of the induction method, which prior to this work had not been assessed. We also tested assumptions of appropriate controls and the spatial extent of expression changes that are important for in vivo SD models. SD clusters were induced with either KCl focal application or optogenetic stimulation in healthy mice. Cortical RNA was extracted and sequenced to identify differentially expressed genes (DEGs). SDs using both induction methods significantly upregulated 16 genes (versus sham animals) that included the cell proliferation-related genes FOS, JUN, and DUSP6, the plasticity-related genes ARC and HOMER1, and the inflammation-related genes PTGS2, EGR2, and NR4A1. The contralateral hemisphere is commonly used as control tissue for DEG studies, but its activity could be modified by near-global disruption of activity in the adjacent brain. We found 21 upregulated genes when comparing SD-involved cortex versus tissue from the contralateral hemisphere of the same animals. Interestingly, there was almost complete overlap (21/16) with the DEGs identified using sham controls. Neuronal activity also differs in SD initiation zones, where sustained global depolarization is required to initiate propagating events. We found that gene expression varied as a function of the distance from the SD initiation site, with greater expression differences observed in regions further away. Functional and pathway enrichment analyses identified axonogenesis, branching, neuritogenesis, and dendritic growth as significantly enriched in overlapping DEGs. Increased expression of SD-induced genes was also associated with predicted inhibition of pathways associated with cell death, and apoptosis. These results identify novel biological pathways that could be involved in plasticity and/or circuit modification in brain tissue impacted by SD. These results also identify novel functional targets that could be tested to determine potential roles in recovery and survival of peri-infarct tissues. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=46 SRC="FIGDIR/small/530317v2_ufig1.gif" ALT="Figure 1"> View larger version (9K): org.highwire.dtl.DTLVardef@1193589org.highwire.dtl.DTLVardef@9f68forg.highwire.dtl.DTLVardef@1a4f56org.highwire.dtl.DTLVardef@14eb6f4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

The Development, but not Expression, of Alcohol Front-loading in C57BL/6J Mice Maintained on LabDiet 5001 is Abolished by Maintenance on Teklad 2920x Rodent Diet

Excessive alcohol (ethanol) consumption, such as binge-drinking, is extremely commonplace and represents a major health concern. Through modeling excessive drinking in rodents, we are beginning to uncover the neurobiological and neurobehavioral causes and consequences of this pattern of ethanol intake. One important factor for modeling binge drinking in mice is that subjects reliably drink to blood ethanol concentrations (BECs) of 80 mg/dl or higher. Drinking-in-the-dark (DID) is a commonly used mouse model of binge drinking, and we have shown these methods reliably result in robust ethanol front-loading and binge-level BECs in C57BL/6J (B6) mice as well as other ethanol-preferring mouse strains/lines. However, establishing the DID model in a new vivarium space forced us to consider the use of rodent diet formulations we had not previously used. The current set of experiments were designed to investigate the role of two standard rodent diet formulations on binge drinking and the development of ethanol front-loading using DID. We found that BECs in animals maintained on LabDiet 5001 (LD01) were double those found in mice maintained on Teklad 2920x (TL20). Interestingly, this effect was paralleled by differences in the degree of front-loading, such that LD01-fed mice consumed approximately twice as much ethanol in the first 15 minutes of the 2-hour DID sessions compared to TL20-fed mice. Surprisingly however, mice that developed front-loading during maintenance on the LD01 diet continued to display front-loading behavior after being switched to the TL20 diet. These data emphasize the importance of choosing and reporting diet formulations when conducting voluntary drinking studies and support the need for further investigation into the mechanisms behind diet-induced differences in binge drinking, particularly front-loading.

neuroscience↗

bioRxiv2021

Compulsive drinking is associated with neural activity patterns reflecting diminished behavioral control and enhanced seeking representations in dorsal medial prefrontal cortex

Drinking despite negative consequences (compulsive drinking) is a central contributor to high-risk alcohol intake and is associated with poor treatment outcomes in humans. We used a rodent model of compulsive drinking to examine the role played by dorsal medial prefrontal cortex (dmPFC), a brain region involved in maladaptive decision-making in addiction, in this clinically critical phenomenon. We developed novel advances in principal component and change point analyses to dissect neural population representations of specific decision-making variables. Compulsive subjects showed weakened representations of behavioral control signals that relate to drinking within a trial, but strengthened session-wide seeking state representations that were associated with drinking engagement at the start of each drinking opportunity. Finally, chemogenetic-based excitation of dmPFC prevented escalation of compulsive drinking. Collectively, these data indicate that compulsive drinking is associated with alterations in dmPFC neural activity that underlie diminished behavioral control and enhanced seeking.

neuroscience↗

bioRxiv2018

Encoding of the Intent to Drink Alcohol by the Prefrontal Cortex is blunted in Rats with a Family History of Excessive Drinking

The prefrontal cortex plays a central role in guiding decision-making, and its function is altered by alcohol use and an individuals innate risk for excessive alcohol drinking. The primary goal of this work was to determine how neural activity in the prefrontal cortex guides the decision to drink. Towards this goal, the within-session changes in neural activity were measured from medial prefrontal cortex (mPFC) of rats performing a drinking procedure that allowed them to consume or abstain from alcohol in a self-paced manner. Recordings were obtained from rats that either lacked or expressed an innate risk for excessive alcohol intake - Wistar or Alcohol Preferring P rats, respectively. Wistar rats exhibited patterns of neural activity consistent with the intention to drink or abstain from drinking, whereas these patterns were blunted or absent in P rats. Collectively, these data indicate that neural activity patterns in mPFC associated with the intention to drink alcohol are influenced by innate risk for excessive alcohol drinking. This observation may indicate a lack of control over the decision to drink by this otherwise well-validated supervisory brain region.

neuroscience↗