Biology subjects

Timme, N.

Publications and source records attributed to Timme, N..

6 recordsLinked to original sources

bioRxiv2024

Reducing maladaptive behavior in neuropsychiatric disorders using network modification

Neuropsychiatric disorders are caused by many factors and produce a wide range of symptomatic maladaptive behaviors in patients. Despite this great variance in causes and resulting behavior, we believe the maladaptive behaviors that characterize neuropsychiatric disorders are most proximally determined by networks of neurons and that this forms a common conceptual link between these disorders. Operating from this premise, it follows that treating neuropsychiatric disorders to reduce maladaptive behavior can be accomplished by modifying the patients network of neurons. In this proof-of-concept computational psychiatry study, we tested this approach in a simple neural network model that produces aversion-resistant alcohol drinking - a key maladaptive behavior associated with alcohol use disorder. We demonstrated that it was possible to predict personalized network modifications that substantially reduced maladaptive behavior without inducing side effects. Furthermore, we found that it was possible to predict effective treatments with limited knowledge of the model and that information about neural activity during certain types of trials was more helpful in predicting treatment than information about model parameters. We hypothesize that this is a general feature of developing effective treatment strategies for networks of neurons. This computational study lays the groundwork for future studies utilizing more biologically realistic network models in conjunction with in vivo data.

neuroscience↗

bioRxiv2023

Non-Consummatory Behavior Signals Predict Aversion-Resistant Alcohol Drinking in Head-Fixed Mice

A key facet of alcohol use disorder is continuing to drink alcohol despite negative consequences (so called "aversion-resistant drinking"). In this study, we sought to assess the degree to which head-fixed mice exhibit aversion-resistant drinking and to leverage behavioral analysis techniques available in head-fixture to relate non-consummatory behaviors to aversion-resistant drinking. We assessed aversion-resistant drinking in head-fixed female and male C57BL/6J mice. We adulterated 20% (v/v) alcohol with varying concentrations of the bitter tastant quinine to measure the degree to which mice would continue to drink despite this aversive stimulus. We recorded high-resolution video of the mice during head-fixed drinking, tracked body parts with machine vision tools, and analyzed body movements in relation to consumption. Female and male head-fixed mice exhibited heterogenous levels of aversion-resistant drinking. Additionally, non-consummatory behaviors, such as paw movement and snout movement, were related to the intensity of aversion-resistant drinking. These studies demonstrate that head-fixed mice exhibit aversion-resistant drinking and that non-consummatory behaviors can be used to assess perceived aversiveness in this paradigm. Furthermore, these studies lay the groundwork for future experiments that will utilize advanced electrophysiological techniques to record from large populations of neurons during aversion-resistant drinking to understand the neurocomputational processes that drive this clinically relevant behavior.

neuroscience↗

bioRxiv2023

Proactive Versus Reactive Control Strategies Differentially Mediate Alcohol Drinking in Wistar and P rats

Problematic alcohol consumption is associated with deficits in decision-making, and alterations in prefrontal cortex neural activity likely contributes. We hypothesized that differences in cognitive control would be evident between male Wistar rats and a model for genetic risk for alcohol use disorder (alcohol-preferring P rats). Cognitive control can be split into proactive and reactive components. Proactive control maintains goal-directed behavior independent of a stimulus whereas reactive control elicits goal-directed behavior at the time of a stimulus. We hypothesized that Wistars would show proactive control over alcohol-seeking whereas P rats would show reactive control over alcohol-seeking. Neural ensembles were recorded from prefrontal cortex during an alcohol seeking task that utilized two session types. On congruent sessions the CS+ was on the same side as alcohol access. Incongruent sessions presented alcohol opposite the CS+. Wistars, but not P rats, exhibited an increase in incorrect approaches during incongruent sessions, suggesting that Wistars utilized the previously learned task-rule. This motivated the hypothesis that ensemble activity reflecting proactive control would be observable in Wistars but not P rats. While P rats showed differences in neural activity at times relevant for alcohol delivery, Wistars showed differences prior to approaching the sipper. These results support our hypothesis that Wistars are more likely to engage proactive cognitive-control strategies whereas P rats are more likely to engage reactive cognitive control strategies. Although P rats were bred to prefer alcohol, differences in cognitive control may reflect a sequela of behaviors that mirror those in humans at risk for an AUD. Significance StatementCognitive control refers to the set of executive functions necessary for goal-directed behavior. It is a major mediator of addictive behaviors and can be subdivided into proactive and reactive cognitive control. We observed behavioral and electrophysiological differences between outbred Wistar rats and the selectively bred Indiana alcohol-preferring P rat while they sought and consumed alcohol. These differences are best explained by reactive cognitive control in P rats and proactive in Wistar rats.

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↗

bioRxiv2020

Exploiting a PAX3-FOXO1-induced synthetic lethal ATR dependency for rhabdomyosarcoma therapy

Pathognomonic PAX3-FOXO1 fusion oncogene expression is associated with poor outcome in rhabdomyosarcoma. Combining genome-wide CRISPR screening with cell- based functional genetic approaches, we here provide evidence that PAX3-FOXO1 induces replication stress, resulting in a synthetic lethal dependency to ATR-mediated DNA damage-response signaling in rhabdomyosarcoma. Expression of PAX3-FOXO1 in muscle progenitor cells was not only sufficient to induce hypersensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibited increased sensitivity to structurally diverse inhibitors of ATR, a dependency that could be validated genetically. Mechanistically, ATR inhibition led to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increased sensitivity of rhabdomyosarcoma cells to PARP inhibition in vitro, and combined ATR and PARP inhibition induced regression of primary patient-derived alveolar rhabdomyosarcoma xenografts in vivo. Moreover, a genome-wide CRISPR activation screen (CRISPRa) identified FOS gene family members as inducers of resistance against ATR inhibitors. Mechanistically, FOS gene family members reduced replication stress in rhabdomyosarcoma cells. Lastly, compassionate use of ATR inhibitors in two pediatric patients suffering from relapsed PAX3-FOXO1-expressing alveolar rhabdomyosarcoma showed signs of tolerability, paving the way to clinically exploit this novel synthetic lethal dependency in rhabdomyosarcoma.

cancer biology↗

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↗