Biology subjects

Vonder Haar, C.

Publications and source records attributed to Vonder Haar, C..

7 recordsLinked to original sources

bioRxiv2026

Pediatric traumatic brain injury elicits acute neuroinflammation and long-term changes in social, cognitive, and decision-making behaviors in male and female rats

Traumatic brain injury (TBI) is one of the leading causes of emergency room visits in children under 10. Children are potentially more vulnerable to the adverse effects of TBI, given that their brains are still developing at the time of injury. Indeed, early life TBI has been linked to cognitive, social, and mood-related impairments later in life. The neuroimmune system has been implicated in adult TBI mechanisms and plays numerous key roles in brain development, making it an interesting candidate for linking pediatric TBI and prolonged behavioral alterations. Here we establish a rat model of mild pediatric TBI to investigate the relationship between early life TBI, acute responses of neuroimmune cells, and chronic behavioral dysregulation. At postnatal day 15, which is roughly equivalent to toddler age, male and female rat pups received a TBI via lateral fluid percussion injury. At 3 days post injury, TBI increased microglia and astrocyte coverage locally in the Perilesional Cortex but not in more distant corticolimbic regions. However, the hippocampus and prefrontal cortex did exhibit increased expression of the phagocytic marker CD68 in microglia, suggesting widespread glial activation even in the absence of gross coverage change. TBI also impacted mast cells, early-response innate immune cells, increasing their number and degranulation in multiple regions. In the juvenile and early adult periods, TBI impaired cognitive function, reduced sociability, and increased avoidance, with no change in anxiety-like behavior. Later in adulthood, TBI continued to impact cognitive behavior, increasing risky decision-making and impairing optimization months after injury. Together, these results suggest that pediatric TBI causes lasting cognitive and social dysregulation, possibly via acute neuroimmune alterations following injury at a critical period of brain development.

neuroscience↗

bioRxiv2026

Frontal Brain Injury Reduces Sensitivity to Reward-Predictive Cues and Remodels the Nucleus Accumbens

Traumatic brain injuries (TBIs) are more than mere lesions and generate a persistent secondary pathology. This, combined with functional reorganization of circuits post-injury, may explain the increased risk for psychiatric disorders in patients with TBI. In the current studies, we demonstrate that frontal TBI changed the Pavlovian behavioral response to reinforcer-predicting cues and reduced the motivational value of cues. TBI also chronically impaired decision-making on a gambling-like task with reinforcer-paired cues. To investigate how these changes occur, we evaluated the nucleus accumbens (NAc) core. At a subacute time point (14 days), we confirmed reduced input to the NAc with optogenetics and evaluated electrophysiological and transcriptional changes. TBI increased neuronal excitability and the single nucleus RNA sequencing profile indicated a substantial stress and inflammatory response, but also high indicators of plasticity, particularly in D1- and D2-positive medium spiny neurons. To evaluate how these subacute changes transitioned to chronic NAc dysfunction, we measured immunohistochemical surrogates of activity post-mortem and recorded calcium activity from the NAc after TBI during Pavlovian conditioning. TBI reduced histological markers of activity and reduced cue-evoked calcium activity. Overall, these data indicate that substantial reorganization of the NAc occurs following frontal brain injury. A primary effect of this is to reduce the salience of environmental cues linked to outcomes. The inability to properly process outcomes could contribute to broader psychiatric symptoms after TBI, including impairments in decision-making, behavioral flexibility, and impulsivity but also presents a potential treatment target.

neuroscience↗

bioRxiv2026

The Effects of Prelimbic Inhibition on Time-based Intervention and Impulsive Choice

Impulsive choice is the suboptimal preference for a smaller-sooner (SS, "impulsive") option over a larger-later (LL, "self-controlled") option. Fixed-interval (FI) training delivers delayed-reinforcement trials to increase LL choices and improve FI timing precision. While there are plenty of studies exploring the neurobiological factors underlying impulsive choice, it is unknown what neurobiological changes account for the FI training effects. The prelimbic cortex (PL) region is implicated in both impulsive choice and timing. To investigate the role of the PL, we used designer receptors exclusively activated by designer drugs (GiDREADDs) to reversibly inhibit the PL during either the FI training phase or the follow-up impulsive choice task in male and female Sprague-Dawley rats. Compared to a control group, the GiDREADDs rats showed reduced LL choices when CNO was administered during the FI training or impulsive choice tasks. GiDREADDS did not alter response rates or latency to choose. Overall, these data demonstrate that inhibition of the PL increases impulsive choice and may block the effect of the FI training to improve self-control.

animal behavior and cognition↗

bioRxiv2025

Caloric restriction worsens decision-making impairments and gut dysbiosis after brain injury in male rats

Traumatic brain injury (TBI) causes long-term deficits in decision-making and disrupts the gut microbiome. Dysbiosis of the gut microbiome is a potential contributor to the development of multiple psychiatric and neurological disorders and may be a contributor to chronic symptoms from TBI. Caloric restriction is often used to assess psychiatric-related behaviors in animals, but also affects the gut microbiome. In the current study, we evaluated the effects of caloric restriction versus free feeding on a frontal controlled cortical impact TBI. Rats were trained on the rodent gambling task, an analog of the Iowa gambling task, to assess risk-based decision-making. The microbiome was sampled through the acute to subacute period post-injury and lesion size and microglia counts evaluated at 10 weeks post-injury. Caloric restriction did not affect decision-making at baseline, but did affect motivational variables. TBI impaired decision-making and this effect was exacerbated by caloric restriction. Other motivation-related variables followed a similar pattern of impairment with TBI driving impairments that were worsened by caloric restriction. The gut microbiome was initially dysbiotic, but largely recovered within 14 days post-injury. Despite this, acute gut measurements were predictive of chronic decision-making impairment. These data indicate a role for the gut microbiome in the evolution of TBI deficits and suggest that interventions targeting the gut may have a limited window of opportunity to treat long-term deficits.

neuroscience↗

bioRxiv2023

Cognitive rehabilitation can improve brain injury-induced deficits in behavioral flexibility and impulsivity linked to impaired reward-feedback activity.

Traumatic brain injury (TBI) affects a large population, resulting in severe cognitive impairments. Although cognitive rehabilitation is an accepted treatment for some deficits, studies in patients are limited in ability to probe physiological and behavioral mechanisms. Therefore, animal models are needed to optimize strategies. Frontal TBI in a rat model results in robust and replicable cognitive deficits, making this an ideal candidate for investigating cognitive rehabilitation. In this study, we report three distinct frontal TBI experiments assessing behavior well into the chronic post-injury period using male Long-Evans rats. First, we evaluated the impact of frontal injury on local field potentials recorded simultaneously from 12 brain regions during a probabilistic reversal learning task (PbR). Next, rats were tested on reversal learning (PbR) or impulsivity (differential reinforcement of low-rate behavior: DRL) and half received salient cues associated with reinforcement contingencies as a form of "cognitive rehabilitation". After rehabilitation on the PbR task, brains were stained for markers of activity. On the DRL, cues were devalued to determine if beneficial effects persisted on impulsive behavior. TBI resulted in outcome salience deficits evident in task performance and reward-feedback signals occurring at beta frequencies in orbitofrontal cortex (OFC) and associated frontostriatal regions. Cognitive rehabilitation improved flexibility and increased OFC activity. Rehabilitation also reduced impulsivity, even after cues were degraded, which was partially mediated by improvements in timing behavior. The current study established a robust platform for investigating cognitive rehabilitation in animals and identified a strong role for dysfunctional OFC signaling after frontal TBI.

neuroscience↗

bioRxiv2023

Statistical power and false positive rates for interdependent outcomes are strongly influenced by test type: Implications for behavioral neuroscience

Statistical errors in preclinical science are a barrier to reproducibility and translation. For instance, linear models (e.g., ANOVA, linear regression) may be misapplied to data that violate assumptions. In behavioral neuroscience and psychopharmacology, linear models are frequently applied to interdependent or compositional data, which includes behavioral assessments where animals concurrently choose between chambers, objects, outcomes, or types of behavior (e.g., forced swim, novel object, place/social preference). The current study simulated behavioral data for a task with four interdependent choices (i.e., increased choice of a given outcome decreases others) using Monte Carlo methods. 16,000 datasets were simulated (1,000 each of 4 effect sizes by 4 sample sizes) and statistical approaches evaluated for accuracy. Linear regression and linear mixed effects regression (LMER) with a single random intercept resulted in high false positives (>60%). Elevated false positives were attenuated in an LMER with random effects for all choice-levels and a binomial logistic mixed effects regression. However, these models were underpowered to reliably detect effects at common preclinical sample sizes. A Bayesian method using prior knowledge for control subjects increased power by up to 30%. These results were confirmed in a second simulation (8,000 datasets). These data suggest that statistical analyses may often be misapplied in preclinical paradigms, with common linear methods increasing false positives, but potential alternatives lacking power. Ultimately, using informed priors may balance statistical requirements with ethical imperatives to minimize the number of animals used. These findings highlight the importance of considering statistical assumptions and limitations when designing research studies.

neuroscience↗

bioRxiv2022

A touchscreen device for behavioral testing in pigs

Pigs are becoming more common research models due to their utility in studying neurological conditions such as traumatic brain injury, Alzheimers disease, and Huntingtons Disease. However, behavioral tasks often require a large apparatus and are not automated, which may disinterest researchers in using important functional measures. To address this, we developed a touchscreen that pigs could be trained on for behavioral testing. A rack-mounted touchscreen monitor was placed in an enclosed, weighted audio rack. A pellet dispenser was operated by a radio frequency transceiver to deliver fruit-flavored sugar pellets from across the testing room. Programs were custom written in Python and executed by a Raspberry Pi. A behavioral shaping program was designed to train pigs to interact with the screen and setup responses for future tasks. Pigs rapidly learned to interact with the screen. To demonstrate efficacy in more complex behavior, two pigs were trained on a delay discounting tasks and two pigs on a color discrimination task. The device held up to repeated testing of large pigs and could be adjusted to the height of minipigs. The device can be easily recreated and constructed at a relatively low cost. Research topics ranging from brain injury to pharmacology to vision could benefit from behavioral tasks designed to specifically interrogate relevant function. More work will be needed to develop tests which are of specific relevance to these disciplines.

animal behavior and cognition↗