Biology subjects

Beeler, J. A.

Publications and source records attributed to Beeler, J. A..

4 recordsLinked to original sources

bioRxiv2026

Vulnerability and Resilience to Activity-Based Anorexia is Not Sex-Dependent

IntroductionAnorexia nervosa (AN) is more prevalent in women than men, although rates in men are rising. Animal models can provide insight into whether this differential prevalence is rooted in biological mechanisms, but prior studies have yielded conflicting findings. Using the activity-based anorexia (ABA) model, we previously demonstrated that female mice exhibit distinct vulnerable and resilient phenotypes. Here, we use this phenotypic framework to investigate sex differences in ABA susceptibility. MethodsWe tested young adult male C57BL/6N mice using the same ABA protocol used to test age-matched C57BL/6N females. Individual differences in daily bodyweight, food intake, water intake, and wheel running were analyzed and compared across sexes. ResultsMales exhibit the same vulnerable and resilient phenotypes as females, with no sex difference in the proportion of mice exhibiting each phenotype or the repertoire of behaviors characterizing them. In both sexes, vulnerable mice exhibit catastrophic weight loss driven by excessive light cycle running, while resilient mice exhibit weight stabilization driven by adaptive changes in consumption. Running during the feeding window revealed that vulnerability is not driven by a decision to run instead of eat in either sex. ConclusionsABA models adaptive and maladaptive responses to food restriction in both sexes. Behavioral responses to starvation are similar across sexes, suggesting that sex differences in AN prevalence may be driven by stronger sociocultural pressures faced by women to lose weight.

neuroscience↗

bioRxiv2025

Striatal signaling tracks naturalistic short-term fluctuations in hunger-satiety

The neuromodulator dopamine is integral to feeding behavior, believed to modulate food pursuit and satiety. Here, we examine how dopamine signaling in the nucleus accumbens changes during consumption as animals transition from hunger to satiety in naturalistic feeding. Dopamine transiently increases during food approach; however, the magnitude of this approach-related increase diminishes across progressive pellet ingestion, reflecting short-term satiation. These approach-related dopamine transients recover during intermeal intervals. Fasting dissociates the regulation of meal size and frequency, reflecting termination and initiation, respectively, with observable differences in dopamine corresponding to changes in meal size but not frequency. Despite substantially decreasing feeding, pharmacological satiation via a glucagon-like peptide-1 (GLP-1) agonist had no impact on average dopamine transients on food approach but abolished the short-term fluctuations related to on-going eating, suggesting that the GLP-1 agonist disengaged or decoupled dopamine from its modulatory role in meal patterning.

neuroscience↗

bioRxiv2025

Accumbal Dopamine and Acetylcholine Dynamics during Psychostimulant Sensitization

Behavioral sensitization to repeated psychostimulant exposure is believed to contribute to the development of addiction. Nucleus accumbens (NAcc) dopamine (DA) is known to be a key substrate in sensitization, though recent work suggests that striatal acetylcholine (ACh) may also play a critical role. However, underlying ACh changes and their relationship to DA signaling have not been characterized. Here, we used dual-color fiber photometry to simultaneously measure DA and ACh in the NAcc shell of mice across repeated injections of cocaine or amphetamine. Repeated exposure progressively elevated locomotor activity and increased slow extracellular DA while attenuating transient DA release. Psychostimulants reduced phasic ACh transient amplitude and frequency, an effect that sensitized with repeated injections. However, the temporal coupling of DA and ACh remained unchanged. To determine whether D2 receptors (D2Rs) on cholinergic interneurons (CINs) drive this effect, we generated CIN-selective D2R knockout (KO) mice. Surprisingly, KOs continued to show an acute decrease in ACh and intact DA-ACh correlations after psychostimulant administration. However, they failed to exhibit sensitization of either DA or ACh in response to repeated psychostimulant administration. Despite this lack of sensitization in underlying neuromodulator signaling, the KO mice nevertheless exhibited behavioral sensitization, though at a slower rate than wild-type. These findings suggest that neural sensitization to psychostimulants is dependent on D2R expressed on CINs, but that behavioral sensitization is not dependent on sensitization of these underlying signals.

neuroscience↗

bioRxiv2024

Opposing Motor Memories in the Direct and Indirect Pathways of the Basal Ganglia

Loss of dopamine neurons causes motor deterioration in Parkinsons disease patients. We have previously reported that in addition to acute motor impairment, the impaired motor behavior is encoded into long-term memory in an experience-dependent and task-specific manner, a phenomenon we refer to as aberrant inhibitory motor learning. Although normal motor learning and aberrant inhibitory learning oppose each other and this is manifested in apparent motor performance, in the present study, we found that normal motor memory acquired prior to aberrant inhibitory learning remains preserved in the brain, suggesting the existence of independent storage. To investigate the neuronal circuits underlying these two opposing memories, we took advantage of the RNA-binding protein YTHDF1, an m6A RNA methylation reader involved in the regulation of protein synthesis and learning/memory. Conditional deletion of Ythdf1 in either D1 or D2 receptor-expressing neurons revealed that normal motor memory is stored in the D1 (direct) pathway of the basal ganglia, while inhibitory memory is stored in the D2 (indirect) pathway. Furthermore, fiber photometry recordings of GCaMP signals from striatal D1 (dSPN) and D2 (iSPN) receptor-expressing neurons support the preservation of normal memory in the direct pathway after aberrant inhibitory learning, with activities of dSPN predictive of motor performance. Finally, a computational model based on activities of motor cortical neurons, dSPN and iSPN neurons, and their interactions through the basal ganglia loops supports the above observations. These findings have important implications for novel approaches in treating Parkinsons disease by reactivating preserved normal memory, and in treating hyperkinetic movement disorders such as chorea or tics by erasing aberrant motor memories.

neuroscience↗