Biology subjects

Chroszcz, M.

Publications and source records attributed to Chroszcz, M..

9 recordsLinked to original sources

bioRxiv2026

The effect of preproenkephalin gene deletion on heart function in mice

Enkephalins, the endogenous ligands of the - and {delta}-opioid receptors, are abundantly expressed in the nervous system and peripheral organs, including the heart. Accumulating evidence suggests that they participate in cardiac development and act as autocrine and paracrine modulators of heart activity. Here, we investigate the role of enkephalins in cardiac physiology using a newly generated mouse strain with a complete ablation of the preproenkephalin (Penk) gene. We find that, although adult mutant mice weighed less, the mutation caused no apparent changes in behavioral phenotype, no increase in anxiety-like behaviors, and only a mild reduction in locomotor activity. There was no effect of Penk deletion on heart weight or size. A comprehensive analysis of left ventricular function using MRI revealed normal basal cardiac performance, except for a significant reduction in the peak fill and ejection rates. There were no significant effects of Penk deletion on left ventricular function after {beta}1-adrenergic stimulation with dobutamine. At the same time, we observed the expected significant differences in heart size and function between male and female mice. In conclusion, our data show that enkephalins are not essential for normal heart development and have a moderate impact on adult heart function under basal conditions.

neuroscience↗

bioRxiv2025

Decreased social, drug, and food reward sensitivity in adolescent mice

Adolescence shapes adaptive adult behaviors. Most studies compare single adolescent and adult age groups using only one type of reward, limiting insight into developmental trajectories underlying behavioral change. Here, we investigated how social, cocaine, and palatable food rewards become associated with environmental contexts in female and male C57BL/6 mice across early- (pubertal onset), mid- (peripubertal phase), and late- (sexual maturity) adolescence, compared to adults. Using the conditioned place preference (CPP) task, we found that generally all rewards induced place preference for the reward-associated context, with only minor effects of sex. In contrast, age significantly influenced CPP expression. Adolescent mice exhibited a significantly reduced CPP compared to adults in palatable food and social CPP paradigms, evident in both decreased mean conditioned context preference and lower proportion of animals that developed a preference after conditioning. Cocaine CPP was not significantly affected by age. Direct comparisons across CPP task outcomes further confirmed that age, rather than reward type or sex, was the primary factor influencing the magnitude of CPP. Specifically, mid- and late-adolescent mice showed reduced mean reward CPP, and mid-adolescents were less likely to express a reward preference relative to adults. Based on the behavioral analyses, we conclude that the lower expression of preference for a conditioned context in adolescent animals is due to developmental changes in reward sensitivity, rather than deficits in learning or higher novelty-seeking behavior.

animal behavior and cognition↗

bioRxiv2025

Changes in social reward across adolescence in male mice

In humans, adolescence is a time of dynamic behavioral and emotional changes, including a transient decrease in affect associated with being among family members. It is not clear if a similar change occurs in rodent species used to model human psychiatric disorders. Here, we investigated the developmental profile of the rewarding value of interactions with siblings across adolescence in male mice, using the social conditioned place preference task. We found that the reward value of social interactions followed a similar course to that in humans: high in early adolescence, it decreased in mid-adolescence and returned to the initial level in late adolescence. The observed change was specific to social interaction, as no age-dependent changes in preference for cocaine-conditioned context were detected. Taken together, these data show similarities between mice and humans in developmental changes in sensitivity to the rewarding effects of interactions with familiar kin.

neuroscience↗

bioRxiv2025

L-DOPA induces spatially discrete changes in gene expression in the forebrain of mice with a progressive loss of dopaminergic neurons

L-3,4-Dihydroxyphenylalanine (L-DOPA) is effective at alleviating motor impairments in Parkinsons disease (PD) patients but has mixed effects on nonmotor symptoms and causes adverse effects after prolonged treatment. Here, we analyzed the spatial profile of L-DOPA-induced gene expression in the forebrain of mice with an inducible progressive loss of dopaminergic neurons (the TIF-IADATCreERT2 strain), with a focus on the similarities and differences in areas relevant to different PD symptoms. The animals received a 14-day L-DOPA treatment, and 1 h after the final drug injection, a spatial transcriptome analysis was performed on coronal forebrain sections. A total of 121 genes were identified as being regulated by L-DOPA. We found that the treatment had widespread effects extending beyond the primary areas involved in dopamine-dependent movement control. An unsupervised clustering analysis of the transcripts recapitulated the forebrain anatomy and indicated both ubiquitous and region-specific effects on transcription. The changes were most pronounced in layers 2/3 and 5 of the dorsal cortex and the dorsal striatum, where a robust increase in the abundance of activity-regulated transcripts, including Fos, Egr1, and Junb, was observed. Conversely, transcripts with a decreased abundance, e.g., Plekhm2 or Pgs1, were identified primarily in the piriform cortex, the adjacent endopiriform nucleus, and the claustrum. Taken together, our spatial analysis of L-DOPA-induced alterations in gene expression reveals the anatomical complexity of treatment effects, identifying novel genes affected by the drug, as well as molecular activation in brain areas relevant to the nonmotor symptoms of PD.

neuroscience↗

bioRxiv2024

μ-Opioid receptor transcriptional variants in the murine forebrain and spinal cord

BackgroundOprm1, the gene encoding the -opioid receptor, has multiple reported transcripts, with a variable 3 region and many alternative sequences encoding the C-terminus of the protein. The functional implications of this variability remain mostly unexplored, though a recurring notion is that it could be exploited by developing selective ligands with improved clinical profiles. Here, we comprehensively examined Oprm1 transcriptional variants in the murine central nervous system. MethodsRNA-seq transcription analyses were performed based on Oxford Nanopore Sequencing (ONS) and 10x Genomics Visium spatial transcriptomics data. The spatial distribution of Oprm1 exons was evaluated via RNAscope in situ hybridization. Tissue and cell-type specificity was assessed based on reanalysis single-cell RNAseq databases. ResultsWe detected a mismatch between transcripts annotated in GRCm38/mm10 and RNA-seq results. Sequencing data indicated that the primary Oprm1 transcript has a 3 terminus located on chr10:6,860,027, which is ~9.5 kilobases downstream of the longest annotated exon 4 end. Long-read sequencing confirmed that the final Oprm1 exon included a 10.2 kilobase long 3 untranslated region. The presence of the long variant was unambiguously confirmed using RNAscope in situ hybridization. The long variant was observed in the thalamus, striatum, cortex and spinal cord. Expression of additional variants of the Oprm1 gene was close to the detection limit. Reanalysis of single-cell sequencing data confirmed these observations and indicated that Oprm1 was expressed mainly in parvalbumin-, somatostatin- and VIP-positive cells. ConclusionThe primary transcript of the Oprm1 mouse gene is a variant with a long 3 untranslated region. Author SummaryOpioids are essential for the management of pain and have multiple other medical indications; however, their addictive properties and widespread misuse have led to a severe modern health crisis. Accordingly, there has been a major effort to develop novel compounds that retain clinical effectiveness while diminishing their addictive potential and other adverse effects. One of the potential avenues for safer opioid drugs is developing compounds that are selective for a specific group of the main targets of opioid medications--the -opioid receptors. Multiple variants the -opioid receptor have been reported, encoded by different transcripts of the Oprm1 gene. Here, we used RNA transcript sequencing and in situ hybridization with probes to detect different parts of Oprm1 transcripts to validate the existence of various reported isoforms. Our main finding is that the primary transcript of the receptor is much longer than the current reference sequences annotated in the mouse genome and has an over 10,000-base-long noncoding sequence at the 3 terminus. Several other types of transcripts are also expressed; however, they represent approximately 15% or less of the total transcript content in each of the examined brain regions. In the context of future research on opioid drugs, these results indicate that it is unlikely that different subpopulations of receptors could be targeted.

genomics↗

bioRxiv2023

Mu-opioid receptor-dependent changes in social reward across adolescence in mice

RationaleSocial behaviors undergo dramatic changes during adolescence, enabling the development of adult social abilities. These changes are intricately linked to the development of the brain reward system and the activity of endogenous opioid signaling. However, the involvement of the opioid system in the development of social behaviors still raises more questions than answers. ObjectivesHere, we investigated the role of the endogenous opioid system in the rewarding effects of social contact in early and late adolescent male mice. MethodsSocial reward was assessed using the social conditioned place preference task in early adolescent (~34 days old) and late adolescent (~41 days old) male mice that received a single dose of the selective opioid receptor antagonists cyprodime (1 mg/kg, i.p.), naltrindole (1 mg/kg, i.p.) or norbinaltorphimine (10 mg/kg, i.p.) before the preference posttest. ResultsThe administration of cyprodime or naltrindole before the posttest significantly increased the preference for the social-conditioned context in early but not late adolescent mice. In contrast, pretreatment with norbinaltorphimine had no effect on context preference. ConclusionsOur findings support a modified version of the state-dependent mu-opioid receptor model of social behavior, where the effects of opioid ligands are not reversed during development but rather weaken or disappear with age. Furthermore, the results indicate that interactions with siblings in early adolescent mice are motivated by negative reinforcement, whereas those in late adolescence are motivated by positive reinforcement.

neuroscience↗

bioRxiv2022

Generalized habitual tendencies in alcohol dependent rats

Habitual responses and ultimately compulsive behavior are thought to be at the core of addiction including alcohol use disorder (AUD). Little is known whether the habitization concerns exclusively the response towards alcohol or generalizes to other daily activities. Here, we address this question in a well-established animal model of AUD - the postdependent rat model - by testing habitual responses towards a sweet palatable reward in two striatal learning paradigms: spatial navigation and reward conditioning. For the spatial navigation task, alcohol-dependent and control rats were tested on a sequential decision-making test after short and prolonged T-Maze training; for the reward conditioning task, rats were trained under a random interval schedule for a short and prolonged period and tested in a satiety devaluation test at each time point. Another cohort of alcohol-naive rats was trained and tested on both paradigms under DREADD (designer receptors exclusively activated by designer drugs)-mediated inactivation of the dorsomedial striatum (DMS) which controls goal-directed behavior. Our results show that alcohol-dependent rats displayed increased habitual behavior to obtain saccharin reward on both paradigms, with overall more habitual choices after prolonged training on the spatial navigation task, and increased habitual responses already after short training on the reward conditioning task. Finally, DREADD-mediated inactivation of the DMS increased habitual behavior in non-dependent rats on both paradigms. Our results provide evidence that a history of alcohol dependence produces a bias towards habitual responding that generalizes to a natural reward in rats. Similarly, a habitual bias was induced in non-dependent rats after inactivation of the DMS, thus confirming the critical role of this region in maintaining goal-directed behavior and suggesting its diminished control in AUD.

neuroscience↗

bioRxiv2022

Prosocial behavior in adult mice is sex-dependent

Prosocial behavior, defined as voluntary behavior intended to benefit another, has long been regarded as a primarily human characteristic. In recent years, it was reported that laboratory animals also favor prosocial choices in various experimental paradigms, thus demonstrating that prosocial behaviors are evolutionarily conserved. Here, we investigated prosocial choices in adult male and female C57BL/6 laboratory mice in a task where a subject mouse is equally rewarded for entering any of the two compartments of the experimental cage, but only entering of the compartment designated as "prosocial" rewards an interaction partner. In parallel we have also assessed two traits that are regarded as closely related to prosociality: sensitivity to social reward and the ability to recognize the affective state of another individual. We find that female, but not male, mice increased frequency of prosocial choices from pretest to test. At the same time, both sexes showed similar rewarding effects of social contact in the conditioned place preference test, and similarly, there was no effect of sex on affective state discrimination measured as the preference for interaction with a hungry or relieved mouse over a neutral animal. These observations bring interesting parallels to differences between sexes observed in humans, and are in line with reported higher propensity for prosocial behavior in human females, but differ with regard to sensitivity to social stimuli in males.

animal behavior and cognition↗

bioRxiv2022

A robust method for measuring social reward in adult mice

Social interactions can be and often are rewarding. The effect of social contact strongly depends on circumstances, and the reward may be driven by varied motivational processes, ranging from parental or affiliative behaviors to investigation or aggression. Reward associated with nonreproductive interactions in rodents is measured using the social conditioned place preference (sCPP) paradigm, where a change in preference for an initially neutral context confirms reinforcing effects of social contact. Here, we revised the sCPP method and reexamined social reward in adult female mice. Contrary to earlier studies, we found that robust rewarding effects of social contact could be detected in adult (14-week-old) female C57BL/6 mice when the sCPP task was refined to remove confounding factors. Strikingly, the rewarding effects of social interaction were only observed among female siblings who remained together from birth. Contact with same-age nonsiblings was not rewarding even after 8 weeks of cohousing. Other factors critical for the social reward effect in the sCPP paradigm included the number of conditioning sessions and the inherent preference for contextual cues. Thus, we show that social interaction is rewarding in adult female mice, but this effect strictly depends on the familiarity of the interaction partners. Furthermore, by identifying confounding factors, we provide a behavioral model to study the mechanisms underlying the rewarding effects of nonreproductive social interaction in adult mice.

animal behavior and cognition↗