The alpha2 nicotinic acetylcholine receptor, a subunit with unique and selective expression in inhibitory interneurons associated with principal cells.

Nicotinic acetylcholine receptors (nAChRs) play crucial roles in various human disorders, with the α7, α4, α6, and α3-containing nAChR subtypes extensively studied in relation to conditions such as Alzheimer's disease, Parkinson's disease, nicotine dependence, mood disorders, and stress disorders. In contrast, the α2-nAChR subunit has received less attention due to its more restricted expression and the scarcity of specific agonists and antagonists for studying its function. Nevertheless, recent research has shed light on the unique expression pattern of the Chrna2 gene, which encodes the α2-nAChR subunit, and its involvement in distinct populations of inhibitory interneurons. This review highlights the structure, pharmacology, localization, function, and disease associations of α2-containing nAChRs and points to the unique expression pattern of the Chrna2 gene and its role in different inhibitory interneuron populations. These populations, including the oriens lacunosum moleculare (OLM) cells in the hippocampus, Martinotti cells in the neocortex, and Renshaw cells in the spinal cord, share common features and contribute to recurrent inhibitory microcircuits. Thus, the α2-nAChR subunit's unique expression pattern in specific interneuron populations and its role in recurrent inhibitory microcircuits highlight its importance in various physiological processes. Further research is necessary to uncover the comprehensive functionality of α2-containing nAChRs, delineate their specific contributions to neuronal circuits, and investigate their potential as therapeutic targets for related disorders.

Behavioral Profiles of Adolescent Alcohol-Preferring/Non-preferring (P/NP) and High/Low Alcohol-Drinking (HAD/LAD) Rats Are Dependent on Line but Not Sex.

Initial contact with alcohol generally occurs during adolescence, and high consumption during this period is associated with increased risk for later alcohol (AUDs) and/or substance use disorders (SUDs). Rodents selectively bred for high or low alcohol consumption are used to identify behavioral characteristics associated with a propensity for high or low voluntary alcohol intake. The multivariate concentric square field™ (MCSF) is a behavioral test developed to study rodents in a semi-naturalistic setting. Testing in the MCSF creates a comprehensive behavioral profile in a single trial. The current aim was to examine the behavioral profiles of adolescent, bidirectionally selectively bred male and female high alcohol-consuming (P and HAD1/2) and low alcohol-consuming (NP and LAD1/2) rat lines, and outbred Wistar rats. Alcohol-naïve rats were tested once in the MCSF at an age between postnatal days 30 and 35. No common behavioral profile was found for either high or low alcohol-consuming rat lines, and the effect of sex was small. The P/NP and HAD2/LAD2 lines showed within pair-dependent differences, while the HAD1/LAD1 lines were highly similar. The P rats displayed high activity and risk-associated behaviors, whereas HAD2 rats displayed low activity, high shelter-seeking behavior, and open area avoidance. The results from P rats parallel clinical findings that denser family history and risk-taking behavior are strong predictors of future AUDs, often with early onset. Contrarily, the HAD2 behavioral profile was similar to individuals experiencing negative emotionality, which also is associated with a vulnerability to develop, often with a later onset, AUDs and/or SUDs.

Behavioral Profiling in Early Adolescence and Early Adulthood of Male Wistar Rats After Short and Prolonged Maternal Separation.

Early-life stress and its possible correlations to genes, environment, and later health outcomes can only be studied retrospectively in humans. Animal models enable the exploration of such connections with prospective, well-controlled study designs. However, with the recent awareness of replicability issues in preclinical research, the reproducibility of results from animal models has been highlighted. The present study aims to reproduce the behavioral effects of maternal separation (MS) previously observed in the multivariate concentric square fieldTM (MCSF) test. A second objective was to replicate the adolescent behavioral profiles previously described in the MCSF test. Male rats, subjected to short or prolonged MS or standard rearing, were subjected to behavioral testing in early adolescence and early adulthood. As seen in previous studies, the behavioral effects of MS in the MCSF were small at both tested time points. When tested in early adolescence, the animals exhibited a similar behavioral profile as previously seen, and the finding of adolescent behavioral types was also reproduced. The distribution of animals into the behavioral types was different than in the initial study, but in a manner consistent with developmental theories, as the current cohort was younger than the previous. Notably, the Shelter seeker behavioral type persisted through development, while the Explorer type did not. The lack of basal behavioral effect after MS is in line with the literature on this MS paradigm; the working hypothesis is that the prolonged MS gives rise to a phenotype predisposed to negative health outcomes but which is not apparent without additional provocation.

Adolescent Exploratory Strategies and Behavioral Types in the Multivariate Concentric Square FieldTM Test.

Adolescence is an important developmental phase with extensive changes in behavior due to remodeling of the brain and hormonal systems. Validation of animal behavioral tests in this age group is therefore of importance as differences to adult behavior are often not clarified. The aim of the present study was to investigate adolescent behavior in the multivariate concentric square fieldTM (MCSF) test and its relationship to other common behavioral tests as well as to a literature dataset of adult animals. Sixty adolescent male Wistar rats were tested in the MCSF and one of four reference tests; the elevated plus maze, the open field with or without start box, or the social play behavior test. Additionally, 12 animals were tested twice in the MCSF. When analyzing the first encounter with the MCSF test, a distinct grouping of the individuals into three behavioral types was observed. Approximately 20% of the animals had high levels of activity and an additional 20% had high levels of shelter seeking-behavior, these groups composed the outlying behavioral types named Explorers and Shelter seekers, respectively, which were distinct from the Main type of animals. When tested in the MCSF for a second time, the adolescent animals showed a recollection of the arena as they changed their behavior in relation to the first encounter. When comparing the MCSF performance to the reference tests, a relationship was found between the MCSF and the other behavioral test entailing forced exploration, while no relationship was found between the MCSF and social play. The adolescent behavioral profile was characterized by decreased risk assessment and a different activity profile than adults. In conclusion, the MCSF test is useful for profiling adolescent rats but the behavioral interpretation differs from that of adults due to differences in behavioral manifestation during adolescence and the presence of natural subgroups. Adolescent exploration shows a relationship across tests, but the MCSF gives more information than any of the other behavioral tests based on forced exploration. Further studies into the neurobiology behind the behavioral types and how different manipulations affect the distribution into the behavioral types are of interest.

Few long-term consequences after prolonged maternal separation in female Wistar rats.

Environmental factors during the early-life period are known to have long-term consequences for the adult phenotype. An intimate interplay between genes and environment shape the individual and may affect vulnerability for psychopathology in a sex-dependent manner. A rodent maternal separation model was here used to study the long-term effects of different early-life rearing conditions on adult behavior, HPA axis activity and long-term voluntary alcohol intake in female rats. Litters were subjected to 15 min (MS15) or 360 min (MS360) of daily maternal separation during postnatal day 1-21. In adulthood, the behavioral profiles were investigated using the multivariate concentric square field™ (MCSF) test or examined for HPA axis reactivity by cat-odor exposure with subsequent characterization of voluntary alcohol intake and associated changes in HPA axis activity. Adult female MS360 offspring showed mostly no, or only minor, effects on behavior, HPA axis reactivity and long-term alcohol intake relative to MS15. Instead, more pronounced effects were found dependent on changes in the natural hormonal cycle or by the choice of animal supplier. However, changes were revealed in corticosterone load after long-term alcohol access, as females subjected to MS360 had higher concentrations of fecal corticosterone. The present findings are in line with and expand on previous studies on the long-term effects of maternal separation in female rats with regard to behavior, HPA axis activity and voluntary alcohol intake. It can also be a window into further studies detailing how early-life experiences interact with other risk and protective factors to impact the adult phenotype and how possible sex differences play a role.

Altered corticosterone levels and social play behavior after prolonged maternal separation in adolescent male but not female Wistar rats.

Early-life socio-environmental factors are crucial for normal developmental processes; adverse experiences early in life can therefore lead to detrimental effects in several physiological systems. The aim of this study was to examine short-term effects of early adverse experiences in a maternal separation (MS) rodent model. In this study two separation conditions were used: daily 15- (MS15) or 360-min (MS360) separation of the litter from the dam during postnatal day 1-21. In early adolescence, male and female offspring were subjected to a single-isolation procedure with analysis of corticosterone levels prior to and after isolation. In addition, social play behavior was assessed during mid-adolescence. There was a clear difference between male and female offspring in both tests performed. There was no difference in corticosterone levels between the female MS groups, whereas MS360 males showed higher baseline and recovery corticosterone levels than MS15 males. The amount of pinning, a specific social play behavior, was affected by rearing with MS360 males having a higher frequency than MS15 males, while there was no difference between the female MS groups. The observation that males but not females are affected by MS360 has previously been reported for adult animals, and herein we show that this difference is present already in adolescence. Changes in corticosterone levels and social behavior following early-life adversity have been associated with adult behavioral alterations, and our results confirm that these changes emerge already within adolescence.

Altered explorative strategies and reactive coping style in the FSL rat model of depression.

Modeling depression in animals is based on the observation of behaviors interpreted as analog to human symptoms. Typical tests used in experimental depression research are designed to evoke an either-or outcome. It is known that explorative and coping strategies are relevant for depression, however these aspects are generally not considered in animal behavioral testing. Here we investigate the Flinders Sensitive Line (FSL), a rat model of depression, compared to the Sprague-Dawley (SD) rat in three independent tests where the animals are allowed to express a more extensive behavioral repertoire. The multivariate concentric square field™ (MCSF) and the novel cage tests evoke exploratory behaviors in a novel environment and the home cage change test evokes social behaviors in the re-establishment of a social hierarchy. In the MCSF test, FSL rats exhibited less exploratory drive and more risk-assessment behavior compared to SD rats. When re-exposed to the arena, FSL, but not SD rats, increased their exploratory behavior compared to the first trial and displayed risk-assessment behavior to the same extent as SD rats. Thus, the behavior of FSL rats was more similar to that of SDs when the rats were familiar with the arena. In the novel cage test FSL rats exhibited a reactive coping style, consistent with the reduced exploration observed in the MCSF. Reactive coping is associated with less aggressive behavior. Accordingly, FSL rats displayed less aggressive behavior in the home cage change test. Taken together, our data show that FSL rats express altered exploratory behavior and reactive coping style. Reduced interest is a core symptom of depression, and individuals with a reactive coping style are more vulnerable to the disease. Our results support the use of FSL rats as an animal model of depression and increase our understanding of the FSL rat beyond the behavioral dimensions targeted by the traditional depression-related tests.

Risk-assessment and risk-taking behavior predict potassium- and amphetamine-induced dopamine response in the dorsal striatum of rats.

Certain personality types and behavioral traits display high correlations to drug use and an increased level of dopamine in the reward system is a common denominator of all drugs of abuse. Dopamine response to drugs has been suggested to correlate with some of these personality types and to be a key factor influencing the predisposition to addiction. This study investigated if behavioral traits can be related to potassium- and amphetamine-induced dopamine response in the dorsal striatum, an area hypothesized to be involved in the shift from drug use to addiction. The open field and multivariate concentric square field™ tests were used to assess individual behavior in male Wistar rats. Chronoamperometric recordings were then made to study the potassium- and amphetamine-induced dopamine response in vivo. A classification based on risk-taking behavior in the open field was used for further comparisons. Risk-taking behavior was correlated between the behavioral tests and high risk takers displayed a more pronounced response to the dopamine uptake blocking effects of amphetamine. Behavioral parameters from both tests could also predict potassium- and amphetamine-induced dopamine responses showing a correlation between neurochemistry and behavior in risk-assessment and risk-taking parameters. In conclusion, the high risk-taking rats showed a more pronounced reduction of dopamine uptake in the dorsal striatum after amphetamine indicating that this area may contribute to the sensitivity of these animals to psychostimulants and proneness to addiction. Further, inherent dopamine activity was related to risk-assessment behavior, which may be of importance for decision-making and inhibitory control, key components in addiction.