{"paper_id":"4530a54b-e319-4d04-bbda-a5def5f90e8c","body_text":"Changes in social reward across adolescence in mice | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Changes in social reward across adolescence in mice Zofia Harda, Marta Klimczak, Klaudia Misiołek, Magdalena Chrószcz, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7535556/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Dec, 2025 Read the published version in Scientific Reports → Version 1 posted 9 You are reading this latest preprint version Abstract 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. Biological sciences/Neuroscience Biological sciences/Psychology Social science/Psychology Figures Figure 1 Figure 2 Figure 3 Introduction Adolescence is a time of rapid behavioral and neural changes, as well as the peak onset age for many mental disorders 1 , 2 . It is postulated that the emergence of psychiatric symptoms during adolescence results from alterations in typical developmental processes 3 . However, causal links between adolescent changes in brain maturation, behavior and pathophysiology have not been firmly established, partly because of the lack of proper animal models. It is thus of great importance to understand to what extent the behavioral development of model animals parallels the features of human adolescence 4 . In male laboratory mice, which descend from Mus musculus species, adolescence typically spans postnatal days (P) 30 to 60, corresponding to ages 11–21 years in humans 5 . Although no precise biological markers define the start or end of adolescence in either species, significant physiological and neural changes occur during this period. For example, rapid increase in serum testosterone levels and nonlinear changes in the expression of D1 and D2 receptors in basal ganglia are observed 6 – 8 . Despite these developmental dynamics, most behavioral studies treat adolescence as a uniform phase 9 – 11 or compare adults to a single adolescent timepoint, usually around P28-30 12,13 , with some notable exceptions 14 , 15 . Here, we hypothesize that social reward in adolescent mice may also develop nonlinearly. One of the characteristic features of human adolescence is changes in social preferences. Whereas infants fully depend on parental care and display strong distress following separation from their mothers, mid-adolescents show a decrease in the time spent with their family members along with an increase in the time spent alone or with peers 16 , 17 . This behavioral shift is accompanied by changes in emotions associated with relatives: early and late adolescents show positive affect in the company of their family members, while mid-adolescents report more negative emotional states 16 . However, it is not known whether affective changes resembling those observed in humans also occur in model animal species. Therefore, the goal of the present study was to assess the reward value of interactions with familiar kin in early, middle and late adolescence in male mice. Results Rewarding effects of interactions with siblings across adolescence To investigate the possible changes in the rewarding effects of social interactions with siblings during adolescence in mice, we used the social conditioned place preference (sCPP) test ( Fig. 1A) 18 with male mice representing early (around postnatal day 33 [P33]), middle (P38) and late (P43) adolescence stages (for information about experimental groups, see Tables S1 and S2 ). Animals were conditioned to associate one environmental context with group housing and another with social isolation, and then were tested to determine context preference. Mice aged 33, and 43 (but not 38) days at posttest showed a significant increase in the time spent in the social context from pretest to posttest, as revealed by significant interaction between age and conditioning ( Fig. 1B, Table S3, Age F 2,63 = 0.2182, p = 0.8046; Pre-Post F 1,63 = 21.69, p < 0.0001; Age x Pre-Post F 2,63 = 3.253, p = 0.0453; post hoc P33 p < 0.0001, P38 p = 0.8958, P43 p = 0.0064). There was no effect of context (i.e., the type of bedding) on preference ( Fig. S1, Table S4 ). It had no significant effect as main factor or in interactions with age or conditioning, while interaction between age and conditioning remains significant when context is added as variable (Context F 1,65 = 1.738, p = 0.1920; Age x Context F 2,65 = 0.6916, p = 0.5044, Pre-Post x Context F 1,65 = 0.1533, p = 0.6967; Age x Pre-Post x Context F 2,65 = 0.2435, p = 0.7846; Age x Pre-Post F 2,65 = 4.288 , p = 0.0178). Thus, interactions with siblings had lower reward value for mid-adolescent mice. The decrease in preference for the compartment associated with social contact in mid-adolescent mice was also clearly apparent in the social preference score ( Fig. 1C ). The score showed that the rewarding effects of social interactions were more than two times lower in mid-adolescent (P38) than in early-adolescent (P33) mice and returned to the early adolescent level in late-adolescent (P43) mice (Age F 2,63 = 3.353, p = 0.0420). Importantly, motor activity was not significantly affected by age or interaction between age and conditioning; thus, it was not a confounding factor ( Fig. 1D, Table S5, Age F 2,63 = 2.279, p = 0.1108; Pre-Post F 1,63 = 85.03, p < 0.0001; Age x Pre-Post F 2,63 = 0.5909, p = 0.5569). Taken together, the results reveal a transient decrease in the rewarding effects of interactions with related individuals in mid-adolescent mice. Social contact Next, we investigated if the change in social behavior in mid-adolescent mice was specific to the rewarding effects of social interactions or if contact seeking was also altered. To explore this possibility, we administered a test in which contact with another mouse is enabled through a transparent, perforated plexiglass wall ( Fig. 2A ) 19 . The interaction partners were siblings reared in the same cage but isolated for one day before the test to match the conditions of the sCPP posttest. We observed no age-related changes in the time spent in the proximity to the partner’s compartment ( Fig. 2B, Table S3, Age F 2,65 = 1.038, p = 0.3648) or the distance between the focal mouse and the partner’s compartment ( Fig. 2C, Age F 1,65 = 0.7805, p = 0.4660). These results might indicate that the decrease in the rewarding effects of interactions with related individuals in mid-adolescent mice was not accompanied by a general decrease in social contact seeking. Rewarding effects of cocaine An alternative explanation for the observed decrease in the rewarding effects of social interactions could be a general anhedonia or impairment in associative learning. To test whether the decrease in the rewarding effects of social interaction reflected a stimulus-independent reduction in the expression of conditioned behaviors, the cocaine-induced CPP was assessed. As expected, a significant increase in time spent in cocaine-paired compartment was observed but without the effect of age or interaction between age and conditioning ( Fig. 3A, Table S3, Age F 2,41 = 0.6877, p = 0.5084; Pre-Post F 1,41 = 14.94, p = 0.004; Age x Pre-Post F 2,41 = 0.3454, p = 0.7100). In line with this interpretation, no significant effect of age on the place preference score was detected ( Fig. 3B, Age F 1,41 = 0.9828, p = 0.3829). No significant effect of age or conditioning on locomotor activity was observed ( Fig. 3C, Age F 2,41 = 0.8940, p = 0.4168; Pre-Post F 1,41 = 0.8799, p = 0.7682; Age x Pre-Post F 2,41 = 0.8897, p = 0.4186). These data show that no general impairment of reward-conditioned preference occurred during mid-adolescence. Discussion We found that the rewarding effects of interactions with familiar kin in male mice exhibit a transient decrease during mid-adolescence (around P36-40). This decrease was specific to social reward, as no change in social contact seeking, and the reward value of cocaine was observed during this period. Our results resemble human data reported by Larson and Richards (1991), who observed that the affect associated with time spent with family members was more positive in 10-year-old and 16-year-old boys than in 12- to 14-year-olds 16 . The age range of 11 to 16 years in male humans corresponds to P30-40 in male mice, and this period is considered “peripubertal” 5 . This may indicate that the phenomenon observed in our study, i.e., the temporary decrease in the reward value of interactions with familiar kin, is evolutionarily conserved. This finding may facilitate future research on the neuronal and physiological underpinnings of rebellious behaviors in adolescence. Our results complement those of two previous studies that assessed the rewarding effects of social interactions using the sCPP paradigm at selected time points in adolescent mice 15 , 20 . In contrast to the methodology presented here, both previous studies used animals that were familiar but were not specifically kept in sibling groups. Our previous research on the reward value of social interactions has shown that eight weeks of familiarization with nonrelated mice is not equivalent to being reared in the same cage before weaning, at least in females, i.e. female mice do not form an sCPP when conditioned as adults in groups coming from different litters and housed together since weaning 18 . Moreover, both previous studies 15 , 20 used a paradigm with only two days of conditioning, which produces different results than the paradigm with six conditioning sessions used in this study 18 , 21 . Bearing these differences in mind, we note that Cann and collaborators (2020) reported that social contact is rewarding in mice tested on postnatal day 29 but not on postnatal day 38, which aligns with our results. Conversely, in the study by Nardou and collaborators (2019), a decrease in the rewarding effects of social interactions during adolescence was not observed in male mice (although it was observed in females). However, the previous results were not interpreted in terms of the possible decrease in the reward value of social interactions during adolescence. Instead, Cann and collaborators conclude that sCPP, under the applied conditions, can be induced in early adolescent, but not adult mice, implying that the observed lack of conditioning effects at the age of 38 days is considered permanent. Results presented in this work, together with a previous paper where adult mice were studied 21 , suggest that sCPP can be induced in late adolescent and adult male mice, provided that the 6-day protocol is used. Recent study by Murray and collaborators (2024) investigated developmental changes in the motivation to obtain social reward in laboratory rats 22 , a species in which the equivalent of P30-40 in mice is P42-55 5 . In this study, the operant conditioning protocol was employed and an unfamiliar conspecific was used as a stimulus animal. The authors found that social motivation is higher in pre-adolescent (P30) and mid-adolescent (P50) rats than in early adolescent animals (P40). This might indicate that the rewarding effects of and motivation to obtain social reward differ depending on the familiarity of the stimulus animal, with mid-adolescence being a period of decreased familiar kin contact seeking, and higher motivation to interact with unfamiliar individuals. A study using the 6-day sCPP protocol on mice housed with familiar and unfamiliar conspecifics in different adolescence timepoints should be performed to test this hypothesis. However, it must be noted that Murray and coworkers use different labels for the developmental periods, and describe P40 as mid-adolescence and P50 as late adolescence 22 . In contrast to social reward, there were no apparent changes in social contact seeking (assessed with the partition test) during adolescence. This finding indicates that the changes in social interactions in adolescent mice are qualitative rather than quantitative. We speculate that the amount of time spent with siblings may not change, but aggressive encounters may replace affiliative interactions. This interpretation is supported by earlier studies showing a profound decrease in passive social contact 23 and play behavior 24 , along with an increase in fighting 23 , 25 , in the second postnatal month of mice life. Strikingly, the cocaine-induced CPP did not change during the adolescent period. These results indicate that the decrease in social CPP in mid-adolescent mice cannot be explained by a general decline in learning abilities and confirm that different neuronal processes underlie the rewarding effects of cocaine and social contact 26 . Developmental changes in cocaine-induced CPP were previously studied in rats, and their results are inconsistent. For example, Brenhouse and coworkers reported a greater cocaine (10 mg/kg)-induced CPP in adolescents (P44) than in adults (P105) 27 . Notably, preadolescent rats (P27-37) showed similar levels of cocaine-induced CPP as adult animals 27 , 28 , which suggests an inverted U-shaped relationship between cocaine reward and age. These results are consistent with previous reports of heightened sensitivity to other drugs of abuse in adolescent animals 29 . Conversely, the results by Badanich and collaborators indicated the highest sensitivity to cocaine reward in pre-adolescent rats, because a low cocaine dose (5 mg/kg) induced CPP only in pre-adolescents (P35), but not in adolescents (P45) or young adults (P60 animals) 30 . This suggests that some factors unidentified yet, for example the level of stress imposed by the experimental protocol, might differentially influence the rewarding effects of cocaine in different sub-periods of adolescence. Obviously, more studies are needed to resolve this issue. Irrespective of these inconsistencies, our results indicate that social and drug reward follow different developmental trajectories in the peri-adolescent period. Although pubertal stage was not directly assessed in our study, previous research allows us to speculate on the physiological changes cooccurring with the observed behavioral shift. The time window analyzed in the present study (i.e. postnatal days 32–46) is a period of dramatic physiological changes associated with sexual development in mice. The first sign of sexual maturation in male mice—balano-preputial separation—appears between P28 and 32 31–33 . Plasma testosterone levels rise rapidly from P30 to P40 and begin to decline slightly after that age 6 , 7 . Neuroanatomical studies show rapid brain development during adolescence, including nonlinear changes in D1 and D2 dopamine receptor expression in the dorsal striatum, with the lowest D1/D2 ratio around PND 35 8 . Physiological changes during puberty are accompanied with behavioral changes, especially in the social domain. Adolescence is a period of social re-orientation, characterized by the emergence of sexual behavior, decreased interest in family members, and increased interest in peers 34 . Social re-orientation towards unfamiliar individuals is considered one of the causes of emigration from natal environment (dispersal). Dispersal begins around postnatal day 30 and continues well into adulthood, with approximately half of the males having migrated from their natal environment by postnatal day 42 35 . Our study suggests that a decrease in rewarding effects of interactions with familiar kin occurring in mid-adolescence might serve as a proximate affective mechanism of dispersal from the natal environment. The main limitation of our study is that it was conducted exclusively on male mice. Sex differences in the developmental trajectory of social and non-social reward valuation is a focus of our next study, currently under review 36 . Taken together, our data show similarities between male mice and humans in the pattern of social reward development. Methods Animals Experiments were performed with C57BL/6 male mice bred at the Maj Institute of Pharmacology animal facility. Mice were housed in a 12/12 h light-dark cycle (lights on at 7 AM) under controlled conditions: a temperature of 22 ± 2 °C and a humidity of 40-60%. After weaning, the mice were housed with all littermates of the same sex. Rodent chow and water were available ad libitum. Home and conditioning cages contained aspen nesting material and aspen gnawing blocks. Behavioral tests were conducted during the light phase under dim illumination (5-10 lux). Social conditioned place preference (sCPP) and social interaction tests were video recorded with additional infrared LED illumination. The age and weight of mice in each experimental group are summarized in Table S1 . Three age groups were studied: early (around postnatal day 33 [P33]), middle (P38) and late (P43) adolescence (for information about experimental groups, see Tables S1 and S2 ). All behavioral procedures were approved by the II Local Bioethics Committee in Krakow (permit numbers 35/2019, 185/2020, 38/2021, 266/2020, 305/2020) and performed in accordance with the Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. The reporting in the manuscript follows the ARRIVE guidelines. Social conditioned place preference The test was performed to assess the rewarding effects of housing with siblings and followed the procedure described previously 18 . The test consisted of three phases: pretest, conditioning, and posttest ( Fig. 1A ). The pretest and posttest phases were performed in a two-compartment cage, as in previously published papers 15,18,21,26,37 . Each cage compartment contained a novel context (context A or context B) defined by type of bedding and gnawing block size and shape. Bedding materials used were beech (context A, P.P.H. \"WO-JAR\", Poland or PPHU Natur-Drew A. Czaja, Poland or Terrario Peak Wilderness, DMR Group, Poland) and cellulose (context B, Scott Pharma Solutions, cat no. L0107). In the home cages, aspen bedding was used (ABEDD, Latvia or Tapvei GLP, Estonia). Mice were allowed to freely explore the test cage for 30 minutes, and the time spent in each compartment was recorded. Animals that spent more than 70% of the pretest time in one of the contexts were excluded ( Table S2 ). After the pretest, animals were returned to their home cages for approximately 24 h. Then, mice were assigned to undergo social conditioning (housing with cage mates) for 24 h in one of the contexts used in the pretest followed by 24 h of isolate conditioning (single housing) in the other context. Conditioning was performed in cages identical to the home cage, with ad libitum access to food and water. To prevent bias, the social context was randomly assigned such that approximately half of the animals received social conditioning in context A and half in context B. In cases where the final number of animals conditioned in each context was not equal (due to an unequal number of animals passing the 70% criterion or unequal number of animals in the litter), we pseudorandomly trimmed the larger group using a Python script (https://zenodo.org/record/8100281) 38 . The exception from completely random selection was introduced to preserve a mean 50% initial context preference during the pretest, i.e., ascertain that the test was fully unbiased ( Table S6 ). Analysis on the full data set (not trimmed) was also performed, to assess the potential interaction between the age and conditioning context on social reward ( Figure S1, Table S4 ). The conditioning phase lasted 6 days (3 days in each context, alternating every 24 h), and then the posttest was performed. Two measures of the rewarding effects of social interactions were used: 1) pretest vs. posttest comparison of the time spent in the social context, 2) score: time spent in the social context minus time spent in the isolation context during the posttest. Social interaction in the partitioned cage This test was carried out to assess social contact seeking with a sibling partner after 24 h of isolation. The procedure was performed in a rectangular cage (48 × 12 cm, 25 cm high) divided by a transparent, perforated plastic wall into two compartments: a smaller partner compartment and a larger focal animal compartment ( Fig. 2A ). One day before the test, the animals were weighed, and the heavier animal from each pair was designated as the focal animal. Next, the animals were habituated to their respective cage compartments for 10 minutes. During habituation, only one mouse was present in the test cage. After habituation, mice were placed in separate home cages for approximately 24 h, after which time the focal animals were placed in the test cage for the second adaptation session (5 minutes). After adaptation, the partner was introduced for 10 minutes. Two measures of social contact seeking were used: time spent in close proximity to the partner’s compartment and distance to the partner’s compartment. Cocaine-induced conditioned place preference For the CPP paradigm, three-compartment cages were used (Med Associates, St. Albans, VT, USAMED-CPP-MSAT); the two peripheral compartments (that contained distinctive visual and tactile cues) were linked to the central compartment by guillotine doors. The test consisted of three phases: pretest, conditioning, and posttest. For the pretest and posttest phases, animals were introduced to the central compartment of the apparatus, and the doors between the compartments were lifted such that the animals could freely explore the apparatus for 20 minutes. Animals that spent more than 70% of the pretest time in one of the contexts were excluded. The less preferred of the two peripheral compartments was designated the cocaine compartment. The next day, the 3-day conditioning phase started. Each day, two 40-minute conditioning sessions were performed, separated by approximately 3 hours, during which animals were kept in their home cages. Before the morning conditioning session, animals received an i.p. saline injection, while before the afternoon session, they were injected with cocaine hydrochloride dissolved in saline (10 mg/kg, 5 μl/g). Immediately after the injection, animals were placed in the respective cage compartment, while the guillotine doors separating the compartments were closed. The posttest was performed on the day after the last conditioning session. The measures used to assess cocaine reward were the same as for the social conditioned place preference. Data analysis The distance traveled and time spent in separate cage compartments in the sCPP and social interaction tests were analyzed automatically using EthoVision XT 15 software (Noldus, The Netherlands). In the social interaction test, the zone close to the partner’s compartment was outlined digitally. In the cocaine-induced CPP test, the position of the mouse was registered automatically by the Med Associates system. Comparisons of sample means were performed using analysis of variance (ANOVA) followed by Sidak’s post hoc correction or Student’s t test for cases with only two samples. The statistical significance threshold was set at p < 0.05. Before the analysis, the Grubbs test for outliers was performed. For sCPP results, the outlier test was performed on “score”, “index 1”, “index 2”, and “distance moved during post-test” parameters before the trimming of the data. While only the “score” measure is shown in the present manuscript, all other measured are available at: https://zenodo.org/records/15284680. The test was performed separately for the context A and B data. Four outliers were detected in the sCPP data: one in the P33 group, two in the P38 group, and one in the P44 group. For the social interaction data, the outlier test was performed on the parameter “time in interaction zone”. No outliers were detected. For the cocaine experiment, the outlier test was performed on “score”, “index 1”, “index 2”, “exploration during posttest”, and “movement during posttest” parameters. No outliers were detected. Data concerning animals excluded from the analysis are presented in Table S2 . The analysis was performed in GraphPad Prism 9.4.1. For full descriptive statistics and statistical test results, see Supplementary Material . Declarations Competing interests The authors declare no competing interest. Funding This work was supported by the Polish National Science Centre [grant number 2016/21/B/NZ4/00198]. Author Contribution Conceptualization: ZH, BZ, RR, JRP; Methodology: ZH, KM, MK, MC and JRP; Investigation: ZH, MK, KM, MC, ŁS, AR and MKJ; Visualization: ZH, KM and JRP; Supervision: BZ, JRP; Writing—original draft: ZH and BZ; Writing—review & editing: ZH, BZ, RR, and JRP with help from all the authors. Acknowledgement This work was supported by the Polish National Science Centre [grant number 2016/21/B/NZ4/00198]. Data Availability All data are available at https://zenodo.org/records/15284680. References Crone, E. A. & Dahl, R. E. Understanding adolescence as a period of social–affective engagement and goal flexibility. Nature Reviews Neuroscience 13 , 636–650 (2012). Kessler, R. C. et al. 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Supplementary Files HardaadolescenceSupplementaryInformationSciRep.pdf Cite Share Download PDF Status: Published Journal Publication published 02 Dec, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 07 Oct, 2025 Reviews received at journal 05 Oct, 2025 Reviews received at journal 05 Oct, 2025 Reviewers agreed at journal 12 Sep, 2025 Reviewers agreed at journal 12 Sep, 2025 Reviewers invited by journal 12 Sep, 2025 Editor assigned by journal 10 Sep, 2025 Submission checks completed at journal 09 Sep, 2025 First submitted to journal 04 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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12:42:45\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":137010,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eSocial conditioned place preference during adolescence. \\u003c/strong\\u003e(\\u003cstrong\\u003ea\\u003c/strong\\u003e)\\u003cstrong\\u003e \\u003c/strong\\u003eSchematic representation of the experimental schedule. (\\u003cstrong\\u003eb\\u003c/strong\\u003e) Time spent in the social context. The graphs show the mean time spent on the social-conditioned context during the pretest and posttest (black dots and line, error values are s.e.m.). The gray points and lines show all individual mice in the corresponding age bracket as indicated above. (\\u003cstrong\\u003ec\\u003c/strong\\u003e) Preference of the social context. The points show mean values of the preference score, i.e., the difference between the time spent in social context and isolation context during posttest of mice at different adolescence stages as indicated below. (\\u003cstrong\\u003ed\\u003c/strong\\u003e) Distance traveled during the tests. Points represent mean distance travelled during pretest and posttest, error bars are s.e.m., gray points and lines represent individual animals. Significant post-hoc (ANOVA with Šidák correction) differences between mean values are shown as: \\u0026nbsp;‘**’ p \\u0026lt;0.01, and ‘***’ p \\u0026lt;0.001.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7535556/v1/356a9ec80947e3ab44177c76.png\"},{\"id\":91860200,\"identity\":\"dbc1f6f5-a84f-4104-a773-c558c1650f11\",\"added_by\":\"auto\",\"created_at\":\"2025-09-22 12:34:45\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":46802,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eSocial contact seeking during adolescence. \\u003c/strong\\u003e(\\u003cstrong\\u003ea\\u003c/strong\\u003e)\\u003cstrong\\u003e \\u003c/strong\\u003eA schematic representation of the task. Mice were tested for seeking social contact with a sibling after 24 h of isolation. (\\u003cstrong\\u003eb\\u003c/strong\\u003e)\\u003cstrong\\u003e \\u003c/strong\\u003eTime spent in the interaction\\u003cstrong\\u003e \\u003c/strong\\u003ezone. The points show mean time spent in the zone, error bars are the s.e.m. (\\u003cstrong\\u003ec\\u003c/strong\\u003e) \\u0026nbsp;Mean distance from the partner’s compartment. Group sizes: P33 n = 10, P38 n = 18, P43 n = 10.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7535556/v1/412928c33728c084197625ea.png\"},{\"id\":91863985,\"identity\":\"4413091b-5ff5-42a5-9a1e-25a2ec49f971\",\"added_by\":\"auto\",\"created_at\":\"2025-09-22 12:58:45\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":93195,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eCocaine-induced conditioned place preference during adolescence. \\u003c/strong\\u003e(\\u003cstrong\\u003ea\\u003c/strong\\u003e) Time spent in the cocaine-conditioned context. The points show mean time spent in the cocaine-paired context during the pretest and posttest, error values are s.e.m.. The gray points and lines show individual mice in age brackets indicated above. \\u0026nbsp;(\\u003cstrong\\u003eb\\u003c/strong\\u003e)\\u003cstrong\\u003e \\u003c/strong\\u003ePreference of the cocaine-conditioned context. The points show mean values of the preference score, i.e. the difference between the time spent in cocaine-conditioned context and saline-paired context during posttest of animals at different adolescence stages as indicated below. \\u0026nbsp;(\\u003cstrong\\u003ec\\u003c/strong\\u003e) Distance traveled during the tests. Points represent mean distance travelled during pretest and posttest, error bars are s.e.m., gray points represent individual animals. \\u0026nbsp;A significant post-hoc (ANOVA with Šidák correction) difference between mean values is shown as: ‘**’ p \\u0026lt;0.01.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7535556/v1/8336f758331ae1f39b482098.png\"},{\"id\":97724579,\"identity\":\"a7e27e48-a90b-4461-90ac-c1180e845098\",\"added_by\":\"auto\",\"created_at\":\"2025-12-08 16:12:43\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1047040,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7535556/v1/0c4efc68-9c57-4605-a675-5ac141ee2503.pdf\"},{\"id\":91862318,\"identity\":\"eab0ff42-9e3e-4bd7-92dd-d39751c97287\",\"added_by\":\"auto\",\"created_at\":\"2025-09-22 12:50:45\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":250478,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"HardaadolescenceSupplementaryInformationSciRep.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7535556/v1/3d858cad8d102d5b5c9aff51.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Changes in social reward across adolescence in mice\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eAdolescence is a time of rapid behavioral and neural changes, as well as the peak onset age for many mental disorders\\u003csup\\u003e\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e\\u003c/sup\\u003e. It is postulated that the emergence of psychiatric symptoms during adolescence results from alterations in typical developmental processes\\u003csup\\u003e\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e\\u003c/sup\\u003e. However, causal links between adolescent changes in brain maturation, behavior and pathophysiology have not been firmly established, partly because of the lack of proper animal models. It is thus of great importance to understand to what extent the behavioral development of model animals parallels the features of human adolescence\\u003csup\\u003e\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eIn male laboratory mice, which descend from \\u003cem\\u003eMus musculus\\u003c/em\\u003e species, adolescence typically spans postnatal days (P) 30 to 60, corresponding to ages 11\\u0026ndash;21 years in humans\\u003csup\\u003e\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u003c/sup\\u003e. Although no precise biological markers define the start or end of adolescence in either species, significant physiological and neural changes occur during this period. For example, rapid increase in serum testosterone levels and nonlinear changes in the expression of D1 and D2 receptors in basal ganglia are observed\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR7\\\" citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u003c/sup\\u003e. Despite these developmental dynamics, most behavioral studies treat adolescence as a uniform phase\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR10\\\" citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e\\u003c/sup\\u003e or compare adults to a single adolescent timepoint, usually around P28-30\\u003csup\\u003e12,13\\u003c/sup\\u003e, with some notable exceptions\\u003csup\\u003e\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e\\u003c/sup\\u003e. Here, we hypothesize that social reward in adolescent mice may also develop nonlinearly.\\u003c/p\\u003e\\u003cp\\u003eOne of the characteristic features of human adolescence is changes in social preferences. Whereas infants fully depend on parental care and display strong distress following separation from their mothers, mid-adolescents show a decrease in the time spent with their family members along with an increase in the time spent alone or with peers\\u003csup\\u003e\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e\\u003c/sup\\u003e. This behavioral shift is accompanied by changes in emotions associated with relatives: early and late adolescents show positive affect in the company of their family members, while mid-adolescents report more negative emotional states\\u003csup\\u003e\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e\\u003c/sup\\u003e. However, it is not known whether affective changes resembling those observed in humans also occur in model animal species. Therefore, the goal of the present study was to assess the reward value of interactions with familiar kin in early, middle and late adolescence in male mice.\\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eRewarding effects of interactions with siblings across adolescence\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eTo investigate the possible changes in the rewarding effects of social interactions with siblings during adolescence in mice, we used the social conditioned place preference (sCPP) test (\\u003cstrong\\u003eFig. 1A)\\u003c/strong\\u003e\\u003csup\\u003e18\\u003c/sup\\u003e with male mice representing early (around postnatal day 33 [P33]), middle (P38) and late (P43) adolescence stages (for information about experimental groups, see \\u003cstrong\\u003eTables S1\\u0026nbsp;\\u003c/strong\\u003eand\\u003cstrong\\u003e\\u0026nbsp;S2\\u003c/strong\\u003e). Animals were conditioned to associate one environmental context with group housing and another with social isolation, and then were tested to determine context preference. Mice aged 33, and 43 (but not 38) days at posttest showed a significant increase in the time spent in the social context from pretest to posttest, as revealed by significant interaction between age and conditioning (\\u003cstrong\\u003eFig. 1B, Table S3,\\u0026nbsp;\\u003c/strong\\u003eAge F\\u003csub\\u003e2,63\\u003c/sub\\u003e = 0.2182, p = 0.8046; Pre-Post F\\u003csub\\u003e1,63\\u003c/sub\\u003e = 21.69, p \\u0026lt; 0.0001; Age x Pre-Post F\\u003csub\\u003e2,63\\u003c/sub\\u003e = 3.253, p = 0.0453; post hoc P33 p \\u0026lt; 0.0001, P38 p = 0.8958, P43 p = 0.0064). There was no effect of context (i.e., the type of bedding) on preference (\\u003cstrong\\u003eFig. S1, Table S4\\u003c/strong\\u003e). It had no significant effect as main factor or in interactions with age or conditioning, while interaction between age and conditioning remains significant when context is added as variable (Context F\\u003csub\\u003e1,65\\u0026nbsp;\\u003c/sub\\u003e= 1.738, p = 0.1920; Age x Context F\\u003csub\\u003e2,65\\u0026nbsp;\\u003c/sub\\u003e= 0.6916, p = 0.5044, Pre-Post x Context F\\u003csub\\u003e1,65\\u0026nbsp;\\u003c/sub\\u003e= 0.1533, p = 0.6967; Age x Pre-Post x Context F\\u003csub\\u003e2,65\\u0026nbsp;\\u003c/sub\\u003e= 0.2435, p = 0.7846; Age x Pre-Post F\\u003csub\\u003e2,65\\u0026nbsp;\\u003c/sub\\u003e= 4.288 , p = 0.0178). Thus, interactions with siblings had lower reward value for mid-adolescent mice. The decrease in preference for the compartment associated with social contact in mid-adolescent mice was also clearly apparent in the social preference score (\\u003cstrong\\u003eFig. 1C\\u003c/strong\\u003e). The score showed that the rewarding effects of social interactions were more than two times lower in mid-adolescent (P38) than in early-adolescent (P33) mice and returned to the early adolescent level in late-adolescent (P43) mice (Age F\\u003csub\\u003e2,63\\u003c/sub\\u003e = 3.353, p = 0.0420). Importantly, motor activity was not significantly affected by age or interaction between age and conditioning; thus, it was not a confounding factor (\\u003cstrong\\u003eFig. 1D, Table S5,\\u0026nbsp;\\u003c/strong\\u003eAge F\\u003csub\\u003e2,63\\u003c/sub\\u003e = 2.279, p = 0.1108; Pre-Post F\\u003csub\\u003e1,63\\u003c/sub\\u003e = 85.03, p \\u0026lt; 0.0001; Age x Pre-Post F\\u003csub\\u003e2,63\\u003c/sub\\u003e = 0.5909, p = 0.5569). Taken together, the results reveal a transient decrease in the rewarding effects of interactions with related individuals in mid-adolescent mice.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSocial contact\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNext, we investigated if the change in social behavior in mid-adolescent mice was specific to the rewarding effects of social interactions or if contact seeking was also altered. To explore this possibility, we administered a test in which contact with another mouse is enabled through a transparent, perforated plexiglass wall\\u0026nbsp;(\\u003cstrong\\u003eFig. 2A\\u003c/strong\\u003e)\\u003csup\\u003e19\\u003c/sup\\u003e. The interaction partners were siblings reared in the same cage but isolated for one day before the test to match the conditions of the sCPP posttest. We observed no age-related changes in the time spent in the proximity to the partner\\u0026rsquo;s compartment (\\u003cstrong\\u003eFig. 2B, Table S3,\\u0026nbsp;\\u003c/strong\\u003eAge F\\u003csub\\u003e2,65\\u003c/sub\\u003e = 1.038, p = 0.3648) or the distance between the focal mouse and the partner\\u0026rsquo;s compartment (\\u003cstrong\\u003eFig. 2C,\\u0026nbsp;\\u003c/strong\\u003eAge F\\u003csub\\u003e1,65\\u003c/sub\\u003e = 0.7805, p = 0.4660). These results might indicate that the decrease in the rewarding effects of interactions with related individuals in mid-adolescent mice was not accompanied by a general decrease in social contact seeking.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eRewarding effects of cocaine\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAn alternative explanation for the observed decrease in the rewarding effects of social interactions could be a general anhedonia or impairment in associative learning. To test whether the decrease in the rewarding effects of social interaction reflected a stimulus-independent reduction in the expression of conditioned behaviors, the cocaine-induced CPP was assessed. As expected, a significant increase in time spent in cocaine-paired compartment was observed but without the effect of age or interaction between age and conditioning (\\u003cstrong\\u003eFig. 3A, Table S3,\\u0026nbsp;\\u003c/strong\\u003eAge F\\u003csub\\u003e2,41\\u003c/sub\\u003e = 0.6877, p = 0.5084; Pre-Post F\\u003csub\\u003e1,41\\u003c/sub\\u003e = 14.94, p = 0.004; Age x Pre-Post F\\u003csub\\u003e2,41\\u003c/sub\\u003e = 0.3454, p = 0.7100). In line with this interpretation, no significant effect of age on the place preference score was detected (\\u003cstrong\\u003eFig. 3B,\\u0026nbsp;\\u003c/strong\\u003eAge F\\u003csub\\u003e1,41\\u003c/sub\\u003e = 0.9828, p = 0.3829). No significant effect of age or conditioning on locomotor activity was observed (\\u003cstrong\\u003eFig. 3C,\\u0026nbsp;\\u003c/strong\\u003eAge F\\u003csub\\u003e2,41\\u003c/sub\\u003e = 0.8940, p = 0.4168; Pre-Post F\\u003csub\\u003e1,41\\u003c/sub\\u003e = 0.8799, p = 0.7682; Age x Pre-Post F\\u003csub\\u003e2,41\\u003c/sub\\u003e = 0.8897, p = 0.4186). These data show that no general impairment of reward-conditioned preference occurred during mid-adolescence.\\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eWe found that the rewarding effects of interactions with familiar kin in male mice exhibit a transient decrease during mid-adolescence (around P36-40). This decrease was specific to social reward, as no change in social contact seeking, and the reward value of cocaine was observed during this period. Our results resemble human data reported by Larson and Richards (1991), who observed that the affect associated with time spent with family members was more positive in 10-year-old and 16-year-old boys than in 12- to 14-year-olds\\u003csup\\u003e\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e\\u003c/sup\\u003e. The age range of 11 to 16 years in male humans corresponds to P30-40 in male mice, and this period is considered \\u0026ldquo;peripubertal\\u0026rdquo;\\u003csup\\u003e\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u003c/sup\\u003e. This may indicate that the phenomenon observed in our study, i.e., the temporary decrease in the reward value of interactions with familiar kin, is evolutionarily conserved. This finding may facilitate future research on the neuronal and physiological underpinnings of rebellious behaviors in adolescence.\\u003c/p\\u003e\\u003cp\\u003eOur results complement those of two previous studies that assessed the rewarding effects of social interactions using the sCPP paradigm at selected time points in adolescent mice\\u003csup\\u003e\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e\\u003c/sup\\u003e. In contrast to the methodology presented here, both previous studies used animals that were familiar but were not specifically kept in sibling groups. Our previous research on the reward value of social interactions has shown that eight weeks of familiarization with nonrelated mice is not equivalent to being reared in the same cage before weaning, at least in females, i.e. female mice do not form an sCPP when conditioned as adults in groups coming from different litters and housed together since weaning\\u003csup\\u003e\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e\\u003c/sup\\u003e. Moreover, both previous studies\\u003csup\\u003e\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e\\u003c/sup\\u003e used a paradigm with only two days of conditioning, which produces different results than the paradigm with six conditioning sessions used in this study\\u003csup\\u003e\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e\\u003c/sup\\u003e. Bearing these differences in mind, we note that Cann and collaborators (2020) reported that social contact is rewarding in mice tested on postnatal day 29 but not on postnatal day 38, which aligns with our results. Conversely, in the study by Nardou and collaborators (2019), a decrease in the rewarding effects of social interactions during adolescence was not observed in male mice (although it was observed in females). However, the previous results were not interpreted in terms of the possible decrease in the reward value of social interactions during adolescence. Instead, Cann and collaborators conclude that sCPP, under the applied conditions, can be induced in early adolescent, but not adult mice, implying that the observed lack of conditioning effects at the age of 38 days is considered permanent. Results presented in this work, together with a previous paper where adult mice were studied\\u003csup\\u003e\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e\\u003c/sup\\u003e, suggest that sCPP can be induced in late adolescent and adult male mice, provided that the 6-day protocol is used.\\u003c/p\\u003e\\u003cp\\u003eRecent study by Murray and collaborators (2024) investigated developmental changes in the motivation to obtain social reward in laboratory rats\\u003csup\\u003e\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e\\u003c/sup\\u003e, a species in which the equivalent of P30-40 in mice is P42-55\\u003csup\\u003e5\\u003c/sup\\u003e. In this study, the operant conditioning protocol was employed and an unfamiliar conspecific was used as a stimulus animal. The authors found that social motivation is higher in pre-adolescent (P30) and mid-adolescent (P50) rats than in early adolescent animals (P40). This might indicate that the rewarding effects of and motivation to obtain social reward differ depending on the familiarity of the stimulus animal, with mid-adolescence being a period of decreased familiar kin contact seeking, and higher motivation to interact with unfamiliar individuals. A study using the 6-day sCPP protocol on mice housed with familiar and unfamiliar conspecifics in different adolescence timepoints should be performed to test this hypothesis. However, it must be noted that Murray and coworkers use different labels for the developmental periods, and describe P40 as mid-adolescence and P50 as late adolescence\\u003csup\\u003e\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eIn contrast to social reward, there were no apparent changes in social contact seeking (assessed with the partition test) during adolescence. This finding indicates that the changes in social interactions in adolescent mice are qualitative rather than quantitative. We speculate that the amount of time spent with siblings may not change, but aggressive encounters may replace affiliative interactions. This interpretation is supported by earlier studies showing a profound decrease in passive social contact\\u003csup\\u003e\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e\\u003c/sup\\u003e and play behavior\\u003csup\\u003e\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e\\u003c/sup\\u003e, along with an increase in fighting\\u003csup\\u003e\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e\\u003c/sup\\u003e, in the second postnatal month of mice life. Strikingly, the cocaine-induced CPP did not change during the adolescent period. These results indicate that the decrease in social CPP in mid-adolescent mice cannot be explained by a general decline in learning abilities and confirm that different neuronal processes underlie the rewarding effects of cocaine and social contact\\u003csup\\u003e\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e\\u003c/sup\\u003e. Developmental changes in cocaine-induced CPP were previously studied in rats, and their results are inconsistent. For example, Brenhouse and coworkers reported a greater cocaine (10 mg/kg)-induced CPP in adolescents (P44) than in adults (P105)\\u003csup\\u003e\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e\\u003c/sup\\u003e. Notably, preadolescent rats (P27-37) showed similar levels of cocaine-induced CPP as adult animals\\u003csup\\u003e\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e\\u003c/sup\\u003e, which suggests an inverted U-shaped relationship between cocaine reward and age. These results are consistent with previous reports of heightened sensitivity to other drugs of abuse in adolescent animals\\u003csup\\u003e\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e\\u003c/sup\\u003e. Conversely, the results by Badanich and collaborators indicated the highest sensitivity to cocaine reward in pre-adolescent rats, because a low cocaine dose (5 mg/kg) induced CPP only in pre-adolescents (P35), but not in adolescents (P45) or young adults (P60 animals)\\u003csup\\u003e\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e\\u003c/sup\\u003e. This suggests that some factors unidentified yet, for example the level of stress imposed by the experimental protocol, might differentially influence the rewarding effects of cocaine in different sub-periods of adolescence. Obviously, more studies are needed to resolve this issue. Irrespective of these inconsistencies, our results indicate that social and drug reward follow different developmental trajectories in the peri-adolescent period.\\u003c/p\\u003e\\u003cp\\u003eAlthough pubertal stage was not directly assessed in our study, previous research allows us to speculate on the physiological changes cooccurring with the observed behavioral shift. The time window analyzed in the present study (i.e. postnatal days 32\\u0026ndash;46) is a period of dramatic physiological changes associated with sexual development in mice. The first sign of sexual maturation in male mice\\u0026mdash;balano-preputial separation\\u0026mdash;appears between P28 and 32\\u003csup\\u003e31\\u0026ndash;33\\u003c/sup\\u003e. Plasma testosterone levels rise rapidly from P30 to P40 and begin to decline slightly after that age\\u003csup\\u003e\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u003c/sup\\u003e. Neuroanatomical studies show rapid brain development during adolescence, including nonlinear changes in D1 and D2 dopamine receptor expression in the dorsal striatum, with the lowest D1/D2 ratio around PND 35\\u003csup\\u003e8\\u003c/sup\\u003e. Physiological changes during puberty are accompanied with behavioral changes, especially in the social domain. Adolescence is a period of social re-orientation, characterized by the emergence of sexual behavior, decreased interest in family members, and increased interest in peers\\u003csup\\u003e\\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e\\u003c/sup\\u003e. Social re-orientation towards unfamiliar individuals is considered one of the causes of emigration from natal environment (dispersal). Dispersal begins around postnatal day 30 and continues well into adulthood, with approximately half of the males having migrated from their natal environment by postnatal day 42\\u003csup\\u003e35\\u003c/sup\\u003e. Our study suggests that a decrease in rewarding effects of interactions with familiar kin occurring in mid-adolescence might serve as a proximate affective mechanism of dispersal from the natal environment.\\u003c/p\\u003e\\u003cp\\u003eThe main limitation of our study is that it was conducted exclusively on male mice.\\u003c/p\\u003e\\u003cp\\u003eSex differences in the developmental trajectory of social and non-social reward valuation is a focus of our next study, currently under review\\u003csup\\u003e\\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eTaken together, our data show similarities between male mice and humans in the pattern of social reward development.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eAnimals\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eExperiments were performed with C57BL/6 male mice bred at the Maj Institute of Pharmacology animal facility. Mice were housed in a 12/12 h light-dark cycle (lights on at 7 AM) under controlled conditions: a temperature of 22 \\u0026plusmn; 2 \\u0026deg;C and a humidity of 40-60%. After weaning, the mice were housed with all littermates of the same sex. Rodent chow and water were available ad libitum. Home and conditioning cages contained aspen nesting material and aspen gnawing blocks. Behavioral tests were conducted during the light phase under dim illumination (5-10 lux). Social conditioned place preference (sCPP) and social interaction tests were video recorded with additional infrared LED illumination. The age and weight of mice in each experimental group are summarized in \\u003cstrong\\u003eTable S1\\u003c/strong\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003eThree age groups were studied: early (around postnatal day 33 [P33]), middle (P38) and late (P43) adolescence (for information about experimental groups, see \\u003cstrong\\u003eTables S1\\u0026nbsp;\\u003c/strong\\u003eand\\u003cstrong\\u003e\\u0026nbsp;S2\\u003c/strong\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eAll behavioral procedures were approved by the II Local Bioethics Committee in Krakow (permit numbers 35/2019, 185/2020, 38/2021, 266/2020, 305/2020)\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003eand performed in accordance with the Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. The reporting in the manuscript follows the ARRIVE guidelines.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSocial conditioned place preference\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe test was performed to assess the rewarding effects of housing with siblings and followed the procedure described previously\\u003csup\\u003e18\\u003c/sup\\u003e. The test consisted of three phases: pretest, conditioning, and posttest (\\u003cstrong\\u003eFig. 1A\\u003c/strong\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eThe pretest and posttest phases were performed in a two-compartment cage, as in previously published papers\\u003csup\\u003e15,18,21,26,37\\u003c/sup\\u003e. Each cage compartment contained a novel context (context A or context B) defined by type of bedding and gnawing block size and shape. Bedding materials used were beech (context A, P.P.H. \\u0026quot;WO-JAR\\u0026quot;, Poland or PPHU Natur-Drew A. Czaja, Poland or Terrario Peak Wilderness, DMR Group, Poland) and cellulose (context B, Scott Pharma Solutions, cat no. L0107). In the home cages, aspen bedding was used (ABEDD, Latvia or Tapvei GLP, Estonia). Mice were allowed to freely explore the test cage for 30 minutes,\\u0026nbsp;and the time spent in each compartment was recorded. Animals that spent more than 70% of the\\u0026nbsp;pretest\\u0026nbsp;time in one of the contexts were excluded (\\u003cstrong\\u003eTable S2\\u003c/strong\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eAfter the pretest, animals were returned to their home cages for approximately 24 h. Then, mice were assigned to undergo social conditioning (housing with cage mates) for 24 h in one of the contexts used in the pretest followed by 24 h of isolate conditioning (single housing) in the other context. Conditioning was performed in cages identical to the home cage, with ad libitum access to food and water. To prevent bias, the social context was randomly assigned such that approximately half of the animals received social conditioning in context A and half in context B. In cases where the final number of animals conditioned in each context was not equal (due to an unequal number of animals passing the 70% criterion or unequal number of animals in the litter), we pseudorandomly\\u0026nbsp;trimmed the larger group using a Python\\u0026nbsp;script (https://zenodo.org/record/8100281)\\u003csup\\u003e38\\u003c/sup\\u003e. The exception from completely random selection was introduced to preserve a mean 50% initial context preference during the pretest, i.e., ascertain that the test was fully unbiased (\\u003cstrong\\u003eTable S6\\u003c/strong\\u003e).\\u0026nbsp;Analysis on the full data set (not trimmed) was also performed, to assess the potential interaction between the age and conditioning context on social reward (\\u003cstrong\\u003eFigure S1, Table S4\\u003c/strong\\u003e). The conditioning phase lasted 6 days (3 days in each context, alternating every\\u0026nbsp;24\\u0026nbsp;h), and then the\\u0026nbsp;posttest\\u0026nbsp;was performed.\\u003c/p\\u003e\\n\\u003cp\\u003eTwo measures of the rewarding effects of social interactions were used: 1) pretest vs. posttest comparison of the time spent in the social context, 2) score: time spent in the social context minus time spent in the isolation context during the posttest.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSocial interaction in\\u0026nbsp;\\u003c/strong\\u003e\\u003cstrong\\u003ethe\\u0026nbsp;\\u003c/strong\\u003e\\u003cstrong\\u003epartitioned cage\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis test was carried out to assess social contact seeking with a sibling partner after 24 h of isolation. The procedure was performed in a rectangular cage (48 \\u0026times; 12 cm, 25 cm high) divided by a transparent, perforated plastic wall into two compartments: a smaller partner compartment and a larger focal animal compartment (\\u003cstrong\\u003eFig. 2A\\u003c/strong\\u003e). One day before the test, the animals were weighed, and the heavier animal from each pair was designated as the focal animal. Next, the animals were habituated to their respective cage compartments for 10 minutes. During habituation, only one mouse was present in the test cage. After habituation, mice were placed in separate home cages for approximately 24 h, after which time the focal animals were placed in the test cage for the second adaptation session (5 minutes). After adaptation, the partner was introduced for 10 minutes. Two measures of social contact seeking were used: time spent in close proximity to the partner\\u0026rsquo;s compartment and distance to the partner\\u0026rsquo;s compartment.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCocaine-induced conditioned place preference\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eFor the CPP paradigm, three-compartment cages were used (Med Associates, St. Albans, VT, USAMED-CPP-MSAT); the two peripheral compartments (that contained distinctive visual and tactile cues) were linked to the central compartment by guillotine doors. The test\\u0026nbsp;consisted of three phases: pretest, conditioning, and posttest. For the pretest and posttest phases, animals were introduced to the central compartment of the apparatus, and the doors between the compartments were lifted such that the animals could freely explore the apparatus for 20 minutes. Animals that spent more than 70% of the pretest time in one of the contexts were excluded. The less preferred of the two peripheral compartments was designated the cocaine compartment. The next day, the 3-day conditioning phase started. Each day, two 40-minute conditioning sessions were performed, separated by approximately 3 hours, during which animals were kept in their home cages. Before the morning conditioning session, animals received an i.p. saline injection, while before the afternoon session, they were injected with cocaine hydrochloride dissolved in saline (10 mg/kg, 5 \\u0026mu;l/g). Immediately after the injection, animals were placed in the respective cage compartment, while the guillotine doors separating the compartments were closed. The posttest was performed on the day after the last conditioning session.\\u0026nbsp;The measures used to assess cocaine reward were the same as for the social conditioned place preference.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eData analysis\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe distance traveled and time spent in separate cage compartments in the sCPP and social interaction tests were analyzed automatically using EthoVision XT 15 software (Noldus, The Netherlands). In the social interaction test, the zone close to the partner\\u0026rsquo;s compartment was outlined digitally. In the cocaine-induced CPP test, the position of the mouse was registered automatically by the Med Associates system. Comparisons of sample means were performed using analysis of variance (ANOVA) followed by Sidak\\u0026rsquo;s post hoc correction or Student\\u0026rsquo;s t test for cases with only two samples. The statistical significance threshold was set at p \\u0026lt; 0.05. Before the analysis, the Grubbs test for outliers was performed. For sCPP results, the outlier test was performed on \\u0026ldquo;score\\u0026rdquo;, \\u0026ldquo;index 1\\u0026rdquo;, \\u0026ldquo;index 2\\u0026rdquo;, and \\u0026ldquo;distance moved during post-test\\u0026rdquo; parameters before the trimming of the data. While only the \\u0026ldquo;score\\u0026rdquo; measure is shown in the present manuscript, all other measured are available at: https://zenodo.org/records/15284680.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThe test was performed separately for the context A and B data. Four outliers were detected in the sCPP data: one in the \\u0026nbsp;P33 group, two in the P38 group, and one in the P44 group. For the social interaction data, the outlier test was performed on the parameter \\u0026ldquo;time in interaction zone\\u0026rdquo;. No outliers were detected. For the cocaine experiment, the outlier test was performed on \\u0026ldquo;score\\u0026rdquo;, \\u0026ldquo;index 1\\u0026rdquo;, \\u0026ldquo;index 2\\u0026rdquo;, \\u0026ldquo;exploration during posttest\\u0026rdquo;, and \\u0026ldquo;movement during posttest\\u0026rdquo; parameters. No outliers were detected. Data concerning animals excluded from the analysis are presented in \\u003cstrong\\u003eTable S2\\u003c/strong\\u003e. The analysis was performed in GraphPad Prism 9.4.1. For full descriptive statistics and statistical test results, see \\u003cstrong\\u003eSupplementary Material\\u003c/strong\\u003e.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003ch2\\u003eCompeting interests\\u003c/h2\\u003e\\u003cp\\u003eThe authors declare no competing interest.\\u003c/p\\u003e\\u003c/p\\u003e\\u003ch2\\u003eFunding\\u003c/h2\\u003e\\u003cp\\u003eThis work was supported by the Polish National Science Centre [grant number 2016/21/B/NZ4/00198].\\u003c/p\\u003e\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eConceptualization: ZH, BZ, RR, JRP; Methodology: ZH, KM, MK, MC and JRP; Investigation: ZH, MK, KM, MC, ŁS, AR and MKJ; Visualization: ZH, KM and JRP; Supervision: BZ, JRP; Writing\\u0026mdash;original draft: ZH and BZ; Writing\\u0026mdash;review \\u0026amp; editing: ZH, BZ, RR, and JRP with help from all the authors.\\u003c/p\\u003e\\u003ch2\\u003eAcknowledgement\\u003c/h2\\u003e\\u003cp\\u003eThis work was supported by the Polish National Science Centre [grant number 2016/21/B/NZ4/00198].\\u003c/p\\u003e\\u003ch2\\u003eData Availability\\u003c/h2\\u003e\\u003cp\\u003eAll data are available at https://zenodo.org/records/15284680.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eCrone, E. 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Social reward requires coordinated activity of accumbens oxytocin and 5HT. \\u003cem\\u003eNature\\u003c/em\\u003e \\u003cstrong\\u003e501\\u003c/strong\\u003e, 179\\u0026ndash;184 (2013).\\u003c/li\\u003e\\n\\u003cli\\u003eHarda, Z. \\u003cem\\u003eet al.\\u003c/em\\u003e Mu and delta opioid receptor antagonists increase the expression of social conditioned place preference in early adolescent mice. 2023.07.19.549691 Preprint at https://doi.org/10.1101/2023.07.19.549691 (2025).\\u003c/li\\u003e\\n\\u003cli\\u003eHarda, Z. \\u003cem\\u003eet al.\\u003c/em\\u003e Changes in social reward across adolescence in male mice. 2025.05.27.656363 Preprint at https://doi.org/10.1101/2025.05.27.656363 (2025).\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"scientific-reports\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"scirep\",\"sideBox\":\"Learn more about [Scientific Reports](http://www.nature.com/srep/)\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Scientific Reports\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Scientific Reports\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7535556/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7535556/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eIn 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.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Changes in social reward across adolescence in mice\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-09-22 12:34:40\",\"doi\":\"10.21203/rs.3.rs-7535556/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2025-10-07T17:25:29+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-10-06T02:00:06+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-10-06T00:22:32+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"231239726089144309776977910592704387648\",\"date\":\"2025-09-12T20:18:18+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"62137280279260962901804277664473416430\",\"date\":\"2025-09-12T19:31:33+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-09-12T19:29:07+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2025-09-10T10:13:08+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2025-09-09T09:13:51+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Scientific Reports\",\"date\":\"2025-09-04T11:10:25+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"scientific-reports\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"scirep\",\"sideBox\":\"Learn more about [Scientific Reports](http://www.nature.com/srep/)\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Scientific Reports\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Scientific Reports\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"2e8358e1-005c-49a9-8027-f311a207aa2e\",\"owner\":[],\"postedDate\":\"September 22nd, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[{\"id\":54651733,\"name\":\"Biological sciences/Neuroscience\"},{\"id\":54651734,\"name\":\"Biological sciences/Psychology\"},{\"id\":54651735,\"name\":\"Social science/Psychology\"}],\"tags\":[],\"updatedAt\":\"2025-12-08T16:09:26+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-7535556\",\"link\":\"https://doi.org/10.1038/s41598-025-30755-2\",\"journal\":{\"identity\":\"scientific-reports\",\"isVorOnly\":false,\"title\":\"Scientific Reports\"},\"publishedOn\":\"2025-12-02 15:57:57\",\"publishedOnDateReadable\":\"December 2nd, 2025\"},\"versionCreatedAt\":\"2025-09-22 12:34:40\",\"video\":\"\",\"vorDoi\":\"10.1038/s41598-025-30755-2\",\"vorDoiUrl\":\"https://doi.org/10.1038/s41598-025-30755-2\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7535556\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7535556\",\"identity\":\"rs-7535556\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}