Journal of Alzheimer’s Disease 69 (2019) 969–977 969 DOI 10.3233/JAD-190253 IOS Press Short Communication Vibrating Tail, Digging, Body/Face Interaction, and Lack of Barbering: Sex-Dependent Behavioral Signatures of Social Dysfunction in 3xTg-AD Mice as Compared to Mice with Normal Aging Virginia Torres-Listaa,b and Lydia Giménez-Llorta,b,∗ a Department of Psychiatry and Forensic Medicine, Faculty of Medicine, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain b Institut de Neurociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain Accepted 16 April 2019 Abstract. Modeling of Alzheimer’s disease (AD), classically focused on the subject-environment interaction, foresees current social neuroscience efforts as improving the predictive validity of new strategies. Here we studied social functioning among congeners in 13–14-month-old mice with normal aging in naturalistic and experimental conditions and depicted behavioral signatures of dysfunction in age-matched 3xTg-AD mice. The most sensitive variables were vibrating tail, digging, body/face and self-grooming, that can be easily used in housing routines and the assessment of strategies. Sex-specific signatures (vibrating tail, digging, and grooming) defined female 3xTg-AD mice ethogram. All animals sleep huddled while barbering was only found in females with normal aging. Keywords: Barbering, behavioral and psychological symptoms of dementia, Dalila effect, digging, ethogram markers, monitoring, sleeping behavior, social behavior, Social Interaction Test, Tube-dominance test INTRODUCTION now opens to the higher level of complexity of social behavior and communication. While personalized medicine urges the depiction Social behavior is a fundamental characteristic of the nuances of individual variability that underlies modulated by endogenous, genetic, and environmen- epidemiology, basic research classically focused on tal factors. Deficits in social interaction are defined the individual specimen as the subject of study [1], by endophenotypes and are present in various psy- chiatric disorders such as autism, schizophrenia, ∗ Correspondence to: Lydia Giménez-Llort, Unitat de Psicolo- depression, and Alzheimer’s disease (AD) with a gia Mèdica, M5-133, Departament de Psiquiatria i Medicina Legal, strong impact on daily life of patients and caregivers Facultat de Medicina, Avgda. Can Domènech, Edifici M, s/n, Campus Bellaterra, Universitat Autònoma de Barcelona, 08193 [2–5]. Conversely, social factors are considered not Cerdanyola del Vallès, Barcelona, Spain. Tel.: +34 93 5812378; only modulators of mental and physical health of peo- Fax: +34 93 5811435; E-mail: lidia.gimenez@uab.cat. ple but also risk factors for symptoms of dementia [6]. ISSN 1387-2877/19/$35.00 © 2019 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0). 970 V. Torres-Lista and L. Giménez-Llort / Behavioral signatures of social dysfunction in male and female 3xTg-AD mice Although social interaction is considered a phenotype performed blind to the experiment, in a counterbal- or endophenotype of AD, the underlying mechanisms anced manner. All procedures were in accordance and causes remain complex [7]. with Spanish legislation on ‘Protection of Animals At the translational level, modeling behavioral Used for Experimental and Other Scientific Purposes’ and psychological symptoms of dementia (BPSD) and the EU Directive (2010/63/UE) on this subject. in murine models of AD has been addressed using The study complies with the ARRIVE guidelines methodological approaches based on the interaction developed by the NC3Rs and the aim to reduce the of the subject with the environment, but few involve number of animals used. the relation with other individuals [8]. Furthermore, social neuroscience efforts to fill the gap are also fore- Home cage sleeping behavior seen as important to improve the predictive validity of new preventive and/or therapeutic strategies for AD Home cage group sleeping behavior was registered [9]. during 3 consecutive days and reported as the inci- Therefore, the present work is aimed to explore dence of animals sleeping together, huddled (entire social functioning (from affiliative behaviors and bodies being pressed up against each other) and/or dominance to aggressive behaviors) among con- dog-piled (similarly to dog-piling), in the same quad- geners in 13-14-month-old male and female mice rant of their home cage [11]. with normal aging in naturalistic and experimental conditions, as well as to depict behavioral signa- Social interaction test tures of social dysfunction as a consequence of genetically-induced amyloid-␤ and tau pathologies A dyad of two unfamiliar mice of the same geno- in age-matched 3xTg-AD mice. At these ages, the type and sex were introduced in a standard home 3xTg-AD model has extensively been described cage and video recorded for 5 min (modification of mimicking advanced stages of disease with hallmark [12]). Behaviors were classified into social (social amyloid and tau pathologies [10]. For that purpose, investigation, aggression, vibrant tail) and non-social we evaluated behavioral interactions with congeners (exploring, digging, self-grooming) interactions. We (group-sleeping, body/face, ano-genital, aggression), also scored the total number of episodes and their total with the context (horizontal and vertical exploratory duration. In order to depict the sequence of behav- activities, digging) and self-actions (self-grooming ioral events, here we propose to plot the latencies and vibrating tail) that can be easily used in housing for each genotype and sex as an ethogram tablature. routines and the assessment of strategies. There, self-grooming and vibrating tail are plotted as self-actions. MATERIALS AND METHODS Barbering or Dalila effect Animals Barbering or Dalila effect, alopecia due to social A total of forty-six 13–14-month-old homozygous interaction between animals, was scored according to male and female 3xTg-AD and their non-transgenic 5-scores Kalueff scale [13]. The incidence per cage (NTg) mice, 7th breeding generations derived from and the affected body area was also recorded in cm2 the same genetic background (C57BL/6×129 sv), [14, 15]. engineered at the University of California Irvine were used [10]. Subjects (group, n, mean age in Tube-dominance test months ± S.D.: male NTg, n = 10, 13 ± 0; male 3xTg- AD, n = 8, 13 ± 0; female NTg, n = 14, 13.57 ± 0.94; In order to know if the Dalila effect was related to female 3xTg-AD, n = 14, 13.71 ± 0.94) were housed dominance, the social range of dyads was assessed in three to four per cage and maintained in Macrolon the Tube-dominance test [11]. Animals were placed cages (35 x 35 x 25 cm) under standard laboratory at the opposite ends of a translucent acrylic tube conditions of food (A03 diet for breeding; A04 diet (diameter: 4 cm, length: 25.5 cm), allowed to advance for maintenance, Panlab, SL, Barcelona) and water through it for a maximum of 120 s or until one of them ad libitum, 22 ± 2◦ C, a 12 h light:dark cycle and rela- (“dominant”) forced the other (“subordinate”) to get tive humidity 50–60%. Behavioral assessments were out of the tube. V. Torres-Lista and L. Giménez-Llort / Behavioral signatures of social dysfunction in male and female 3xTg-AD mice 971 Statistical analysis Barbering or Dalila effect Results are expressed as mean ± S.E.M. or inci- Dalila effect was present only in the female NTg dence. Statistics using SPSS 15.0 as detailed in the group, with an incidence of 0.40 ± 0.16, a severity legends, with significance considered at p < 0.05. score of 0.80 ± 0.35 and 0.25 ± 0.12 cm2 of body affected area. The three variables showed significant differences as compared to null presence in 3xTg-AD RESULTS (all F < 2.170, p > 0.05). Home cage sleeping behaviors Tube-dominance test All mice (100%) slept huddled, curled together, First contact was faster in 3xTg-AD mice close to each other, in a quadrant of the cage, inde- (1.21 ± 1.21 s versus. NTg: 2.00 ± 0.00 s, p < 0.05) pendently of the genotype or sex. but no differences were shown in the latency of with- drawn mice (1.42 ± 0.13 s versus NTg: 3.42 ± 2.33 s) or total duration of the test (16.00 ± 1.19 s versus Social interaction test NTg: 11.42 ± 2.06 s). The ethogram tablature (Fig. 1) showed a con- sistent sequence of actions in the NTg mice, with DISCUSSION the only distinction of vibrating tail that was antic- ipated in the females. The ethogram started with The present work identifies, for the first time, exploration (horizontal and vertical), followed by first vibrating tail, digging, body/face interaction, and body/face social interaction done before the end of lack of barbering as variables that can be used as the first minute. In the second minute, ano-genital behavioral signatures of AD-social phenotype in the interaction and self-grooming were observed. Dig- 3xTg-AD mice, with sex-specificity and their inte- ging appeared around the third minute of the test, gration with non-social behaviors. We assessed a followed in males or preceded in females by vibrat- rank of social aspects, from affiliative behaviors and ing tail. In the 3xTg-AD mice, the tablature showed dominance to aggression, using experimental and sex and genotype differences. As compared to their naturalistic conditions that can be used for behav- NTg counterparts, males were delayed in the elic- ioral monitoring. Thus, we used social interaction itation of social interactions, while vibrating tail and tube-dominance tests but also we recorded affil- was advanced similarly to NTg females. In contrast, iative behaviors developed in the home cage such as female 3xTg-AD showed a very early elicitation of sleeping behavior and barbering. vibrating tail and an anticipated digging that was The quantitative and qualitative analysis of the performed before the elicitation of social behaviors. ethogram elicited in the SIT evidenced that the Body/face and ano-genital interactions were consec- expression of social behaviors (body/face contact utively performed, and grooming was delayed to the and ano-genital contact, no aggressions) was very third minute of the test, as compared to all the other consistent in NTg mice, independently of sex. groups. These differences were found reflected in The behavioral repertoire started with a neophobia the respective variables of total duration and num- response toward the environment (horizontal and ver- ber of episodes of social (Fig. 2) and non-social tical exploration of the new cage), followed by the (Fig. 3) behaviors elicited among congeners in the interaction with conspecifics, and afterwards by the social interaction test (SIT). Incidence of aggression expression of behaviors related to enhanced emo- was 1/8 in male 3xTg-AD mice with a latency of tionality such as grooming behavior and digging. In 213 s, and absent in the other experimental groups. contrast, the ‘vibrating tail’ appeared as a distinctive Overall, the most sensitive variables were vibrating profile for female sex, as it was earlier expressed. tail (duration, episodes, and latency), digging (latency This behavior, when elicited in rodents by systemic and episodes), body/face (episodes, duration, and administration of glutamatergic agonist NMDA, is latency), and self-grooming (latency) (all F > 3.289, related to increased excitability [16]. In agreement p < 0.001). with the increased vulnerability of 3xTg-AD to the 972 V. Torres-Lista and L. Giménez-Llort / Behavioral signatures of social dysfunction in male and female 3xTg-AD mice Fig. 1. Social interaction test ethogram tablature of 14-month-old male and female 3xTg-AD mice at advanced-stages of the disease and age- and sex-matched NTg mice with normal aging. Results are mean ± SEM of latency of events shown by NTg (male, n = 10; female, n = 14) and 3xTg-AD mice (male, n = 8; female, n = 14) in the social interaction test. Multivariate General Linear Modelling: G, genotype effect and S, sex effect *p<0.05 and **p<0.01, followed by Duncan’s post-hoc test comparisons a p < 0.05 different all group and b p < 0.05 different to genotype. Student’s t-test ***p < 0.001, **p < 0.01, and *p < 0.05 versus NTg mice. Student’s t-test & p < 0.05 versus male NTg mice and, # p < 0.05 versus male 3xTg-AD mice. occurrence of anxious-like behaviors in new envi- profile, was significantly enhanced and advanced on ronments [8], the ethogram in the SIT was found time. Thus, it was early expressed, in more occa- disrupted in the 3xTg-AD mice. The ‘vibrating tail’, sions (episodes) and had longer total duration. These also the most distinctive behavior of the female sex variables entitle vibrating tail as a selective and sen- V. Torres-Lista and L. Giménez-Llort / Behavioral signatures of social dysfunction in male and female 3xTg-AD mice 973 Fig. 2. Social interactions (body/face and ano-genital contacts) and vibrating tail shown in the SIT by 14-month-old male and female 3xTg- AD mice at advanced-stages of the disease and age- and sex-matched NTg mice with normal aging. Results are mean ± SEM of latency of events, total duration and total number of episodes. NTg (male, n = 10; female, n = 14) and 3xTg-AD mice (male, n = 8; female, n = 14) in the social interaction test. Multivariate General Linear Modelling: G, genotype effect and S, sex effect *p < 0.05 and **p < 0.01 and followed by post-hoc Duncan’s test comparisons *p < 0.05 versus all the other groups, a p < 0.05 versus the NTg mice, same sex, b p < 0.05 versus male counterpart, c p < 0.05 versus male NTg mice. sitive tool for sex-dependent expression of the social month-old male 3xTg-AD mice showed increased anxiety-like profile in 3xTg-AD mice. marble-burying that was related to neophobia, mod- Digging in the sawdust was sensitive to genotype ulable by handling, reversed by chronic treatment and sex. In a precedent work, we showed that 12- with risperidone [17] and modified by chronic caf- 974 V. Torres-Lista and L. Giménez-Llort / Behavioral signatures of social dysfunction in male and female 3xTg-AD mice Fig. 3. Non-social interactions (rearings, corners, self-grooming, and digging) shown in the SIT by 14-month-old male and female 3xTg-AD mice at advanced-stages of the disease and age- and sex-matched NTg mice with normal aging. Results are mean ± SEM of latency of events and total number of episodes. NTg (male, n = 10; female, n = 14) and 3xTg-AD mice (male, n = 8; female, n = 14) in the social interaction test. Multivariate General Linear Modelling: G, genotype effect and S, sex effect *p < 0.05 and **p < 0.01 and followed by post-hoc Duncan’s test comparisons *p < 0.05 versus all the other groups, a p < 0.05 versus the NTg mice, same sex, b p < 0.05 versus male counterpart, c p < 0.05 versus male NTg mice. feine [18]. This behavior has been considered to the previous actions are altered, as it is the case serve to measure digging rather than evoke bury- here, the latency of self-grooming reflects the pre- ing [19], while Deacon [20] typified marble burying vious sequence of behaviors, and could be consider and digging in mice as simple methods for in vivo less ‘specific’ by itself. For this reason, grooming identification of biological impacts. was not chosen among the behaviors cited as rel- Self-grooming was also affected in the SIT, in evant for the behavioral signature. With regards to agreement with delayed grooming in 15-month-old social grooming in home-cage conditions, mutual male and female 3xTgAD assessed in an open-field grooming is considered an affiliative behavior. How- test [21] but advanced in females when engaged ever, presence of barbering described as Dalila effect, in active copying-with-stress strategies [22]. Here, more prevalent in females, illustrates a unidirectional latency of self-grooming allowed to distinguish the behavior resulting of barber whiskers by plucking female 3xTg-AD genotype. According to the ‘action [15] done by one mouse (Dalila) that remains with programs’ described by Lat [23] for mice and rats its fur intact. There are several hypotheses about this when they habituate in the open-field, self-grooming phenomenon in rodents such as genetic, environmen- emerges once the other behaviors or actions (fear- tal, social hierarchies, stress, and certain disorders of explorations) have been completed. Therefore, when obsessive-compulsive spectrum [13]. Here, the Dalila V. Torres-Lista and L. Giménez-Llort / Behavioral signatures of social dysfunction in male and female 3xTg-AD mice 975 effect was present only in the NTg females, while type, whereas being hyperactive in the open-field 3xTg-AD females exhibited similar performances in and elevated plus-maze. They associated it with the tube-dominance test. deficits in social memory [29, 30]. At the same age, o Common genetic mechanisms link sensorimotor male Thy1-hAPPL nd/Swe+ mice assessed in this test gating deficits with abnormal social behavior. For also displayed reduced social interest, interpreted by instance, Dvl1 knock out mice modeling psychotic decreased social memory or discrimination [31]. 23- disorders show differences in whisker trimming, month-old female Tg2576 mice are also impaired in deficits in nest-building, less huddling sleeping, sub- social memory and open-field habituation tests [32]. ordinate responses, and deficits in acoustic and tactile The present work using a social paradigm of prepulse inhibition [11]. In the case of 3xTgAD mice, genotype and sex-matched dyads contributes to this spectrum is only partially observed as impaired the growing efforts to study social behaviors in individual [24] and group [25] nesting, some deficits rodents [1,9] with special attention to its complex- in their prepulse startle response [26], social alter- ity in models of AD (i.e., [25, 27, 29–31]). This is ations when interacting with NTg mice [27], and here important because several studies have shown that we report reduced social interaction with congeners social environment (rearing conditions, enrichment, in SIT and lack of whisker trimming. However, sleep- cohabitation, isolation, psychosocial stress) can be ing behavior was found intact. determinant and exert distinct impact in cognitive These differences in social behavior of 3xTg-AD and BPSD-like symptoms as well as underlying neu- mice may be associated not only to their prominent robiological substrates and AD neuropathology [30, anxious-like profile exhibited since young adulthood 33–35]. Finally, we propose that the identification of [8]. Several authors postulate it can be influenced by genotype- and sex-specific variables of behavior that apathy, agitation, possible deficits social memory, all can be used as signatures are of special interest for considered as first clinically symptomatic manifes- behavioral monitoring of animals in husbandry rou- tations of AD [6, 28]. Bories et al. [27], the first tines as well as in the follow-up during the assessment to report both sex- and age-dependent alterations in of preventive/therapeutic strategies, mainly in female social behavior in the 3xTg-AD mice, evaluated the sex which is the one at higher risk of developing the deficits in terms of normal/enhanced/reduced pat- disease [36]. terns measured as sniffing, crawling over or under, following, escape behavior, and grooming the part- ner. In their social interaction paradigm, they tested ACKNOWLEDGMENTS 3xTg-AD versus NTg pairs of aged- and sex-matched animals, minimizing the occurrence of aggressive We thank Prof. Frank M LaFerla Institute for behaviors and anxiogenic situations, as also shown Memory Impairments and Neurological Disorders, by no differences in grooming behavior observed Department of Neurobiology and Behavior, Univer- during the SIT. In their work, the authors reported sity of California, Irvine, USA, for kindly providing that male dyads of one 3xTg-AD mice with NTg the progenitors of the Spanish colonies of 3xTg-AD partners showed similar number of social events in and NTg mice. The work has been supported by the SIT at 12 months of age but social disinhi- Instituto de Salud Carlos III – Subdirección General bition at 18 months. In contrast, females showed de Evaluación y Fomento de la Investigación (AES- an advanced pattern with disinhibition followed by PI10/00283), co-financed by the European Regional decreased sociability. Most importantly, as shown by Development Fund (ERDF), 2017-SGR-1468 and correlation analysis, social changes were not related ArrestAD H2020 Fet-OPEN-1-2016-2017-737390 to genetically-induced amyloid-␤ or tau neuropatho- to LGL. logical hallmarks of disease. 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