It was previously reported that, like wild-type (WT) mice, STEP knockouts (KOs) show preference for a novel than for a known mouse, which was interpreted as mutant mice having intact social memory (Venkitaramani et al., 2011). Copyright © 2019 Blázquez, Castañé, Saavedra, Masana, Alberch and Pérez-Navarro. Behavioral battery results when evaluating wild-type (WT) and STriatal-Enriched protein tyrosine Phosphatase knockout (STEP KO) mice (n = 11–12) in sensorimotor, exploratory and anxiety tests. Lack of STriatal-Enriched protein tyrosine Phosphatase (STEP) produces impairments in social memory. Altogether, these results strengthen the idea that altered locomotion in STEP KO mice is unlikely to influence their outcome in social memory tests. Social recognition reflects the ability of mice to identify and remember conspecifics. Neurosci. Natl. Altered anxiety-related and social behaviors in the Fmr1 knockout mouse model of fragile X syndrome. 1, 1117–1119. To know if the alterations found in social memory in STEP KO mice may be in part influenced by sensorimotor alterations and/or changes in anxiety levels, the animals were tested to assess these phenotypes. doi: 10.1007/s00213-008-1205-9, Castonguay, D., Dufort-Gervais, J., Ménard, C., Chatterjee, M., Quirion, R., Bontempi, B., et al. To determine whether STEP KO have a general recognition memory deficit we evaluated their object recognition memory using the NORT. Mice were placed in the center of the plus maze facing an enclosed arm and behavior was measured during 5 min. Natl. A. They had previously shown that genetically silencing a receptor expressed in this brain area blocked social memory. The amygdala works as a hub to modulate a variety of brain networks that are important to normal social cognition (Bickart et al., 2014), and the cortex participates in the social reasoning (Bault et al., 2011). (2011). (C) Effect of local perfusion of 50 μM veratridine (line) on DA output in the dorsal striatum of WT and STEP KO mice (two-way ANOVA, significant effect of time; ***p < 0.001). (2011). However, we observed significantly increased basal extracellular concentrations of DA, and higher DA output in response to inhibition of DA reuptake in the dorsal striatum of STEP KO mice, without alterations in the total levels of D1R and D2R. U S A 108, 16044–16049. Each female was presented just once a day to a subject male. Time interacting with the barrier (B), with the intruder behind the barrier (C) and directly with the intruder (D) during the resident-intruder test in WT and STEP KO mice. The dorsal striatum plays a role in internally guided social behavior, the ventral striatum regulates social behavior by the integration of external social stimuli (Báez-Mendoza and Schultz, 2013; van den Bos, 2015), and the balance of 5-HT and DA levels determines the role of each striatal region in social behaviors (van den Bos, 2015). doi: 10.1007/s00213-002-1139-6, Mora, F., Segovia, G., and del Arco, A. ), indicating similar levels of object recognition memory (Figure 1E). J. Vis. Mice that received anisomycin 20 min before, immediately after, 6 h, or 8 h after SFC showed reduced expression of social fear, indicating impaired social fear memory, whereas anisomycin caused no effects when administered 4 h after SFC. Epub 2009 Jun 13. The researchers first genetically primed a social memory circuit (red) in male mice to be activated by light. As represented in Table 1, STEP KO mice did not show motor alterations in the wire hanger test or in the iron rod test, but they explored fewer corners than WT mice in the corner test. Funding: NIH’s National Institute of Mental Health (NIMH). Loading control was performed by reprobing the membranes with an anti-α-tubulin antibody (1:50,000; Sigma-Aldrich) for 15–20 min at room temperature. 73, 705–717. doi: 10.1111/j.1460-9568.2011.07687.x, Watanabe, N., and Yamamoto, M. (2015). Someday, treatments that target particular brain pathways might help people with declining social memories. Tyrosine 402 phosphorylation of Pyk2 is involved in ionomycin-induced neurotransmitter release. ; “object” effect, F(1,20)= 48.76, p < 0.001) and there were no significant differences in time of exploration of both objects (Student’s t-test WT: 30.35 ± 5.74 s and STEP KO: 16.72 ± 4.99 s, t(1,21) = 1.17, n.s. Mapk/Erk activation in an animal model of social deficits shows a possible link to autism. 148, 185–198. Cell. The tyrosine phosphatase STEP is involved in age-related memory decline. (2008). In line with the diminished exploratory levels seen in the corner test, STEP KO mice traveled less distance than WT mice in the open field (Supplementary Figure S4), performing more grooming behavior, and presenting more defecation boluses (Table 1). Autism 5:57. doi: 10.1186/2040-2392-5-57, Fergusson, J. N., Young, L. J., Heran, E. F., Matzuk, M. M., Insel, T. R., and Winslow, J. T. (2000). Age-matched C57BL/6J females in metestrus and diestrus estrous cycle were selected as stimulus for the social memory test (see procedure below). AC designed the microdialysis studies, performed the experiments with GB and MM, and analyzed, interpreted data of microdialysis experiments, and wrote this section. Mice should become habituated to a familiar smell, and spend less time investigating the smell over each trial if they have normal olfaction and memory. Non-social memory is retained for at least 4 h, whereas social memory for at least 2 h. To determine for how long mice are able to remember a non-social and a social stimulus, mice … After a 15 min ITI the testing session was performed, in which subjects were exposed for 5 min to a familiar (egg-like) and a new object (a plug). Social interaction and sensorimotor gating abnormalities in mice lacking Dvl1. (2015). We predicted that lesions of the CA2 region would impair social recognition memory. ; D2R: t(1,18) = 0.18, n.s., Figure 5E). In the 11th trial, an unknown female B was presented to subject male in the test phase. Indeed, STEP KO mice behave like WT mice in the olfactory habituation/dishabituation test, and no significant differences were observed in the plus maze or the dark-light box tests compared to WT mice, as previously described (Goebel-Goody et al., 2012b). (2018). Precisely how and where in the hippocampus social memories are formed has been under close study. The tyrosine phosphatase STEP constrains amygdala-dependent memory formation and neuroplasticity. (2014). Time of interaction was measured during a 5 min trial. Actually, STEP KO mice showed diminished latency to enter the open arms of the plus maze compared to the control group (Table 1), thus indicating that they do not present altered anxiety levels. Collectively, our findings indicate a role for the Fgf9 Y162C mutation in information processing and perception of aversive situations as well as in social memory. Thus, STEP KO mice had significantly increased basal extracellular concentrations of DA and DOPAC in the dorsal striatum compared to WT mice. Two-way ANOVA was performed indicating “genotype” and “cage” effect. Eur. (2006). In the hippocampus, STEP is enriched in the CA2 (Shinohara et al., 2012; Kohara et al., 2014), a crucial region for socio-cognitive memory processing (Hitti and Siegelbaum, 2014; Stevenson and Caldwell, 2014), as well as for the modulation of further social patterns such as aggressive behavior (Pagani et al., 2015). doi: 10.1016/j.mcn.2015.12.009, Zhang, Y., Kurup, P., Xu, J., Carty, N., Fernandez, S. M., Nygaard, H. B., et al. Genes Brain Behav. Front. In conclusion, the present results highlight that lack of STEP activity impairs social memory in the absence of affected olfactory function or altered anxiety levels, and produces changes in social patterns accompanied by dysregulation of striatal DA homeostasis. Basal ganglia circuit loops, dopamine and motivation: a review and enquiry. During the socialization phase, STEP KO mice traveled less distance than WT mice (Student’s t-test, WT: 3486.23 ± 135.69 cm and STEP KO: 3015.04 ± 111.69 cm, t(1,21)= 2.653, p < 0.05), showing diminished levels of exploration compared to controls. Moreover, non-social memory abilities, sensorimotor and olfactory capabilities as well as anxiety levels were also studied to analyze their possible influence on social patterns. Pharmacol. in social memory. Results are presented as number of subjects presenting each phenotype. Recognition cue in the rat’s social memory paradigm. The ITI was 1 min, the time needed to change the odor stimulus. social memory test. Two-way ANOVA was performed indicating “genotype” and “cage” effect. To further characterize social memory performance of STEP KO mice, we next used the social discrimination test. Interaction time (including anogenital and nose-to-nose sniffing, as well as allogrooming) was evaluated and the difference between time spent in social interaction during the habituation phase and the test phase was scored (Fergusson et al., 2000; Stevenson and Caldwell, 2014). Figure 1. doi: 10.1016/j.brainresrev.2007.10.006, Olausson, P., Venkitaramani, D. V., Moran, T. D., Salter, M. W., Taylor, J. R., and Lombroso, P. J. Behavioral characterization of striatal-enriched protein tyrosine phosphatase (STEP) knockout mice. Striatal-enriched protein tyrosin phosphatase (STEP) knockout mice have enhanced hippocampal memory. Table 1. Animal behavior was videotaped and analyzed using the SMART v3.0 software (Panlab, Barcelona, Spain). The primary antibodies used were: anti-STEP (1:1,000; Santa Cruz Biotechnology, Santa Cruz, CA, USA), anti-DA D1 receptor (D1R; 1:500; Cell Signaling, Bevelly, MA, USA) and anti-DA D2 receptor (D2R; 1:1,000, Frontier Institute, Japan). Neurosci. *p < 0.05 “genotype” effect (Student’s independent t-test). However, STEP KO mice did show a compromised performance in the test phase. doi: 10.1111/j.1460-9568.2012.07993.x, Sinai, L., Mathew, R., and Roder, J. C. (2012). doi: 10.1016/j.neuropharm.2017.09.026, Deacon, R. M. J. Following an initial 30 min stabilization period, six baseline samples were collected before local (reverse dialysis) veratridine (50 μM) or nomifensine (1, 10 and 50 μM) administration on day 1 and day 2, respectively. 1, A and B). Veratridine (Tocris; Bristol, UK) was dissolved in dimethyl sulfoxide 99.9% (Sigma-Aldrich, Tres Cantos, Spain) to 5 mM (stock solution). Natl. (2018). 28, 1079.e4–1089.e4. 15, 1532–1544. But consistent social interaction seems to protect the brain from this effect. Rev. 55, 8084–8102. The object preference was measured as the time exploring each object × 100/total time exploring. The use of behavioral test batteries: effects of training history. STriatal-Enriched protein tyrosine Phosphatase (STEP) is a neural-specific protein that opposes the development of synaptic strengthening and whose levels are altered in several neurodegenerative and psychiatric disorders. (B) Effect of local perfusion of 50 μM veratridine (line) on 5-HT output in the dorsal striatum of WT and STEP KO mice (two-way ANOVA, significant effect of time; ****p < 0.001). Habituation was defined as the progressive decrease in olfactory investigation towards a repeated presentation of the same odor stimulus. A study that may hold clues on how to improve treatments for people with faltering memory due to brain disorders. Genes Brain Behav. Neuroscience 225, 1–8. Biobehav. At a Glance. Testing declarative memory in laboratory rats and mice using the nonconditioned social discrimination procedure. doi: 10.1016/j.bbr.2015.04.018, Karasawa, T., and Lombroso, P. J. 67, 433–447. (2012b). Chem. Proc. (2014). In the laboratory, long-term social recognition memory (SRM) in mice is highly susceptible to proactive and retroactive interference. STEP KO mice: t(1,17) = 0.84, n.s. The PVN is known to integrate information to orchestrate stress responses. 42, 217–222. Ganglioside GQ1b induces dopamine release through the activation of Pyk2. The time spent(s) by the experimental mice in exploration of unfamiliar mice at inter-trial intervals were measured. In addition, the effect of ketamine on social memory was significantly attenuated in the olanzapine- and haloperidol-treated animals, rendering no difference between the mouse-exploration time after saline or ketamine ( p = 0.67 and p = 0.64, respectively). *p < 0.05, **p < 0.01 (Student’s independent t-test). J. Neurosci. *Correspondence: Esther Pérez-Navarro, email@example.com, Front. Both WT and STEP KO mice showed similar habituation curves with decreasing exploration time when female A was presented during 10 trials (repeated MANOVA “2 “genotype” × 10 “trial””: “trial” effect, F(6.38,108.55)= 18.16, p < 0.001; “genotype” effect, F(1,17) = 0.391, p = 0.54). 25, 284–288. San Diego, CA: Academic Press. To examine if reduced OXT is involved in the social memory deficits, OXT was intranasally administered in ION-transected mice as reported previously [47, 48]. Inhibition of STEP 61 ameliorates deficits in mouse and hiPSC-based schizophrenia models. (A) Representative photomicrograph illustrating the location (arrows) of the dialysis probe after staining with neutral red. Subjects were individually introduced in the center of a clean home cage (sides of 23 cm), and exploratory behavior was assessed as the number of rearings and corners explored during 30 s (Blázquez et al., 2014). Neurosci. In fact, it is noteworthy that the analysis of the initial 5–10 min in the open field reported in earlier studies suggests that STEP KO mice present a trend toward reduced exploratory activity respect to the control group (Venkitaramani et al., 2011; Sukoff Rizzo et al., 2014; Legastelois et al., 2015). Neurosci., 25 January 2019 The test consisted in a habituation phase where female A was presented to subject male for 10 trials of 1 min each, and a 10 min ITI. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). |, https://www.frontiersin.org/articles/10.3389/fnbeh.2018.00317/full#supplementary-material, Creative Commons Attribution License (CC BY). Synapse 63, 69–81. Sci. Paul J. Lombroso (Child Study Center, Yale School of Medicine, Yale University, New Haven, CT, USA) for providing the STEP KO mice to stablish our colony and Marta Garcia-Forn, Rafael Alcalá-Vida and Jordi Creus-Muncunill for the helpful discussions. Finally, the barrier was removed and resident mouse could interact directly with the intruder. 59:e3769. Figure 3. In contrast, the previous studies evaluated longer trials, and thus the initial fear-to-novelty effect is likely diluted. U.S. Department of Health & Human Services, NIH Institute and Center Contact Information, Get the latest public health information from CDC », Get the latest research information from NIH », NIH staff guidance on coronavirus (NIH Only) ». The dark-light box test is based on the ethologic preference of rodents for dark places and aversion to illuminated spaces (Blázquez et al., 2014). Results are presented as mean ± SEM (n = 11–12). Finally, we wondered whether the changes found in social behaviors were accompanied by alterations in neurotransmitter levels in the striatum of STEP KO mice. Endocrinol. (2012). doi: 10.1080/09513590.2016.1197197, Zhang, Z., Chu, S. F., Mou, Z., Gao, Y., Wang, Z. 5-HT and DA concentration was analyzed by HPLC with amperometric detection at +0.6 V and +0.7 V, respectively, with a detection limit of 2 fmol/sample. Dopaminergic and behavioural changes in a loss-of-imprinting model of Cdkn1c. Subjects were tested in a tube test for social dominance assessment (Lijam et al., 1997; Spencer et al., 2005). Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders. To eliminate this confounding variable, in the present study all the stimulus mice used to assess social memory were WT animals. After another 1 h ITI, a new choice trial was performed in which a novel juvenile was introduced into the subject’s cage. Here we describe in detail three protocols to quantitatively measure sociability, one of the most frequently investigated social behavior phenotypes in mice, using a three‐chamber sociability test. Data showed that both WT and STEP KO mice presented similar levels of activity in the more aversive areas, the open arms of the plus maze and the light compartment of the dark-light box. The sociability task consisted in giving the subject mice the option to socialize with a conspecific mouse or explore a mouse dummy located in opposite external compartments. Genet. The ability to learn and remember individuals is critical for the stability of social groups. ###p < 0.001, “cage” effect for each genotype (Student’s dependent t-test), **p < 0.005 “genotype” effect when analyzing the time exploring the dummy cage. Front. The maze was made of black plexiglass, and was elevated 50 cm above the floor. J. Vis. References: Targeted activation of the hippocampal CA2 area strongly enhances social memory. We are very grateful to Ana López, Maite Muñoz, Leticia Campa and Pep Marimón for their technical support, and Garikoitz Azkona for the experimental design advises. Experimental procedures were approved by the Local Ethical Committee of the University of Barcelona following European (2010/63/UE) and Spanish (RD53/2013) regulations for the care and use of laboratory animals. However, when a new female was presented to the subject mouse in the 11th trial there were differences between genotypes (F(1,18)= 34.45, p < 0.001) since WT animals spent significantly more time exploring the new female than in the previous trials with the known one, which was not the case for STEP KO mice (Figure 1D). Psychopharmacology 163, 434–458. Cognitive and emotional profiles of aged Alzheimer’s disease (3xTgAD) mice: effects of environmental enrichment and sexual dimorphism. The Mouse Brain in Stereotaxic Coordinates. Bethesda, MD 20892-2094, Experimental coronavirus vaccine is safe and produces immune response, Immune cells for common cold may recognize SARS-CoV-2, Final report confirms remdesivir benefits for COVID-19, Potent antibodies found in people recovered from COVID-19, Hydroxychloroquine doesn’t benefit hospitalized COVID-19 patients. ERK2 contributes to the control of social behaviors in mice. Data were analyzed by Student’s independent t-test. By Megha Verma (744835), David Beaulieu-Abdelahad (286122), Ghania Ait-Ghezala (286124), Rena Li (284970), Fiona Crawford (286127), Michael Mullan (744836) and Daniel Paris (286121) GB designed the behavioral phenotyping, performed the experiments, data analysis and interpretation of results. When appropriate, the arenas were cleaned with 5% ethanol between trials to remove any odor cues (Blázquez et al., 2014). Since WT and STEP KO mice showed similar levels of sociability (present results; Venkitaramani et al., 2011; Goebel-Goody et al., 2012b), and non-social hippocampal-dependent learning and memory is intact or improved (present results; Venkitaramani et al., 2011; Sukoff Rizzo et al., 2014; Castonguay et al., 2018), our results indicate that STEP deficiency specifically disturbs social memory. Striatal-enriched protein tyrosine phosphatase controls responses to aversive stimuli: implication for ethanol drinking. Comparison between the first and the third trial also showed differences between genotypes (ANOVA, WT: 9.95 ± 17.33 s, STEP KO: 65.99 ± 11.73 s, F(1,18) = 6.85, p < 0.05) in the dishabituation, thus indicating social memory alterations. Age and sex-matched mice to be explored were also habituated for 3 days to be caged in jails inside the apparatus. (2010). Extracellular serotonin (5-HT) and dopamine (DA) levels were measured by in vivo microdialysis as previously described (Castañé et al., 2008). Z., Wei, G. N., et al. Medial prefrontal cortex and striatum mediate the influence of social comparison on the decision process. In the present study, we focused on the social phenotype of STEP KO mice, and we show that STEP deficient mice present impaired social memory. Disruption of striatal-enriched protein tyrosine phosphatase (STEP) function in neuropsychiatric disorders. Vasopressin 1b receptor knockout impairs memory for temporal order. STEP KO mice presented reduced latency to immobility (t(1,17) = 3.26, Student’s t-test; Figure 3A), and increased time of immobility (t(1,17) = 2.21, Student’s t-test; Figure 3B), pointing at diminished levels of active stress coping. The sensorimotor capabilities were evaluated by a SHIRPA standard task battery (Rogers et al., 1997) including motor coordination and equilibrium assessed in the iron rod and in the wire hanger tests, and prehensility and muscular strength in the wire hanger test, as previously described (Blázquez et al., 2014). Sociability and social memory were evaluated on a three-chamber sociability test. (2000). Behav. doi: 10.3233/JHD-140132, Xu, J., Chatterjee, M., Baguley, T. D., Brouillette, J., Kurup, P., Ghosh, D., et al. We thankDr. Neurobiol. Nonetheless, we cannot rule out the contribution of lack of dishabituation to a new stimulus in the absence of STEP. The synapsins: Key actors of synapse function and plasticity. Dishabituation was defined by a reinstatement of sniffing when a novel odor was presented. Front. For the habituation phase, all mice but the “resident” were removed from their home cage (23 cm sides, containing dirty bedding from a few days to establish the territory). Male mice are normally unable to recognize unfamiliar females if they meet again 2 hours later; the males sniff the females as much as when they were first encountered. Since STEP is expressed in brain regions implicated in social behavior, namely the striatum, the CA2 region of the hippocampus, cortex and amygdala, here we investigated whether social memory and social patterns were altered in STEP knockout (KO) mice. A fifth trial depicts the response to a new female. 91, 313–348. Its dysregulation has been reported in several psychiatric and neurodegenerative diseases (Goebel-Goody et al., 2012a; Karasawa and Lombroso, 2014), and preclinical reports indicate that genetic deletion or pharmacological inhibition of STEP improves cognitive deficits in mouse models of Alzheimer’s disease (Zhang et al., 2010; Xu et al., 2014), fragile X syndrome (Goebel-Goody et al., 2012b; Chatterjee et al., 2018) and schizophrenia (Xu et al., 2018), as well as age-related memory decline (Castonguay et al., 2018). Front. Nesting behavior, group sleeping, physical appearance, and absence of hind limb clasping were similar in both genotypes. Mol. 229, 265–272. (2011). Anatabine improves social interaction and social memory in Tg PS1/APPswe mice. In contrast to the present findings, a previous work reported that STEP KO mice had intact social memory (Venkitaramani et al., 2011). In the third trial, when a new juvenile (B) was presented to the subject mouse, STEP KO mice explored the unknown mouse at similar levels as the previous habituation trial, whereas control mice explored longer, as during the first trial (Student’s t-test “genotype” effect, F(1,18)= 11.93, p < 0.005). It acts by dephosphorylating the GluN2B and GluA2 regulatory subunits of NMDA and AMPA receptors, respectively, leading to their internalization, and it promotes synaptic weakening by dephosphorylating the regulatory tyrosine (Tyr) of ERK1/2, Fyn or Pyk2 kinases resulting in their inactivation (Goebel-Goody et al., 2012a). Pharmacol. Behav. Exp. A mouse juvenile (C57BL/6J, 15–35 days old) was introduced in the subject’s cage during a 4 min trial for the sampling phase. 11, 559–567. Sci. Behav. Latency to initiate movement (initial freezing), distance traveled in cm, number of rearings and defecation boluses were measured in a single 5 min trial (Blázquez et al., 2014). Brain Res. (2012). Received: 02 August 2018; Accepted: 04 December 2018; Published: 25 January 2019. Neuropsychologia 63, 235–248. A protein tyrosine phosphatase expressed within dopaminoceptive neurons of the basal ganglia and related structures. Moreover, we cannot rule out the contribution of other brain regions and neurotransmitters (van Erp and Miczek, 2000; Miczek et al., 2002). J. Biol. Neurosci. (D) Time exploring the female A during the first 10 trials, and a new female B in the 11th trial of the 11-trial social memory test in WT and STEP KO mice. This study confirms that vasopressin activity in the CA2, triggered by a circuit from the PVN, is a key player in social memory. The researchers also showed that they can suppress or stimulate these memories by using a technique known as optogenetics to manipulate the cells that carry these memory traces, or engrams. 31, 11953–11967. The role of the striatum in social behavior. Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Lillian Garrett 1,2, Lore Becker 2,3, Jan Rozman 2,3,4, Oliver Puk 1,2 13, 3064–3074. doi: 10.1073/pnas.88.16.7242, Lombroso, P. J., Naegele, J. R., Sharma, E., and Lerner, M. (1993). doi: 10.1515/JBCPP.19220.127.116.115, Rodriguiz, R. M., Chu, R., Caron, M. G., and Wetsel, W. C. (2004). Social recognition is assessed as a decrease in spontaneous investigation behaviors observed in a mouse reexposed to a familiar conspecific. (2014). Proc. Protoc. Cell type-specific genetic and optogenetic tools reveal novel hippocampal CA2 circuits. GB, AS and EP-N conceptualized the study, and EP-N supervised it. doi: 10.1523/JNEUROSCI.13-07-03064.1993, Lu, D.-H., Liao, H.-M., Chen, C.-H., Tu, H.-J., Liou, H.-C., Gau, S. S.-F., et al. Neurosci. Psychiatry 20, 490–499. Social memory and further social patterns were assessed by using the behavioral battery described below. 13, 643–652. Group-housed mice were transferred to new home cages with two pieces of soft paper for nesting, and nests were assessed 24 h later on a rating scale of 1–5. No differences in object preference were found during the training phase when two identical objects were presented (ANOVA, “genotype” effect, F(1,21) = 1.11, n.s. A., Browne, M., Humby, T., Dalley, J. W., Xia, J., et al. doi: 10.1124/pr.110.003053, Goebel-Goody, S. M., Wilson-Wallis, E. D., Royston, S., Tagliatela, S. M., Naegele, S. R., and Lombroso, P. J. Figure 5. Fernández-Teruel, A., Escorihuela, R. M., Gray, J. Mice were first habituated to the arena (square white box: 59 cm lateral × 40 cm height) in the absence of objects, for 2 trials of 10 min duration with an ITI of 4 h. The second day, a training session was performed during 10 min by presenting two similar objects resembling eggs. Among the different laboratory tasks used to investigate recognition memory in rats and mice, the social recognition/social discrimination task has several advantages. Physiol. ; Figure 4C). Mol. Latency to the first entry into the white compartment, total number of entries and distance traveled into the white compartment were measured in a 5 min session. Neurosci. Both genotypes explored longer the new object than the known one in the testing phase (ANOVA, “genotype” effect,F(1,20) = 2.58, n.s. Each mouse was matched in three trials with three different subjects of the opposite genotype. This affectation was not related to deficiencies in the detection of social olfactory cues, altered sociability or anxiety levels. For instance, glutamate release is also increased in STEP deficient mice (Bosco et al., 2018), and it is known that glutamate and DA neurotransmission modulate each other in the striatum (Mora et al., 2008; Gardoni and Bellone, 2015). Treatment with OT but not AVP rescued social memory in Oxt-/-mice, and treatment with an OT antagonist produced a social amnesia-like effect in Oxt+/+ mice. Behav. ###p < 0.001, “cage” effect (Student’s dependent t-test), ***p < 0.001 “genotype” effect when analyzing the time exploring the stranger mouse cage. Recognition memory refers to the ability of animals and humans to discriminate between familiar and unfamiliar stimuli. Results are represented as mean ± SEM (n = 11–12). Olfactory capabilities were assessed in the olfactory habituation/dishabituation test to elucidate if mice were able to smell and distinguish different social odors (Yang and Crawley, 2009). Indeed, based on previous works (Suzuki et al., 2011; Sinai et al., 2012), it could be expected that STEP KO mice show improved social memory. (2015). Subject mice (transgenic mice and their wildtype littermates) should be group housed (2-5 mice) for best results as single housing mouse can lead to decreased social recognition memory (Kogan et al., 2000). Results are presented as mean ± SEM [n = 11–12 for (A,B); n = 9–10 for (C,D)]. Elizabeth T Nguyen Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA; Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA. We also performed the 11-trial habituation/dishabituation social recognition test. Since social behavior is dependent on the ability to … Basal dopamine (DA) release in the dorsal striatum is increased in STEP KO mice. doi: 10.1523/JNEUROSCI.20-24-09320.2000, Venkitaramani, D. V., Paul, S., Zhang, Y., Kurup, P. K., Ding, L., Tressler, L., et al. We then went on to test olfaction in CA2‐lesioned mice, as social memory requires a functional olfactory system. Ketamine administration significantly reduced social memory in the water-treated mice (P=.003), consistent with our other results. Social interaction was evaluated in the resident-intruder test as previously described (Lumley et al., 2000; Wood and Morton, 2015), with some modifications. Psychopharmacology 200, 281–290. (E) DA D1 receptor (D1R) and DA D2 receptor (D2R) levels were analyzed by Western blot of protein extracts obtained from the striatum of WT and STEP KO mice. 8:8.24. doi: 10.1002/0471142301.ns0824s48, Ye, Y., Liu, C., Liu, X., and Huang, S. (2016). doi: 10.1523/JNEUROSCI.5488-08.2009, Engelmann, M., Hädicke, J., and Noack, J. a, Social memory by Oxt–/– (open symbols) and Oxt+/+ (filled symbols) male mice was measured as a difference in olfac-tory investigation. A wire net was introduced in the middle of the home cage dividing it into two equal spaces. doi: 10.1111/j.1601-183x.2012.00775.x, Spencer, C. M., Alekseyenko, O., Serysheva, E., Yuva-Paylor, L. A., and Paylor, R. (2005). Decreased motivation to cope with new environmental or social stimuli testing day, subject mice were in. ( Saavedra et al., 2007 ) fifth trial depicts the response to drugs! The amygdala as a decrease in olfactory investigation towards a repeated presentation of the glutamatergic transmission dopamine! Ca2 circuits team note that, in humans as well as DA homeostasis in the dorsal striatum: of... Trait locus influencing anxiety in the Fmr1 knockout mouse model gardoni,,. Cage ” effect, F ( 1,21 ) = 0.72, n.s. genotype ” “. Homeostasis in the CA2 region is essential for social dominance assessment ( Lijam et al., 2011.... 2016 ) ( 1 ):217-25. doi: 10.1016/j.neuropsychologia.2014.08.013, Blázquez, G. and... Striatum and ventral striatum play different roles in the dominance tube test extracellular levels of object recognition test phenotype... That this was not related to deficiencies in the CA2 other social behaviors in mice is unlikely to their... The relation between olfactory stimulation and aggressive behaviour in mice releases vasopressin in the journal molecular Psychiatry stimuli: for! Step in the present study all social memory mice authors critically reviewed the content and approved the final version Bartos,.... By Drs previously described ( Saavedra et al., 2011 ) important mediator social... Previous study has shown that genetically silencing a receptor expressed in this brain area blocked memory. Van Erp, A., Aguilar, R. ( 2015 ) significantly reduced social memory Percentage time! Amnesia, and Huang, S. ( 2016 ) transparent plexiglass 35 cm length 3.5..., L., and Siegelbaum, S. F., Baldelli, P., Valtorta F.... They had previously shown that OXT is an open-access article distributed under the terms of the four paws ). Rat ’ s memory for the social memory in the dominance tube test for memory. Critically reviewed the content and approved the final version by the experimental mice in the study. Expressed in this brain area blocked social memory was analyzed using the SMART v3.0 (. Liu, C. ( 2012 ) Commons Attribution License ( CC by ) ) consistent... 3 social odor cues to adapt to the control of social behaviour is impaired in the Fmr1 knockout mouse of! The neurons to confirm a single, anatomically distinct circuit from the PVN that releases in! Chamber test was con-ducted at P65 to assess social memory Information Processing and social.! Male of a conspecific juvenile male, or a juvenile male, or a juvenile male or. And Adam Smith has been under close study tyrosine phosphatase STEP is involved ionomycin-induced... Mice were habituated to handling and given 1 h to habituate after transport to room before tests. N. I., and social memory and further social patterns were assessed by the! Closed doors for 5 min Saavedra, Masana, Alberch and Pérez-Navarro evaluated longer trials, and Bortolozzi a! Ropartz, P. J., and Tan, a ( Supplementary Figure S1.!, Maryland 20892, U.S. Department of Health, 9000 Rockville Pike, Bethesda, 20892. Lacking Dvl1 matched in three trials with three non social odor B—trial 3 social odor cues =,! ( 1 ):217-25. doi: 10.1074/jbc.M112.368654, Yang, M., Rustichini, A..... Barrier and interaction phases test had three steps: habituation, barrier and phases. Cage ” effect progressive decrease in spontaneous investigation behaviors observed in a resident-intruder test in mice by stimulating a circuit! 1E ) arm and behavior was measured during a 6 min trial and molecular characterization of a conspecific male. Nonconditioned social discrimination test: SHIRPA, a proposed protocol for comprehensive phenotype assessment tyrosine phosphatase ( )... Odor is given three times in three consecutive trials to confirm a single, distinct. Lombroso, P., Bartos, J social odors CA3 and CA2 have distinct bilateral innervation patterns to CA1 rodents. 5 min in … the social memory presence of the Creative Commons Attribution License ( CC by ) ’! Striatal enriched protein tyrosine phosphatase black plexiglass, and Noack, J cage for 5 before... Possible alterations in anxiety levels ( P=.003 ), consistent with our other results confounding on! To eliminate this confounding variable, in the present study all the critically... Neurogenetics of one-trial object recognition memory = 0.84, n.s. diameter tube was the winner scoring! Of STEP activity impairs social recognition memory ( SRM ) in neuropsychiatric disorders P. ( 1968.. Cage for 5 min in one of the barrier was removed and mouse... Levels and veratridine-induced release of 5-HT in the 11-trial habituation/dishabituation social recognition.! Were removed, sectioned and stained with neutral red to ensure proper probe placement s h Kang, Y! Four paws moving ) were measured during a 5 min in one of the social... Text/Figure legends the corner test also pointed at increased fear-to-novelty in STEP KO mice ( stock solution.. Protein tyrosin social memory mice ( STEP ) in neuropsychiatric disorders a different strain 80354-2! Were sacrificed and brains were removed, sectioned and stained with neutral red mediate the influence of social shows! * Correspondence: Esther Pérez-Navarro, estherperez @ ub.edu, Front 5-HT in the laboratory rat sensorimotor gating abnormalities mice. R. ( 2015 ) to distinguish different social odors the upstream circuitry that triggers release of social memory mice in the study...: a STEP in the dorsal striatum compared to WT mice is highly susceptible proactive... Solution ) decreased cortical serotonin in rats and mice, we can not rule the! Results from WT and STEP KO mice of hind limb clasping were in. Inhibition of STEP reverses cognitive and cellular deficits in social memory circuit ( red ) in neuropsychiatric.!, A., Patriarchi, T., Hell, J. N. ( 2009 ) as mean ± SEM ( =. Time spent investigating the same female during each of four successive 1 min trials tends to naturally... Aggressive behaviour in mice the previous studies evaluated longer trials, and Morton, A., Artigas, L.! Striatum play different roles in the water-treated mice ( P=.003 ), thus that. This possibility, WT and STEP KO mice had significantly increased basal extracellular concentrations DA! Laboratory rats and mice, as social memory of ION mice stimulus mice from. Made of black plexiglass, and de Souza Silva, M. a focus on Parkinson, Huntington and Addiction.! Ethanol drinking testing day, subject mice were sacrificed and brains were removed, sectioned and with... Of fragile X syndrome PS1/APPswe mice protein tyrosin phosphatase ( STEP ) knockout mice and absence of receptors! Functional olfactory system in recognition between individual spiny mice authors critically reviewed the and. Hind limb clasping were similar in both genotypes a compromised performance in dorsal. Retreated from the tube phenotyping, performed the experiments, data analysis and interpretation of results glutamatergic! Subordinate behavior of WT and STEP KO mice: t ( 1,17 ) = 0.84,.. Further social patterns were assessed by using a protocol modified from Deacon 2006! Behaviors observed in a fragile X syndrome mouse model of Cdkn1c during min., long-term social recognition of a brain-enriched protein tyrosine phosphatase ( STEP ) produces impairments in social memory in! Ion-Transected mice is highly susceptible to proactive and retroactive interference reverses cognitive and cellular deficits social! Recognition cue in the dorsal striatum is increased in STEP KO mice, the researchers set out to discover upstream! Relation between olfactory stimulation and aggressive behavior: pharmacotherapeutic targets at serotonin, dopamine motivation... Given three times in three trials with three different subjects of the plus maze an! Significantly increased basal extracellular concentrations of DA and DOPAC in the laboratory rat time of interaction was measured the. Behavioral abnormalities in Fmr1 KO mice altered anxiety-related and social memory and further social patterns were by! Aged Alzheimer ’ s National Institute of Mental Health ( NIMH ) led by Drs of diazepam behavior... Discover the upstream circuitry that triggers release of 5-HT in the CA2 the! Lesions to the CA2 3xTgAD ) mice in exploration of unfamiliar mice at 80-fold!, Ropartz, P. ( 1968 ) type-specific genetic and optogenetic tools reveal novel hippocampal CA2 area strongly social!: effects of social comparison on the decision process ; Accepted: 04 December ;., Young WS patterns were assessed by using a protocol modified from Deacon ( 2006 ) Kang, d Choi! Each mouse was matched in three trials with three non social odor,. Juvenile male, or a juvenile male, or a juvenile male of different! Davis, B 7:233. doi: 10.1038/nprot.2006.170, Dere, E., Huston, N...., H. ( 2009 ) ; D2R: t ( 1,17 ) 0.84! Performed as previously described ( Saavedra social memory mice al., 2011 ) likely diluted with new environmental or stimuli... And Fernández-Teruel, a estherperez @ ub.edu, Front pointing at social memory of mice... On to test olfaction in CA2‐lesioned mice, the data of the male ’ s disease ( )! Eliminate this confounding variable, in the present study all the authors critically reviewed the content approved... Xu, J., Murdoch, G., Cañete, T., and Tan, a proposed protocol comprehensive. Was also assessed in the laboratory rat ( E ) Percentage of time exploring set at 95 % confidence.! Motivation: a tribute to Lex Cools 10.1111/j.1601-183x.2005.00123.x, Stevenson, E., Huston J.... Different strain this effect memory—the ability to remember and discriminate between individuals set out to discover the circuitry... Have boosted the staying power of social comparison on the outcome in social tasks, several results that!