Major Neurotransmitter Systems in Dorsal Hippocampus and Basolateral Amygdala Control Social Recognition Memory
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Major neurotransmitter systems in dorsal hippocampus and basolateral amygdala control social recognition memory Carolina Garrido Zinna, Nicolas Clairisb, Lorena Evelyn Silva Cavalcantea, Cristiane Regina Guerino Furinia, Jociane de Carvalho Myskiwa,1,2, and Ivan Izquierdoa,1,2 aMemory Center, Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul, 90610-000 Porto Alegre, RS, Brazil; and bDépartement de Biologie, Ecole Normale Supérieure de Lyon, 69007 Lyon, France Contributed by Ivan Izquierdo, June 21, 2016 (sent for review May 23, 2016; reviewed by Federico Bermudez-Rattoni and Julietta Frey) Social recognition memory (SRM) is crucial for reproduction, forming structures in SRM. Historically, the next step to ascertain a pu- social groups, and species survival. Despite its importance, SRM is tative brain mechanism in a behavior is to examine the eventual still relatively little studied. Here we examine the participation of role of known neurotransmitters in those structures within the the CA1 region of the dorsal hippocampus (CA1) and the basolateral mechanism (13, 15). amygdala (BLA) and that of dopaminergic, noradrenergic, and his- Classic neurotransmitters, such as norepinephrine, dopamine, taminergic systems in both structures in the consolidation of SRM. and histamine, have been suggested to play a role on SRM; the Male Wistar rats received intra-CA1 or intra-BLA infusions of different pharmacological elevation or depletion of norepinephrine in the drugs immediately after the sample phase of a social discrimination central nervous system, respectively, enhances or disrupts social task and 24-h later were subjected to a 5-min retention test. Animals recognition in rats (18). The direct infusion of the norepinephrine treated with the protein synthesis inhibitor, anisomycin, into either reuptake inhibitor, nisoxetine, into the olfactory bulb improves the CA1 or BLA were unable to recognize the previously exposed the ability of rats to identify conspecifics (19) and dopamine juvenile (familiar) during the retention test. When infused into the β-hydroxylase knockout mice that are unable to synthetize nor- CA1, the β-adrenoreceptor agonist, isoproterenol, the D1/D5 do- epinephrine show a SRM deficit (20). These findings suggest that paminergic receptor antagonist, SCH23390, and the H2 histamin- norepinephrine plays an important role in the formation of SRM ergic receptor antagonist, ranitidine, also hindered the recognition but there is a notable lack of knowledge about the role of the nor- of the familiar juvenile 24-h later. The latter drug effects were epinephrine receptors involved, especially the β-adrenoreceptors, more intense in the CA1 than in the BLA. When infused into the which have been shown to be important for other types of rec- BLA, the β-adrenoreceptor antagonist, timolol, the D1/D5 dopamine ognition memory: for example, object recognition (21–24) and receptor agonist, SKF38393, and the H2 histaminergic receptor ago- odor recognition (25–29). nist, ranitidine, also hindered recognition of the familiar juvenile 24-h There is also evidence that SRM can be modulated by dopa- later. In all cases, the impairment to recognize the familiar juvenile mine. During social interaction dopaminergic neurotransmission was abolished by the coinfusion of agonist plus antagonist. in the nucleus accumbens is enhanced (30, 31). Systemic ad- Clearly, both the CA1 and BLA, probably in that order, play major ministration and direct infusion into the nucleus accumbens or roles in the consolidation of SRM, but these roles are different in into the frontal cortex of D1 dopamine receptor agonist im- β each structure vis-à-vis the involvement of the -noradrenergic, proves SRM (32, 33) but systemic injection of D1 dopamine D1/D5-dopaminergic, and H2-histaminergic receptors therein. receptor antagonist disrupts social learning (32, 34). Evidence social memory | basolateral amygdala | hippocampus | norepinephrine | Significance dopamine The hippocampus and basolateral amygdala—modulated by ocial recognition memory (SRM) is essential for social inter- β-noradrenergic, D1/D5 dopaminergic, and H2-histaminergic Saction, adaptive social behavior, reproduction, and survival — – receptors control memory processing of many memories, but (1 6). In rodents, SRM is assessed by using their natural tendency their role in social recognition memory (SRM) has been little to investigate unfamiliar conspecifics more persistently than fa- studied. SRM is fundamental for the establishment of social miliar ones in what has become known as the social-discrimination relationships and, consequently, for the formation and stability paradigm (3, 5, 7–9). This discrimination relies largely on odor “ ” of social groups. The social deficits of psychiatric disorders, recognition by rodents, called by many social odor (10). Other such as autism and schizophrenia, are believed to be caused by sensory are deemed much less important for social recogni- alterations in SRM processing by the hippocampus and amyg- tion (10, 11). dala. Here we examine the involvement of the hippocampus To establish whether a given brain structure or cellular en- and basolateral amygdala—and β-noradrenergic, D1/D5 dopa- semble is important for a given type of behavior, the effect of minergic, and H2-histaminergic receptors therein—in SRM protein synthesis inhibition in that structure on the particular consolidation. The results suggest an important and complex behavior is often measured; if a deleterious effect is found, then modulation of this process, which may help to elucidate the the structure is assumed to play a role in that behavior (for ex- basis of inappropriate social behavior in psychiatric patients. ample, see refs. 3 and 12). After this process, some key bio- chemical processes related to protein synthesis would be studied Author contributions: C.G.Z., N.C., C.R.G.F., J.d.C.M., and I.I. designed research; C.G.Z., (13, 14). In the case of SRM, Kogan et al. (3) showed that, in N.C., L.E.S.C., and C.R.G.F. performed research; C.G.Z., N.C., L.E.S.C., C.R.G.F., J.d.C.M., mice, SRM is dependent upon protein synthesis and cyclic and I.I. analyzed data; and C.G.Z., J.d.C.M., and I.I. wrote the paper. adenosine monophosphate responsive-element-binding protein Reviewers: F.B.-R., National University of Mexico; and J.F., Lunds University. (CREB) function in the hippocampus. Given the fact that the The authors declare no conflict of interest. hippocampus and the basolateral amygdala (BLA) work in close 1J.d.C.M. and I.I. contributed equally to this work. association in the making and the regulation of many types of 2To whom correspondence may be addressed. Email: [email protected] or memory (13–17), we decided to study the participation of both [email protected]. E4914–E4919 | PNAS | Published online August 1, 2016 www.pnas.org/cgi/doi/10.1073/pnas.1609883113 Downloaded by guest on September 27, 2021 of the dorsal hippocampus and the BLA, and the second ad- PNAS PLUS dresses the role of the major norepinephrine, dopamine, and histamine receptors in those structures in the consolidation of SRM. We investigated first the effect of the protein synthesis inhibitor, anisomycin (Ani), on SRM when infused into the CA1 or the BLA. Subsequently, we studied the participation of β-adrenergic, D1/D5 dopamine, and H2 histamine receptors on the consolidation of SRM by infusing their agonists and antag- onists into the CA1 or BLA. Results Effect of Ani Given into the CA1 or the BLA on the Consolidation of SRM. Animals received intra-CA1 or intra-BLA microinfusions of vehicle (Veh) or Ani (100 μg per side) immediately after the sample phase of a social discrimination task and 24-h later were subjected to a 5-min retention test. As shown in Fig. 1, animals that received Veh into the CA1 (Fig. 1A) or the BLA (Fig. 1B) immediately after the sample phase were able to recognize the familiar juvenile 24-h later [one-sample t test: (Fig. 1A)Veht(9) = 3.577, P < 0.01; (Fig. 1B)Veht(8) = 4.124, P < 0.01]. In contrast, animals that received intra-CA1 infusions of Ani spent about the same time exploring the novel (N) and the familiar (F) juveniles Fig. 1. Effect of Ani given into the CA1 or BLA on the consolidation of SRM. [one-sample t test: (Fig. 1A) Ani t(9) = 0.3542, P > 0.1] during The schematic representation on the top of the figure shows the behavioral the retention test. Additionally, animals that received Ani into protocol used in this and in the following experiments. Animals were sub- the BLA spent more time exploring the familiar juvenile than the jected to a social discrimination task and, immediately after the sample phase, t B t = P > received intra-CA1 (A;1μL per side) or intra-BLA (B;0.5μL per side) infusions of novel one [one-sample test: (Fig. 1 ) Ani (7) 2.306, 0.05] vehicle (Veh) or Ani (100 μg per side). Twenty-four hours later, animals were during the retention test. These results suggest that animals subjected to a 5-min retention test in the presence of the familiar juvenile (F) treated with Ani in either structure were unable to recognize the and a novel one (N). Dots indicate the theoretical mean of 50%. Data are familiar juvenile 24-h after the sample phase. One-way ANOVA ± = – expressed as mean SEM (n 8 10 animals per group) and presented as showed significant differences among groups [CA1: F(3, 36) = percentage of total exploration time. *P < 0.05 and ***P < 0.001 Veh-N vs. 6.952, P < 0.001; BLA: F = 18.95, P < 0.0001]. Bonferroni ’ (3, 30) Ani-N, Bonferroni s Multiple Comparison test after one-way ANOVA. posttest revealed significant differences between Veh-N and Ani-N groups on the retention test when infused with intra-CA1 P < P < shows that the dopamine type 1 receptor is important for social ( 0.05) or intra-BLA ( 0.001) immediately after the interaction (35) and object-recognition memory (21).