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An operative olfactory bulb (OB) is critical to social recognition memory (SRM) in rodents, which involves identifying conspecifics. Furthermore, OB also allocates synaptic plasticity events related to olfactory memories in their intricate neural circuit. Here, we asked whether the OB is a target for brain-derived neurotrophic factor (BDNF), a well-known mediator of plasticity and memory. Adult ICR-CD1 male mice had their SRM evaluated under the inhibition of BDNF-dependent signaling directly in the OB. We also quantified the expression of BDNF in the OB, after SRM acquisition. Our results presented an amnesic effect of anti-BDNF administered 12â¯h post-training. Although the western blot showed no statistical difference in pro-BDNF and BDNF expression, the analysis of fluorescence intensity in slices suggests SRM acquisition decreases BDNF in the granular cell layer of the OB. Next, to test the ability of BDNF to rescue SRM deficit, we administered the human recombinant BDNF (rBDNF) directly in the OB of socially isolated (SI) mice. Unexpectedly, rBDNF did not rescue SRM in SI mice. Furthermore, BDNF and pro-BDNF expression in the OB was unchanged by SI. Our study reinforces the OB as a plasticity locus in memory-related events. It also adds SRM as another type of memory sensitive to BDNF-dependent signaling.
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Factor Neurotrófico Derivado del Encéfalo , Bulbo Olfatorio , Humanos , Ratones , Masculino , Animales , Bulbo Olfatorio/fisiología , Ratones Endogámicos ICR , Reconocimiento en Psicología/fisiología , MemoriaRESUMEN
Remembering conspecifics is paramount for the establishment and maintenance of groups. Here we asked whether the variability in social behavior caused by different breeding strategies affects social recognition memory (SRM). We tested the hypothesis that the inbred Swiss and the outbred C57BL/6 mice behave differently on SRM. Social memory in C57BL/6 mice endured at least 14 days, while in Swiss mice lasted 24 h but not ten days. We showed previously that an enriched environment enhanced the persistence of SRM in Swiss mice. Here we reproduced this result and added that it also increases the survival of adult-born neurons in the hippocampus. Next, we tested whether prolonged SRM observed in C57BL/6 mice could be changed by diminishing the trial duration or using an interference stimulus after learning. Neither short acquisition time nor interference during consolidation affected it. However, social isolation impaired SRM in C57BL/6 mice, similar to what was previously observed in Swiss mice. Our results demonstrate that SRM expression can vary according to the mouse strain, which shows the importance of considering this variable when choosing the most suitable model to answer specific questions about this memory system. We also demonstrate the suitability of both C57BL/6 and Swiss strains for exploring the impact of environmental conditions and adult neurogenesis on social memory.
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Reconocimiento en Psicología , Aislamiento Social , Ratones , Animales , Ratones Endogámicos C57BL , Reconocimiento en Psicología/fisiología , Hipocampo , Neurogénesis/fisiologíaRESUMEN
The formation of social memory between individuals of the opposite sex is crucial for expanding mating options or establishing monogamous pair bonding. A specialized neuronal circuit that regulates social memory could enhance an individual's mating opportunities and provide a parallel pathway for computing social behaviors. While the influence of light exposure on various forms of memory, such as fear and object memory, has been studied, its modulation of social recognition memory remains unclear. Here, we demonstrate that acute exposure to light impairs social recognition memory (SRM) in mice. Unlike sound and touch stimuli, light inhibits oxytocin neurons in the supraoptic nucleus (SON) via M1 SON-projecting intrinsically photosensitive retinal ganglion cells (ipRGCs) and GABAergic neurons in the perinuclear zone of the SON (pSON). We further show that optogenetic activation of SON oxytocin neurons using channelrhodopsin is sufficient to enhance SRM performance, even under light conditions. Our findings unveil a dedicated neuronal circuit through which luminance affects SRM, utilizing a non-image-forming visual pathway, distinct from the canonical modulatory role of the oxytocin system.
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Pyramidal cells in hippocampal area CA2 have synaptic properties that are distinct from the other CA subregions. Notably, this includes a lack of typical long-term potentiation of stratum radiatum synapses. CA2 neurons express high levels of several known and potential regulators of metabotropic glutamate receptor (mGluR)-dependent signaling including Striatal-Enriched Tyrosine Phosphatase (STEP) and several Regulator of G-protein Signaling (RGS) proteins, yet the functions of these proteins in regulating mGluR-dependent synaptic plasticity in CA2 are completely unknown. Thus, the aim of this study was to examine mGluR-dependent synaptic depression and to determine whether STEP and the RGS proteins RGS4 and RGS14 are involved. Using whole cell voltage-clamp recordings from mouse pyramidal cells, we found that mGluR agonist-induced long-term depression (mGluR-LTD) is more pronounced in CA2 compared with that observed in CA1. This mGluR-LTD in CA2 was found to be protein synthesis and STEP dependent, suggesting that CA2 mGluR-LTD shares mechanistic processes with those seen in CA1, but in addition, RGS14, but not RGS4, was essential for mGluR-LTD in CA2. In addition, we found that exogenous application of STEP could rescue mGluR-LTD in RGS14 KO slices. Supporting a role for CA2 synaptic plasticity in social cognition, we found that RGS14 KO mice had impaired social recognition memory as assessed in a social discrimination task. These results highlight possible roles for mGluRs, RGS14, and STEP in CA2-dependent behaviors, perhaps by biasing the dominant form of synaptic plasticity away from LTP and toward LTD in CA2.
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Proteínas RGS , Receptores de Glutamato Metabotrópico , Animales , Ratones , Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Plasticidad Neuronal , Células Piramidales/fisiología , Receptores de Glutamato Metabotrópico/metabolismo , Proteínas RGS/genética , Proteínas RGS/metabolismoRESUMEN
The prefrontal cortex (PFC) plays critical roles in social cognition and emotional regulation in humans and rodents; however, its involvement in social recognition memory in mice remains unclear. Here, we examined the roles of the PFC in short-term and long-term social recognition memory, social motivation, and anxiety-related behavior in C57BL/6J male mice. Sham control and PFC-lesioned mice underwent four different behavioral tests. In the social recognition test, composed of three daily trials over 3 consecutive days, the control mice spent less time investigating the juvenile stimulus mouse both within each day and across days. By contrast, while social investigation behavior in PFC-lesioned mice decreased across the three trials within each day, it did not decrease over the 3-day testing period. These results indicate that the PFC has an important role in long-term, but not short-term, social recognition memory. The control and PFC-lesioned mice exhibited similar social motivation in the three-chamber test - both groups preferred the juvenile mouse to the empty cylinder and did not prefer the adult mouse. In addition, the PFC lesion had no impact on anxiety-related behavior or general activity in the light-dark transition test or the open field test. Our findings demonstrate that the PFC is essential for long-term social recognition memory and that it plays a critical role in higher-order social cognition.
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Corteza Prefrontal , Reconocimiento en Psicología , Animales , Humanos , Masculino , Memoria a Largo Plazo , Memoria a Corto Plazo/fisiología , Ratones , Ratones Endogámicos C57BL , Corteza Prefrontal/fisiología , Reconocimiento en Psicología/fisiologíaRESUMEN
BACKGROUND: Social recognition memory (SRM) is the ability to distinguish familiar from novel conspecifics and is crucial for survival and reproductive success across social species. We previously reported that oxytocin (OXT) receptor (OXTR) signaling in the CA2/CA3a of dorsal hippocampus is essential to promote the persistence of long-term SRM, yet how the endogenous OXT system influences CA2 outputs to regulate long-term SRM formation remains unclear. METHODS: To achieve a selective deletion of CA2 OXTRs, we crossed Amigo2-Cre mice with Oxtr-floxed mice to generate CA2-specific Oxtr conditional knockout (Oxtr-/-) mice. A three-chamber paradigm test was used for studying SRM in mice. Chemogenetic and optogenetic targeting strategies were employed to manipulate neuronal activity. RESULTS: We show that selective ablation of Oxtr in the CA2 suffices to impair the persistence of long-term SRM but has no effect on sociability and social novelty preference in the three-chamber paradigm test. We find that cell-type specific activation of OXT neurons within the hypothalamic paraventricular nucleus enhances long-term SRM and this enhancement is blocked by local application of OXTR antagonist L-368,899 into dorsal hippocampal CA2 (dCA2) region. In addition, chemogenetic neuronal silencing in dCA2 demonstrated that neuronal activity is essential for forming long-term SRM. Moreover, chemogenetic terminal-specific inactivation reveals a crucial role for dCA2 outputs to ventral CA1 (vCA1), but not dorsal lateral septum, in long-term SRM. Finally, targeted activation of the dCA2-to-vCA1 circuit effectively ameliorates long-term SRM deficit observed in Oxtr-/- mice. CONCLUSIONS: These findings highlight the importance of hippocampal CA2 OXTR signaling in governing the persistence of long-term SRM and identify a hippocampal circuit linking dCA2 to vCA1 necessary for controlling long-term SRM formation.
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Receptores de Oxitocina , Reconocimiento en Psicología , Animales , Hipocampo/metabolismo , Memoria a Largo Plazo , Ratones , Neuronas/fisiología , Receptores de Oxitocina/genética , Receptores de Oxitocina/metabolismo , Reconocimiento en Psicología/fisiologíaRESUMEN
Social recognition is the ability of animals to identify and recognize a conspecific. The consolidation of social stimuli in long-term memory is crucial for the establishment and maintenance of social groups, reproduction and species survival. Despite its importance, little is known about the circuitry and molecular mechanisms involved in the social recognition memory (SRM). Serotonin (5-hydroxytryptamine, 5-HT) is acknowledged as a major neuromodulator, which plays a key role in learning and memory. Focusing on the more recently described 5-HT receptors, we investigated in the CA1 region of the dorsal hippocampus the participation of 5-HT5A, 5-HT6 and 5-HT7 receptors in the consolidation of SRM. Male Wistar rats cannulated in CA1 were subjected to a social discrimination task. In the sample phase the animals were exposed to a juvenile conspecific for 1 h. Immediately after, they received different pharmacological treatments. Twenty-four hours later, they were submitted to a 5 min retention test in the presence of the previously presented juvenile (familiar) and a novel juvenile. The animals that received infusions of 5-HT5A receptor antagonist SB-699551 (10 µg/µL), 5-HT6 receptor agonist WAY-208466 (0.63 µg/µL) or 5-HT7 receptor agonist AS-19 (5 µg/µL) intra-CA1 were unable to recognize the familiar juvenile. This effect was blocked by the coinfusion of WAY-208466 plus 5-HT6 receptor antagonist SB-271046 (10 µg/µL) or AS-19 plus 5-HT7 receptor antagonist SB-269970 (5 µg/µL). The present study helps to clarify the neurobiological functions of the 5-HT receptors more recently described and extends our knowledge about mechanisms underlying the SRM.
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Receptores de Serotonina , Serotonina , Animales , Hipocampo/metabolismo , Masculino , Ratas , Ratas Wistar , Receptores de Serotonina/metabolismo , Reconocimiento en Psicología , Serotonina/farmacologíaRESUMEN
Social recognition memory reflects the ability of the social animals to recognize and remember familiar individuals of the same species. The unique ability for mammals to recognize conspecifics is essential and beneficial when animals conduct daily social activities. This brief review summarizes a brain network underlying social recognition memory and explores the possible relationships between social isolation and social recognition memory. Finally, we introduce some possible related molecular mechanisms underlying social recognition memory. These findings help us explore potential targeting brain areas or circuits of social communication disorder.
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Hipocampo , Reconocimiento en Psicología , Animales , Encéfalo , Hipocampo/fisiología , Mamíferos , Reconocimiento en Psicología/fisiología , Conducta SocialRESUMEN
Previous studies have shown that atypical dopamine-transporter-inhibitors such as modafinil and its analogues modify behavioral and cognitive functions in rodents. Here, we tested potential promnestic effects of the novel, more dopamine-transporter selective modafinil analogue CE-158 in the social discrimination memory task in male mice. Systemic administration of CE-158 1 h before the social learning event prevented the impairment of social-recognition memory following retroactive interference 3 h after the learning session of a juvenile conspecific. This effect was dose-dependent, as mice treated with 10 mg/kg, but not with 1 mg/kg CE-158, were able to discriminate between the novel and familiar conspecific despite the presentation of an interference stimulus, both 3 h and 6 h post learning. However, when 10 mg/kg of the drug was administered after learning, CE-158 failed to prevent social memory from interference. Paralleling these behavioral effects, the systemic administration of 10 mg/kg CE-158 caused a rapid and sustained elevation of extracellular dopamine in the nucleus accumbens, a brain area where dopaminergic signaling plays a key role in learning and memory function, of freely moving mice, while 1 mg/kg was not sufficient for altering dopamine levels. Taken together, our findings suggest promnestic effects of the novel dopamine-transporter-inhibitor CE-158 in a social recognition memory test that may be in part mediated via increased dopamine-neurotransmission in the nucleus accumbens. Thus, selective-dopamine-transporter-inhibitors such as CE-158 may represent interesting drug candidates for the treatment of memory complaints observed in humans with cognitive impairments and dementia.
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Dopamina , Núcleo Accumbens , Animales , Aprendizaje , Masculino , Ratones , Modafinilo/farmacología , Reconocimiento en PsicologíaRESUMEN
Growing evidence indicates that brain carbonic anhydrases (CAs) are key modulators in cognition, particularly in recognition and aversive memories. Here we described a role for these enzymes also in social recognition memory (SRM), defined as the ability to identify and recognize a conspecific, a process that is of paramount importance in gregarious species, such as rodents and humans. Male adult Wistar rats were submitted to a social discrimination task and, immediately after the sample phase, received bilateral infusions of vehicle, the CAs activator D-phenylalanine (D-Phen, 50 nmols/side), the CAs inhibitor acetazolamide (ACTZ; 10 nmols/side) or the combination of D-Phen and ACTZ directly in the CA1 region of the dorsal hippocampus or in the medial prefrontal cortex (mPFC). Animals were tested 30 min (short-term memory) or 24 h later (long-term memory). We found that inhibition of CAs with infusion of ACTZ either in the CA1 or in the mPFC impaired short-term SRM and that this effect was completely abolished by the combined infusion of D-Phen and ACTZ. We also found that activation of CAs with D-Phen facilitated the consolidation of long-term SRM in the mPFC but not in CA1. Finally, we show that activation of CAs in CA1 and in the mPFC enhances the persistence of SRM for up to 7 days. In both cases, the co-infusion of ACTZ fully prevented D-Phen-induced procognitive effects. These results suggest that CAs are key modulators of SRM and unveil a differential involvement of these enzymes in the mPFC and CA1 on memory consolidation.
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Anhidrasas Carbónicas , Hipocampo , Corteza Prefrontal , Reconocimiento en Psicología , Animales , Anhidrasas Carbónicas/fisiología , Hipocampo/fisiología , Masculino , Corteza Prefrontal/fisiología , Ratas , Ratas Wistar , Reconocimiento en Psicología/fisiologíaRESUMEN
Women are vulnerable to developing mental disorders that are associated with circulating estrogens. Estrogens, especially 17ß-estradiol (E2), have a wide array of effects on the brain, affecting many behavioral endpoints associated with mental illness. By using a total estrogen receptor (ER) α knockout (KO), an ERα knock in/knock out (KIKO) that lacks a functional DNA-binding domain, and wild type (WT) controls treated with either oil or E2, we evaluated ERα signaling, dependent and independent of the estrogen response element (ERE), on avoidance behavior, social interactions and memory, and palatable ingestive behavior using the open field test, the elevated plus maze, the light dark box, the 3-chamber test, and palatable feeding. We found that ERα does not mediate control of anxiety-like behaviors but rather yielded differences in locomotor activity. In evaluating social preference and social recognition memory, we observed that E2 may modulate these measures in KIKO females but not KO females, suggesting that ERE-independent signaling is likely involved in sociability. Lastly, observations of palatable (high-fat) food intake suggested an increase in palatable eating behavior in oil-treated KIKO females. Oil-treated KO females had a longer latency to food intake, indicative of an anhedonic phenotype compared to oil-treated WT and KIKO females. We have observed that social-related behaviors are potentially influenced by ERE-independent ERα signaling and hedonic food intake requires signaling of ERα.
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Reacción de Prevención , Receptor alfa de Estrógeno , Conducta Alimentaria , Interacción Social , Animales , Conducta Animal , Estradiol/farmacología , Estradiol/fisiología , Receptor alfa de Estrógeno/genética , Estrógenos/farmacología , Femenino , Ratones , Ratones Noqueados , Elementos de RespuestaRESUMEN
P21-activated kinase 3 (PAK3) gene mutations are linked to several neurodevelopmental disorders, but the underlying mechanisms remain unclear. In this study, we used a tetracycline-inducible system to control the expression of a mutant PAK3 (mPAK3) protein in immediate early gene, namely cFos, positive cells to disrupt PAK signaling, specifically in cells activated by social interaction in transgenic mice. We show that the expression of mPAK3-GFP proteins was in cFos-expressing excitatory and inhibitory neurons in various brain regions, such as the cortex and hippocampus, commonly activated during learning and memory. Basal expression of mPAK3-GFP proteins in cFos-positive cells resulted in social recognition memory deficits in the three-chamber social interaction test, without affecting locomotor activity or other forms of memory. The social memory deficit was rescued by doxycycline to halt the mPAK3-GFP transgene expression. In addition, we show that the expression of mPAK3-GFP proteins in a subset of cFos-positive cells, induced by an antecedent short social interaction, termed social pairing, was sufficient to impair social recognition memory. These results indicate that normal PAK signaling in cFos-positive cells activated during social interaction is critical for social memory.
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Memoria , Proteínas Proto-Oncogénicas c-fos/metabolismo , Transducción de Señal , Interacción Social , Quinasas p21 Activadas/metabolismo , Animales , Ansiedad/fisiopatología , Conducta Animal , Doxiciclina/farmacología , Proteínas Fluorescentes Verdes/metabolismo , Locomoción , Ratones Transgénicos , Neuronas/metabolismo , Olfato , TransgenesRESUMEN
BACKGROUND: Matrix metallopeptidase 9 (MMP9) has been implicated in a variety of neurological disorders, including Alzheimer's disease (AD), where MMP9 levels are elevated in the brain and cerebrovasculature. Previously our group demonstrated apolipoprotein E4 (apoE4) was less efficient in regulating MMP9 activity in the brain than other apoE isoforms, and that MMP9 inhibition facilitated beta-amyloid (Aß) elimination across the blood-brain barrier (BBB) METHODS: In the current studies, we evaluated the impact of MMP9 modulation on Aß disposition and neurobehavior in AD using two approaches, (1) pharmacological inhibition of MMP9 with SB-3CT in apoE4 x AD (E4FAD) mice, and (2) gene deletion of MMP9 in AD mice (MMP9KO/5xFAD) RESULTS: Treatment with the MMP9 inhibitor SB-3CT in E4FAD mice led to reduced anxiety compared to placebo using the elevated plus maze. Deletion of the MMP9 gene in 5xFAD mice also reduced anxiety using the open field test, in addition to improving sociability and social recognition memory, particularly in male mice, as assessed through the three-chamber task, indicating certain behavioral alterations in AD may be mediated by MMP9. However, neither pharmacological inhibition of MMP9 or gene deletion of MMP9 affected spatial learning or memory in the AD animals, as determined through the radial arm water maze. Moreover, the effect of MMP9 modulation on AD neurobehavior was not due to changes in Aß disposition, as both brain and plasma Aß levels were unchanged in the SB-3CT-treated E4FAD animals and MMP9KO/AD mice compared to their respective controls. CONCLUSIONS: In total, while MMP9 inhibition did improve specific neurobehavioral deficits associated with AD, such as anxiety and social recognition memory, modulation of MMP9 did not alter spatial learning and memory or Aß tissue levels in AD animals. While targeting MMP9 may represent a therapeutic strategy to mitigate aspects of neurobehavioral decline in AD, further work is necessary to understand the nature of the relationship between MMP9 activity and neurological dysfunction.
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Enfermedad de Alzheimer/metabolismo , Ansiedad/metabolismo , Metaloproteinasa 9 de la Matriz/deficiencia , Interacción Social , Aprendizaje Espacial/fisiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/genética , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/genética , Ansiedad/psicología , Encéfalo/metabolismo , Femenino , Compuestos Heterocíclicos con 1 Anillo/farmacología , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Masculino , Metaloproteinasa 9 de la Matriz/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Presenilina-1/genética , Interacción Social/efectos de los fármacos , Aprendizaje Espacial/efectos de los fármacos , Sulfonas/farmacología , Sulfonas/uso terapéuticoRESUMEN
Social recognition memory (SRM) forms the basis of social relationships of animals. It is essential for social interaction and adaptive behavior, reproduction and species survival. Evidence demonstrates that social deficits of psychiatric disorders such as autism and schizophrenia are caused by alterations in SRM processing by the hippocampus and amygdala. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and its receptors PAC1, VPAC1 and VPAC2 are highly expressed in these regions. PACAP is a pleiotropic neuropeptide that modulates synaptic function and plasticity and is thought to be involved in social behavior. PACAP signaling also stimulates the nitric oxide (NO) production and targets outcomes to synapses. In the present work, we investigate the effect of the infusion of PACAP-38 (endogenous neuropeptide and potent stimulator of adenylyl cyclase), PACAP 6-38 (PAC1/VPAC2 receptors antagonist) and S-Nitroso-N-acetyl-DL-penicillamine (SNAP, NO donor) in the CA1 region of the hippocampus and in the basolateral amygdala (BLA) on the consolidation of SRM. For this, male Wistar rats with cannulae implanted in CA1 or in BLA were subjected to a social discrimination paradigm, which is based on the natural ability of rodents to investigate unfamiliar conspecifics more than familiar one. In the sample phase (acquisition), animals were exposed to a juvenile conspecific for 1 h. Immediately, 60 or 150 min after, animals received one of different pharmacological treatments. Twenty-four hours later, they were submitted to a 5 min retention test in the presence of the previously presented juvenile (familiar) and a novel juvenile. Animals that received infusions of PACAP 6-38 (40 pg/side) into CA1 immediately after the sample phase or into BLA immediately or 60 min after the sample phase were unable to recognize the familiar juvenile during the retention test. This impairment was abolished by the coinfusion of PACAP 6-38 plus SNAP (5 µg/side). These results show that the blockade of PACAP/PAC1/VPAC2 signaling in the CA1 and BLA during a restricted post-acquisition time window impairs the consolidation of SRM and that the SNAP is able to abolish this deficit. Findings like this could potentially be used in the future to influence studies of psychiatric disorders involving social behavior.
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Complejo Nuclear Basolateral/efectos de los fármacos , Región CA1 Hipocampal/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/efectos de los fármacos , Reconocimiento en Psicología/efectos de los fármacos , Percepción Social/efectos de los fármacos , Animales , Complejo Nuclear Basolateral/metabolismo , Región CA1 Hipocampal/metabolismo , Consolidación de la Memoria/efectos de los fármacos , Donantes de Óxido Nítrico/farmacología , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/farmacología , Ratas , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/efectos de los fármacos , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/metabolismo , Receptores de Tipo II del Péptido Intestinal Vasoactivo/efectos de los fármacos , Receptores de Tipo II del Péptido Intestinal Vasoactivo/metabolismo , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/efectos de los fármacos , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/metabolismo , Reconocimiento en Psicología/fisiología , S-Nitroso-N-Acetilpenicilamina/farmacologíaRESUMEN
Prenatal alcohol exposure (PAE) and early-life adversity (ELA) both negatively impact social neurobehavioral development, including social recognition memory. Importantly, while individuals with PAE are more likely to experience ELA, relatively few studies have assessed the interaction of these two early insults on adolescent social behavior development. Here, we combine animal models of PAE and ELA to investigate both their unique and interactive effects on social neurobehavioral function in early and late adolescent male and female rats. Behavioral testing was followed by assessment of hypothalamic expression of oxytocin (OT) and vasopressin (AVP), key neuropeptides in the regulation of social behavior. Our results indicate that PAE and ELA have unique sex- and age-specific effects on social recognition memory and OT/AVP expression, with more pronounced neurobehavioral changes observed in males than in females in both early and late adolescence. Specifically, ELA impaired social recognition in early adolescent females regardless of prenatal treatment, while males showed deficits in both early and late adolescence in response to unique and interactive effects of PAE and ELA. Neurobiological data suggest that these perinatal insults differentially impact the OT and AVP systems in a sexually dimorphic manner, such that the OT system appears to be particularly sensitive to PAE in males while the AVP system appears to be more vulnerable to ELA in females. Taken together, our data provide novel insight into how the early postnatal environment may mediate outcomes of PAE as well as the power of animal models to interrogate the relationship between these pre- and postnatal insults.
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Experiencias Adversas de la Infancia , Efectos Tardíos de la Exposición Prenatal , Animales , Etanol , Femenino , Humanos , Masculino , Modelos Animales , Oxitocina , Embarazo , Ratas , Conducta SocialRESUMEN
Oxytocin regulates social behaviors and has been linked to the etiology of autism and schizophrenia. Oxytocin and another hypothalamic neuropeptide, melanin concentrating hormone (MCH), share several physiological actions such as emotion, social behavior and recognition, maternal care, sexual behavior and stress, which suggests that these two systems may interact, however, how they would do it is not known. Here, we study the interactions between the oxytocin and MCH systems in behaviors related to autism and schizophrenia. Specifically, we examined the synaptic inputs of the oxytocin-to the MCH neurons. We selectively deleted oxytocin receptors (OXTR) from MCH neurons (OXTR-cKO mice) using a Cre/loxP recombinase-technology, and used rabies-mediated circuit mapping technique to reveal the changes in the direct monosynaptic inputs to MCH neurons. We examined the behavioral responses of OXTR-cKO mice. Deletion of OXTR from MCH neurons induced a significant decrease in the primary inputs received by MCH neurons from the paraventricular nucleus and the lateral hypothalamus, and from the nucleus accumbens and ventral tegmental area. While OXTR-cKO mice exhibited similar social interactions as control mice, they displayed significantly impaired social recognition memory and increased stereotypic behavior. Our study identifies a selective role for the oxytocin-MCH pathway in social recognition memory and stereotyped behavior that are relevant to psychiatric disorders such as schizophrenia and autism, and warrant further investigation of this circuit to uncover potential benefit of targeting the oxytocin-MCH circuit as a novel therapeutic target for treatment of social recognition deficits in these two disorders.
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Hormonas Hipotalámicas/deficiencia , Melaninas/deficiencia , Neuronas/metabolismo , Hormonas Hipofisarias/deficiencia , Receptores de Oxitocina/deficiencia , Reconocimiento en Psicología/fisiología , Interacción Social , Sinapsis/metabolismo , Animales , Hormonas Hipotalámicas/genética , Masculino , Melaninas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Oxitocina/deficiencia , Oxitocina/genética , Hormonas Hipofisarias/genética , Receptores de Oxitocina/genética , Sinapsis/genéticaRESUMEN
Toluene intoxication produces deleterious effects on cognitive function, which has been associated with the inhibition of N-methyl-d-aspartate receptor (NMDAR). The present study determined whether N,N-dimethylglycine (DMG), a nutrient supplement and a partial agonist for NMDAR glycine binding site, could counteract recognition memory deficits and hippocampal synaptic dysfunction after acute toluene exposure. Male ICR mice were treated with toluene (250-750 mg/kg) for monitoring the sociability and social novelty in three-chamber test and long-term potentiation (LTP) of hippocampal synaptic transmission. Moreover, the combined effects of DMG (30-100 mg/kg) pretreatment with toluene (750 mg/kg) on three-chamber test, novel location and object recognition test and synaptic function were determined. Toluene decreased the sociability, preference for social novelty, hippocampal synaptic transmission and LTP in a dose-dependent manner. DMG pretreatment significantly reduced the toluene-induced memory impairment in social recognition, object location and object recognition and synaptic dysfunction. Furthermore, NMDAR glycine binding site antagonist, 7-chlorokynurenic acid, abolished the protective effects of DMG. These results indicate that DMG could prevent toluene-induced recognition memory deficits and synaptic dysfunction and its beneficial effects might be associated with modulation of NMDAR. These findings suggest that DMG supplementation might be an effective approach to prevent memory problems for the workers at risk of high-level toluene exposure or toluene abusers.
Asunto(s)
Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/prevención & control , Plasticidad Neuronal/efectos de los fármacos , Reconocimiento en Psicología/efectos de los fármacos , Sarcosina/análogos & derivados , Tolueno/toxicidad , Animales , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Masculino , Trastornos de la Memoria/psicología , Ratones , Ratones Endogámicos ICR , Plasticidad Neuronal/fisiología , Reconocimiento en Psicología/fisiología , Sarcosina/farmacología , Sarcosina/uso terapéutico , Solventes/toxicidadRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, motor impairments, and accumulation of hallmark proteins, amyloid-beta (Aß) and tau. Traditionally, transgenic mouse models for AD have focused on Aß pathology, however, recently a number of tauopathy transgenic models have been developed, including the TAU58/2 transgenic model. Cannabidiol (CBD), a non-toxic constituent of the Cannabis sativa plant, has been shown to prevent and reverse cognitive deficits in Aß transgenic mouse models of AD. Importantly, the therapeutic properties of CBD on the behavioural phenotype of tauopathy mouse models have not been investigated. We assessed the impact of chronic CBD treatment (i.e. 50 mg/kg CBD i.p. administration starting 3 weeks prior to behavioural assessments) on disease-relevant behaviours of 4-month-old TAU58/2 transgenic males in paradigms for anxiety, motor functions, and cognition. TAU58/2 transgenic males demonstrated reduced body weight, anxiety and impaired motor functions. Furthermore, they demonstrated increased freezing in fear conditioning compared to wild type-like animals. Interestingly, both sociability and social recognition memory were intact in AD transgenic mice. Chronic CBD treatment did not affect behavioural changes in transgenic males. In summary, 4-month-old TAU58/2 transgenic males exhibited no deficits in social recognition memory, suggesting that motor deficits and changes in anxiety at this age do not impact on social domains. The moderate increase in fear-associated memory needs further investigation but could be related to differences in fear extinction. Future investigations will need to clarify CBD's therapeutic potential for reversing motor deficits in TAU58/2 transgenic mice by considering alternative CBD treatment designs including changed CBD dosing.
Asunto(s)
Cannabidiol/administración & dosificación , Proteínas tau/genética , Animales , Ansiedad/genética , Conducta Animal , Peso Corporal , Extinción Psicológica , Masculino , Ratones , Ratones TransgénicosRESUMEN
Memory transience is essential to gain cognitive flexibility. Recently, hippocampal neurogenesis is emerging as one of the mechanisms involved in the balance between persistence and forgetting. Social recognition memory (SRM) has its duration prolonged by neurogenesis. However, it is still to be determined whether boosting neurogenesis in distinct phases of SRM may favor forgetting over persistence. In the present study, we used enriched environment (EE) and memantine (MEM) to increase neurogenesis. SRM was ubiquitously prolonged by both, while EE after the memory acquisition did not favor forgetting. Interestingly, the proportion of newborn neurons with mature morphology in the dorsal hippocampus was higher in animals where persistence prevailed. Finally, one of the main factors for dendritic growth is the formation of cytoskeleton. We found that Latrunculin A, an inhibitor of actin polymerization, blunted the promnesic effect of EE. Altogether, our results indicate that the mechanisms triggered by EE to improve SRM are not limited to increasing the number of newborn neurons.
Asunto(s)
Memoria/fisiología , Neurogénesis/fisiología , Neuronas/fisiología , Reconocimiento en Psicología/fisiología , Conducta Social , Actinas/antagonistas & inhibidores , Amnesia/inducido químicamente , Amnesia/psicología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Dendritas/efectos de los fármacos , Proteína Doblecortina , Ambiente , Antagonistas de Aminoácidos Excitadores/farmacología , Hipocampo/citología , Hipocampo/efectos de los fármacos , Inmunohistoquímica , Memantina/farmacología , Consolidación de la Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Tiazolidinas/farmacologíaRESUMEN
Social recognition memory (SRM) enables the distinction between familiar and strange conspecifics, a fundamental ability for sociable species, such as rodents and humans. There is mounting evidence that the medial prefrontal cortex plays a prominent role both in shaping social behavior and in recognition memory. Glutamate is the major excitatory neurotransmitter in the brain, and activity of its ionotropic receptors is known to mediate both synaptic plasticity and consolidation of various types of memories. However, whether these receptors are required in the medial prefrontal cortex (mPFC) for SRM consolidation remains elusive. To address this issue, we submitted rats to a social discrimination paradigm, administered infusions of NMDA- and AMPA/kainate-receptors antagonists into the prelimbic (PrL) subdivision of the mPFC at different post-encoding time points and evaluated long-term memory retention twenty-four hours later. We found that blocking NMDA receptors immediately after the sample phase, but not 3 h later, impaired SRM consolidation, whereas the blockade of AMPA/kainate receptors immediately and 3 h, but not 6 h after the sample phase, prevented long-term memory consolidation. These results highlight the importance of the mPFC in social cognition and may contribute towards the understanding of the dysfunctional social information processing that underlies multiple neuropsychiatric disorders.