Short-term Social Recognition Research Articles

Oxytocin receptors in the prefrontal cortex play important roles in short-term social recognition in mice

We examined the roles of oxytocin (OT) receptors in the prefrontal cortex (PFC) in short- and long-term social recognition and anxiety-related behaviors in mice. Mice injected with high or low doses of an OT receptor antagonist (OTA) or vehicle performed the social recognition test, the open-field test, and the light–dark transition test. In the social recognition test, with three daily trials over three consecutive days, control mice showed short-term recognition of a conspecific on all three days. In contrast, a high-dose injection of OTA impaired short-term social recognition on the second and third days, and it was impaired by a low-dose injection of OTA on the third day. These results suggested that OTA injection into the PFC dose-dependently inhibited short-term social recognition within each day. All three groups did not show any long-term social recognition across three days. OTA injection did not affect anxiety related behavior in the open-field and light–dark transition tests. Our findings demonstrated that OT receptors in the PFC played important roles in short-term social recognition.

The prelimbic cortex but not the anterior cingulate cortex plays an important role in social recognition and social investigation in mice.

The prefrontal cortex (PFC) has been implicated in social cognitive functions and emotional behaviors in rodents. Each subregion (prelimbic cortex, PL; infralimbic cortex; and anterior cingulate cortex, ACC) of the PFC appears to play a different role in social and emotional behaviors. However, previous investigations have produced inconsistent data, and few previous studies directly compared the roles of the PFC subregions using the same experimental paradigm. Accordingly, in the present study, we examined the role of the PL and the ACC in short-term social recognition, social investigation, and anxiety-related behaviors in C57BL/6J mice. We subjected mice with a lesioned PL or ACC, as well as those in a sham control group, to tests of social recognition and social novelty where juvenile and adult male mice were used as social stimuli. In the social recognition test, the PL-lesioned mice exhibited habituation but not dishabituation regardless of whether they encountered juvenile or adult mice. In a subsequent social novelty test, they spent less time engaged in social investigation compared with the control mice when adult mice were used as social stimuli. These results suggest that PL lesions impaired both social recognition and social investigation. In contrast, ACC-lesioned mice did not exhibit impaired short-term social recognition or social investigation regardless of the social stimulus. Furthermore, PL lesions and ACC lesions did not affect anxiety-related behavior in the open field test or light-dark transition test. Our findings demonstrate that the PL but not the ACC plays an important role in social recognition and social investigation.

Isolation driven changes in Iba1-positive microglial morphology are associated with social recognition memory in adults and adolescents

Microglia are critical for regulation of neuronal circuits that mature from adolescence to adulthood. The morphological complexity and process length of microglia can indicate different activation states. These states are sensitive to a variety of environmental and stress conditions. Microglia are sensitive to many factors that also regulate social behavior, and in turn, microglial manipulations can impact social function. Brief social isolation is one factor that can lead to robust social changes. Here, we explored the role of microglia in the effects of brief social isolation on social recognition memory. Using morphological measures of Iba1 to index microglial intensity, complexity, and process length, we identified different effects of brief isolation on microglial complexity in the basal region of the amygdala between adults and adolescents alongside overall increases in intensity of Iba1 in several cortical brain regions. Short-term social recognition memory is sensitive to the amount of social engagement, and provides an opportunity to test if social engagement produced by brief isolation enhances social learning in a manner that relies on microglia. We found that brief isolation facilitated social interaction across ages but had opposing effects on short-term social recognition. Isolation increased novel partner investigation in adolescents, which is consistent with better social recognition, but increased familiar partner investigation in adults. Depletion of microglia with PLX3397 prevented these effects of brief isolation in adolescents, and reduced them in adults. These results suggest that distinct changes in microglial function driven by the social environment may differentially contribute to subsequent social recognition memory during development.

Altered neural oscillations and behavior in a genetic mouse model of NMDA receptor hypofunction

Abnormalities in electroencephalographic (EEG) biomarkers occur in patients with schizophrenia and those clinically at high risk for transition to psychosis and are associated with cognitive impairment. Converging evidence suggests N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a central role in the pathophysiology of schizophrenia and likely contributes to biomarker impairments. Thus, characterizing these biomarkers is of significant interest for early diagnosis of schizophrenia and development of novel treatments. We utilized in vivo EEG recordings and behavioral analyses to perform a battery of electrophysiological biomarkers in an established model of chronic NMDAR hypofunction, serine racemase knockout (SRKO) mice, and their wild-type littermates. SRKO mice displayed impairments in investigation-elicited gamma power that corresponded with reduced short-term social recognition and enhanced background (pre-investigation) gamma activity. Additionally, SRKO mice exhibited sensory gating impairments in both evoked-gamma power and event-related potential amplitude. However, other biomarkers including the auditory steady-state response, sleep spindles, and state-specific power spectral density were generally neurotypical. In conclusion, SRKO mice demonstrate how chronic NMDAR hypofunction contributes to deficits in certain translationally-relevant EEG biomarkers altered in schizophrenia. Importantly, our gamma band findings suggest an aberrant signal-to-noise ratio impairing cognition that occurs with NMDAR hypofunction, potentially tied to impaired task-dependent alteration in functional connectivity.

Protein synthesis and actin polymerization in the rapid effects of 17β-estradiol on short-term social memory and dendritic spine dynamics in female mice

Estrogens rapidly facilitate learning and memory, including social recognition – the ability of an animal to recognize another. In ovariectomized female mice, systemic or dorsal hippocampal administration of 17β-estradiol (E2) facilitates short-term social recognition memory within 40 min. Within the same timeframe, E2 increases dendritic spine density in CA1 dorsal hippocampal neurons of behavioural task-naïve mice and in hippocampal sections. Mechanisms underlying these effects remain unclear. Estrogens rapidly modulate actin cytoskeletal dynamics through actin polymerization and the translation of key synaptic proteins. We first determined doses of actin polymerization inhibitor latrunculin A (LAT) and protein synthesis inhibitor anisomycin (ANI) that would block short-term social recognition memory when infused into the dorsal hippocampus of ovariectomized female mice 15 min prior to testing. The highest doses that did not block social recognition prevented the facilitating effects of E2, whereas DNA transcription inhibitor, actinomycin D, could not block social recognition. As task performance may interfere with E2-facilitated increases in dendritic spine density, dendritic spine density and length were examined in task-performing and task-naïve mice. E2 increased dendritic spine density 15 but not 40 min following treatment, regardless of whether the animal had performed the social recognition task. This effect was blocked by LAT, but not ANI. Thus, both actin polymerization and protein synthesis are necessary for E2 to rapidly facilitate social recognition, whereas actin polymerization, but not protein synthesis, is required for the rapid increase in dendritic spine density brought on by E2.

NMDA Receptor in Vasopressin 1b Neurons Is Not Required for Short-Term Social Memory, Object Memory or Aggression.

The arginine vasopressin 1b receptor (Avpr1b) plays an important role in social behaviors including aggression, social learning and memory. Genetic removal of Avpr1b from mouse models results in deficits in aggression and short-term social recognition in adults. Avpr1b gene expression is highly enriched in the pyramidal neurons of the hippocampal cornu ammonis 2 (CA2) region. Activity of the hippocampal CA2 has been shown to be required for normal short-term social recognition and aggressive behaviors. Vasopressin acts to enhance synaptic responses of CA2 neurons through a NMDA-receptor dependent mechanism. Genetic removal of the obligatory subunit of the NMDA receptor (Grin1) within distinct hippocampal regions impairs non-social learning and memory. However, the question of a direct role for NMDA receptor activity in Avpr1b neurons to modulate social behavior remains unclear. To answer this question, we first created a novel transgenic mouse line with Cre recombinase knocked into the Avpr1b coding region to genetically target Avpr1b neurons. We confirmed this line has dense Cre expression throughout the dorsal and ventral CA2 regions of the hippocampus, along with scattered expression within the caudate-putamen and olfactory bulb (OB). Conditional removal of the NMDA receptor was achieved by crossing our line to an available floxed Grin1 line. The resulting mice were measured on a battery of social and memory behavioral tests. Surprisingly, we did not observe any differences between Avpr1b-Grin1 knockout mice and their wildtype siblings. We conclude that mice without typical NMDA receptor function in Avpr1b neurons can develop normal aggression as well as short-term social and object memory performance.

Impaired social behaviour and molecular mediators of associated neural circuits during chronic Toxoplasma gondii infection in female mice

Toxoplasma gondii (T. gondii) is a neurotropic parasite that is associated with various neuropsychiatric disorders. Rodents infected with T. gondii display a plethora of behavioural alterations, and Toxoplasma infection in humans has been strongly associated with disorders such as schizophrenia, in which impaired social behaviour is an important feature. Elucidating changes at the cellular level relevant to neuropsychiatric conditions can lead to effective therapies. Here, we compare changes in behaviour during an acute and chronic T. gondii infection in female mice. Further, we notice that during chronic phase of infection, mice display impaired sociability when exposed to a novel conspecific. Also, we show that T. gondii infected mice display impaired short-term social recognition memory. However, object recognition memory remains intact. Using c-Fos as a marker of neuronal activity, we show that infection leads to an impairment in neuronal activation in the medial prefrontal cortex, hippocampus as well as the amygdala when mice are exposed to a social environment and a change in functional connectivity between these regions. We found changes in synaptic proteins that play a role in the process of neuronal activation such as synaptophysin, PSD-95 and changes in downstream substrates of cell activity such as cyclic AMP, phospho-CREB and BDNF. Our results point towards an imbalance in neuronal activity that can lead to a wider range of neuropsychiatric problems upon T. gondii infection.

Mice with genetic deletion of the heparin-binding growth factor midkine exhibit early preclinical features of Parkinson’s disease

There is considerable evidence showing that the neurodegenerative processes that lead to sporadic Parkinson's disease (PD) begin many years before the appearance of the characteristic motor symptoms and that impairments in olfactory, cognitive and motor functions are associated with time-dependent disruption of dopaminergic neurotransmission in different brain areas. Midkine is a 13-kDa retinoic acid-induced heparin-binding growth factor involved in many biological processes in the central nervous system such as cell migration, neurogenesis and tissue repair. The abnormal midkine expression may be associated with neurochemical dysfunction in the dopaminergic system and cognitive impairments in rodents. Here, we employed adult midkine knockout mice (Mdk(-/-)) to further investigate the relevance of midkine in dopaminergic neurotransmission and in olfactory, cognitive and motor functions. Mdk(/-) mice displayed pronounced impairments in their olfactory discrimination ability and short-term social recognition memory with no gross motor alterations. Moreover, the genetic deletion of midkine decreased the expression of the enzyme tyrosine hydroxylase in the substantia nigra reducing partially the levels of dopamine and its metabolites in the olfactory bulb and striatum of mice. These findings indicate that the genetic deletion of midkine causes a partial loss of dopaminergic neurons and depletion of dopamine, resulting in olfactory and memory deficits with no major motor impairments. Therefore, Mdk(-/-) mice may represent a promising animal model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD.

Dimebolin is a 5-HT 6 antagonist with acute cognition enhancing activities

Dimebolin (Dimebon™), is a non-selective antihistamine approved in Russia for the treatment of allergy. Recently, this drug has been shown to be neuroprotective in cellular models of Alzheimer's disease and Huntington's disease, and to preserve cognitive function when chronically administered to AF64A lesioned rats. Interests in identifying the molecular targets of dimebolin have intensified with reports of efficacy in clinical trials with Alzheimer's patients. Dimebolin has been found to interact with a number of molecular targets including acetylcholinesterases, N-methyl- d-aspartate receptors, and voltage-gated calcium channels, with potencies in the range of 5–50 μM. In the present study, the action of dimebolin at the serotonin 5-HT 6 receptor was investigated. Dimebolin binds with moderate affinity to both the human and rat recombinant 5-HT 6 receptor ( K i = 26.0 ± 2.5 nM and 119.0 ± 14.0 nM respectively) as well as the native rat 5-HT 6 receptor, and acts as an antagonist in functional cAMP assays. Furthermore, dimebolin occupies the 5-HT 6 receptor in vivo as assessed by ex vivo autoradiography, with a dose–occupancy relationship similar to that of the selective 5-HT 6 antagonist SB-399885. Finally, both SB-399885 and dimebolin produce an acute enhancement of short-term social recognition memory, although dimebolin is approximately 10-fold less potent than SB-399885. Taken together, these studies demonstrate that dimebolin antagonizes the 5-HT 6 receptor with higher affinity than other targets characterized to date, and suggest that this activity may play a role in the acute cognition enhancing effects of this compound in preclinical models and in the clinic.

Differential gender-related susceptibility to learning and memory deficits in mice submitted to neonatal freezing microgyria model

Sexual dimorphism during mammalian neural development seems to contribute to differential gender-related incidence in malformations of cortical development in both humans and rodents. Here we investigated the existence of differential gender-related susceptibility to learning and memory deficits and brain injury severity in mice submitted to a microgyria model. Newborn male and female C57BL/6 mice (P0) were submitted to a unilateral freezing lesion (FL) using a cooled steel probe, placed over the right midline anteroposterior plane. Mice were allowed to survive for 12–14 weeks and then were submitted to behavioral tasks and brain morphological analyses. Injured mice from both genders did not present gross locomotor alterations, and the freezing lesion resulted in similar brain damage in male and female mice. Additionally, a selective disruption in the short-term social recognition memory was observed in injured male mice while the long-term inhibitory avoidance memory was not affected by both the factors. These results indicate a reduced susceptibility of female to short-term social-memory deficits induced by neonatal model of microgyria in mice, suggesting that the cognitive deficits induced by freezing lesions in rodents may not be entirely related to the severity of brain injury.

Short-term social recognition memory deficit and atypical social and physiological stressor reactivity in seizure-susceptible El mice

The present studies characterize working memory capabilities in the El mouse model of epilepsy using a species-typical social recognition memory task. As the El mouse exhibits a stress hyper-reactivity phenotype, the impact of hypertonic saline consumption, a memory modulatory treatment, upon social recognition performance was also examined. The hypotheses under test were: (1) that seizure susceptible El mice would perform poorly in the short-term working memory task relative to seizure resistant ddY controls, and (2) that the behavioral and neural responses to stressor exposure would be atypical in El mice. Results revealed a short-term working memory deficit and altered reactivity to social, environmental, and physiological stressors in El mice. In Experiment 1, El mice exhibited poor sociability and decreased olfactory investigation times, both anxiogenic-like traits, compared to ddY controls. In Experiment 2, El mice exhibited poor working memory performance compared to capable performance in ddY controls. Social recognition memory in ddY mice was abolished, however, by salt-loading whereas El mice were unaffected by exposure to this physiological stressor. In Experiment 3, all salt-loaded mice exhibited enhanced brain stress neuropeptide (corticotropin releasing factor-CRF) content, and salt-loaded El mice exhibited a 70% reduction in handling-induced seizures. These findings suggest that El mice exhibit high emotionality as well as atypical reactions to stressor exposure, and that these characteristics impact social working memory performance and seizure susceptibility.

Neonatal novelty exposure, dynamics of brain asymmetry, and social recognition memory.

Brief and transient early-life stimulation via neonatal handling and neonatal novelty exposure can lead to differential changes within the right and left brains. In rats, these lateralized changes have been demonstrated behaviorally, neuroanatomically, and neurophysiologically. Recently, we found that neonatal novelty exposure can prolong the duration of social recognition memory from less than 2 hr to at least 24 hr among male rats reared in social isolation and that this enhancement is associated with an initial right-turn preference in a novel testing cage. In contrast to stable forms of asymmetry, such as handedness, we show that this turning asymmetry is dynamic-decreasing as the animal adjusts to the novel testing environment over a 2-day period. This change in turning asymmetry was found only among animals that experienced neonatal novelty exposure during the first 3 weeks of their lives. Furthermore, individual differences in short-term social recognition memory for a conspecific can be predicted by this change in functional asymmetry.