Social Interactions of DAT-HET Epi-Genotypes Differing for Maternal Origins: The Development of a New Preclinical Model of Socio-Sexual Apathy

Social interaction is essential for life and is impaired in many psychiatric disorders like schizophrenia, au-tism, depression and major anxiety disorder. Monoamine transmission plays a key role in social behavior and both genetic and epigenetic modifications of dopamine and noradrenaline neurotransmission-related genes can affect the levels of social interaction. Since heterozygous individuals for a specific genetic trait possess only one mutant allele of that trait, in order to better evaluate the role of the interaction between genetics and epigenetics in unmasking latent genetically-determined predispositions, our interest has focused on studying the interplay between genetics and epigenetics influences on social behavior in male rats obtained by two different breeding schemes: a first group by breeding of knock-out (KO) male rats with wild-type (WT) female dams (homogeneous heterozygous offspring, termed MAT-HET), and a second group of heterozygous DAT male offspring by breeding of KO male and DAT-heterozygous female subjects (to obtain comparable control pups, termed MIX-HET). Their social behavior was then assessed by partner preference, social preference and elicited preference tests. In the first test MIX-HET and MAT-HET male mice had choice between two WT females one in estrous and the other not in estrous. In the second test they met either a MIX-HET or a WT male rodent. Also, the expression of the noradrenaline transporter (NET) was assessed in the prefrontal cortex, hippocampus and hypothalamus of MAT, MIX and WTs by immunofluorescence in order to estimate its involvement in the expression of social behavior. Our results show that MIX-HET focal rodents tend to have an asocial behavior when in contact with a female in estrous, and their behavior is similar to when the stimulus is a MIX-HET male. MAT-HET male rodents, instead, tend to be very attracted by the female in estrous, but they ignore the MIX-HET stimulus. MIX-HET progeny showed a lower expression of noradrenaline transporter in both hypothalamus and hippocampus with respect to MAT-HET rats, whereas MAT-HET rats displayed increased noradrenaline transporter immunofluorescence in the hypothalamus and in the hippocampus with respect to WT rats, while no difference was observed in the prefrontal cortex. Therefore we can hypothesize that the differences observed between the two heterozygous groups may be attributable to an epigenetic factor: the different maternal care received. These data can open new perspectives towards increased the preclinical knowledge about autism and bipolar disorder.

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Social Interactions of Dat-Het Epi-Genotypes Differing for Maternal Origins: The Development of a New Preclinical Model of Socio-Sexual Apathy

Biomedicines ◽

10.3390/biomedicines9070778 ◽

2021 ◽

Vol 9 (7) ◽

pp. 778

Author(s):

Anna Brancato ◽

Sara L. M. Lo Russo ◽

Anna Sara Liberati ◽

Cristiana Carbone ◽

Silvia Zelli ◽

...

Keyword(s):

Social Behavior ◽

Social Interactions ◽

Psychiatric Disorders ◽

Dopamine Transporter ◽

Social Preference ◽

Male Rats ◽

Abnormal Behavior ◽

Preclinical Model ◽

Behavioral Differences ◽

Focal Male

Social interaction is essential for life but is impaired in many psychiatric disorders. We presently focus on rats with a truncated allele for dopamine transporter (DAT). Since heterozygous individuals possess only one non-mutant allele, epigenetic interactions may unmask latent genetic predispositions. Homogeneous “maternal” heterozygous offspring (termed MAT-HET) were born from dopamine-transporter knocked-out (DAT-KO) male rats and wild-type (WT) mothers; “mixed” heterozygous offspring (termed MIX-HET) were born from both DAT-heterozygous parents. Their social behavior was assessed by: partner-preference (PPT), social-preference (SPT) and elicited-preference (EPT) tests. During the PPT, focal MIX-HET and MAT-HET males had a choice between two WT females, one in estrous and the other not. In the SPT, they met as stimulus either a MIX-HET or a WT male. In the EPT, the preference of focal male WT rats towards either a MIX- or a MAT-HET stimulus was tested. MIX-HET focal males showed an abnormal behavior, seeming not interested in socializing either with a female in estrous or with another male if MIX-HET. Focal MAT-HET males, instead, were very attracted by the female in estrous, but totally ignored the MIX-HET male. We assessed the expression of noradrenaline transporter (NET) in prefrontal cortex, hippocampus and hypothalamus, finding differences between the two offspring. MIX-HETs’ hypothalamus and hippocampus showed less NET than MAT-HETs, while the latter, in turn, showed higher NET than WTs. These behavioral differences between heterozygous groups may be attributed to different maternal cares received. Results allow preclinical understanding of epigenetic factors involved in social-behavior abnormalities, typical of many psychiatric disorders.

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Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction

10.1101/598342 ◽

2019 ◽

Author(s):

Ashley L. Comer ◽

Tushare Jinadasa ◽

Lisa N. Kretsge ◽

Thanh P.H. Nguyen ◽

Jungjoon Lee ◽

...

Keyword(s):

Prefrontal Cortex ◽

Social Interaction ◽

Social Behavior ◽

Social Interactions ◽

Confocal Imaging ◽

Immune Gene ◽

Causative Role ◽

Severe Mental Disorder ◽

Brain Disorder ◽

Spine Development

ABSTRACTSchizophrenia is a severe mental disorder with an unclear pathophysiology. Increased expression of the immune gene C4 has been linked to a greater risk of developing schizophrenia; however, it is unknown whether C4 plays a causative role in this brain disorder. Using confocal imaging and whole-cell electrophysiology, we demonstrate that overexpression of C4 in mouse prefrontal cortex neurons leads to perturbations in dendritic spine development and hypoconnectivity, which mirror neuropathologies found in schizophrenia. We find evidence that microglia-neuron interactions and microglia-mediated synaptic engulfment are enhanced with increased expression of C4. We also show that C4-dependent circuit dysfunction in the frontal cortex leads to decreased social interactions in juvenile mice. These results demonstrate that increased expression of the schizophrenia-associated gene C4 causes aberrant circuit wiring in the developing prefrontal cortex and leads to deficits in early social behavior, suggesting that altered C4 expression contributes directly to schizophrenia pathogenesis.

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Prefrontal-amygdalar oscillations related to social interaction behavior in mice

10.1101/2021.11.03.467135 ◽

2021 ◽

Author(s):

Takuya Sasaki ◽

Nahoko Kuga ◽

Reimi Abe ◽

Kotomi Takano ◽

Yuji Ikegaya

Keyword(s):

Prefrontal Cortex ◽

Social Interaction ◽

Social Behavior ◽

Basolateral Amygdala ◽

Neuronal Population ◽

Social Avoidance ◽

Wild Type ◽

Interaction Behavior ◽

Neurophysiological Mechanisms ◽

Medial Pfc

The medial prefrontal cortex and amygdala are involved in the regulation of social behavior and associated with psychiatric diseases but their detailed neurophysiological mechanisms at a network level remain unclear. We recorded local field potentials (LFPs) from the dorsal medial PFC (dmPFC) and basolateral amygdala (BLA) while mice engaged on social behavior. We found that in wild-type mice, both the dmPFC and BLA increased 4–7 Hz oscillation power and decreased 30–60 Hz power when they needed to attend to another target mouse. In mouse models with reduced social interactions, dmPFC 4–7 Hz power further increased especially when they exhibited social avoidance behavior. In contrast, dmPFC and BLA decreased 4–7 Hz power when wild-type mice socially approached a target mouse. Frequency-specific optogenetic manipulations of replicating social approach-related LFP patterns restored social interaction behavior in socially deficient mice. These results demonstrate a neurophysiological substrate of the prefrontal cortex and amygdala related to social behavior and provide a unified pathophysiological understanding of neuronal population dynamics underlying social behavioral deficits.

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A new model as an early life manipulation: Fake mother

European Psychiatry ◽

10.1016/j.eurpsy.2017.02.315 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S346-S346

Author(s):

M. Kucukkarapinar ◽

A. Dönmez ◽

S. Candansayar ◽

A. Bozkurt ◽

E. Akçay

Keyword(s):

Prefrontal Cortex ◽

Social Interaction ◽

Social Behavior ◽

Aggressive Behavior ◽

Early Life ◽

Social Interaction Test ◽

Protein Levels ◽

Maternal Odor ◽

Interaction Test

IntroductionEarly life stressful events cause long-term neural changes that are associated with psychiatric disorders.ObjectiveEarly life manipulations focus on commonly the impact of remaining separate from the mother in a specific period of time. The maternal odor is required for pups to approach the mother for nursing. What happens when there is a mother that smell like a real mother but does not take care her own pups?AimTo investigate the fake mother effects on adult rat's behavioral changes, NMDR2B protein level changes in prefrontal cortex and hippocampus.MethodsWistar rats were used. Fake mother (n:13), early handling (n:12), maternal separation (n:14) and control (n:12) were the study groups. A fake mother is an object that smells like a real dam. When the real mother is separated from own pups fake mother stays with the pups for an hour. Manipulations were made during the postnatal first 14 days. Behavioral tests (social interaction test, elevated plus maze, novel object recognition test) were made between postnatal 62 and 78 days. NMDAR2B protein levels in prefrontal cortex and hippocampus were evaluated by using ELISA at postnatal 78 days.ResultsIn social interaction test, fake mother group exhibited less social behavior and more aggressive behavior than the other groups. Their long-term memory functions were the lowest. NMDAR2B protein levels in the hippocampus increased in rats that exposed to early stressful life events.ConclusionThese results support that being raised by fake mother increases aggressive behavior and decrease social behavior in adulthood.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Viral-mediated Zif268 expression in the prefrontal cortex protects against gonadectomy-induced working memory, long-term memory, and social interaction deficits in male rats

Neuroscience ◽

10.1016/j.neuroscience.2016.10.062 ◽

2017 ◽

Vol 340 ◽

pp. 243-257 ◽

Cited By ~ 7

Author(s):

Amanda M. Dossat ◽

Hussam Jourdi ◽

Katherine N. Wright ◽

Caroline E. Strong ◽

Ambalika Sarkar ◽

...

Keyword(s):

Working Memory ◽

Prefrontal Cortex ◽

Social Interaction ◽

Male Rats ◽

Long Term Memory ◽

Term Memory

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Sex-dependent effects of traumatic stress on social behavior and neuronal activation in the prefrontal cortex and amygdala

10.1101/2021.12.16.473017 ◽

2021 ◽

Author(s):

Mariia Dorofeikova ◽

Chandrashekhar D Borkar ◽

Katherine Weissmuller ◽

Lydia Smith-Osborne ◽

Samhita Basavanhalli ◽

...

Keyword(s):

Prefrontal Cortex ◽

Social Interaction ◽

Social Behavior ◽

Acute Stress ◽

Negative Impact ◽

Early Gene ◽

Central Nucleus ◽

Dependent Manner ◽

Neuronal Activation ◽

Footshock Stress

Social behavior is complex and fundamental, and deficits in social behavior are common pathological features for a variety of psychiatric disorders including anxiety, depression, and posttraumatic stress disorder. Acute stress has a negative impact on social behavior, and these effects may vary based on sex. The aim of this study was to explore the effect of footshock stress on the sociability of male and female C57Bl/6J mice. Animals were divided into two main groups of footshock exposure or context exposure control. Each group had mice that were treated with either the benzodiazepine alprazolam, or vehicle. Neuronal activation during social interaction was assessed using immunohistochemistry against the immediate early gene product cFos. Footshock stress induced a significantly increased latency to approach a social interaction counterpart in both sexes. Stress-induced increases in defensive tail-rattling behavior elicited during the sociability test were sex-dependent and alleviated by alprazolam. Alprazolam also lowered social exploration and neuronal activation in the infralimbic medial prefrontal cortex. Social interaction induced sex-dependent differences in cFos activation in the lateral subdivision of the central nucleus of the amygdala and ventromedial intercalated cell clusters. Overall, our results suggest that acute footshock stress induces alterations in sociability and patterns of cFos activation in a sex-dependent manner.

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Oxytocin receptors influence the development and maintenance of social behavior in zebrafish (Danio rerio).

10.1101/2021.06.26.449566 ◽

2021 ◽

Author(s):

Anja Gemmer ◽

Kristina Mirkes ◽

Lukas Anneser ◽

Tim Eilers ◽

Caroline Kibat ◽

...

Keyword(s):

Social Behavior ◽

Social Preference ◽

Autism Spectrum ◽

Social Impairment ◽

Wild Type ◽

Knock Out ◽

Oxytocin Receptors ◽

Shoaling Behavior ◽

Kinetics Of

Zebrafish are highly social teleost fish and an excellent model to study social behavior. The neuropeptide Oxytocin is associated different social behaviors as well as disorders resulting in social impairment like autism spectrum disorder. However, how Oxytocin receptor signaling affects the development and expression kinetics of social behavior is not known. In this study we investigated the role of the two oxytocin receptors, Oxtr and Oxtrl, in the development and maintenance of social preference and shoaling behavior in 2- to 8-week-old zebrafish. Using CRISPR/Cas9 mediated oxtr and oxtrl knock-out fish, we found that the development of social preference is accelerated if one of the Oxytocin receptors is knocked-out and that the knock-out fish reach significantly higher levels of social preference. Moreover, oxtr-/- fish showed impairments in the maintenance of social preference. Social isolation prior to testing led to impaired maintenance of social preference in both wild-type and oxtr and oxtrl knock-out fish. Knocking-out one of the Oxytocin receptors also led to increased group spacing and reduced polarization in a 20-fish shoal at 8 weeks post fertilization, but not at 4. These results show that the development and maintenance of social behavior is influenced by the Oxytocin receptors and that the effects are not just pro- or antisocial, but dependent on both the age and social context of the fish.

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Development of social behaviour in young zebrafish.

10.1101/017863 ◽

2015 ◽

Author(s):

Elena Dreosti ◽

Gonçalo Lopes ◽

Adam R. Kampff ◽

Stephen W. Wilson

Keyword(s):

Social Interaction ◽

Social Behavior ◽

Simple Form ◽

Social Behaviour ◽

Social Preference ◽

Acute Exposure ◽

Adult Zebrafish ◽

Larval Zebrafish ◽

Stage Of Development ◽

Social Animals

Adult zebrafish are robustly social animals whereas larva is not. We designed an assay to determine at what stage of development zebrafish begin to interact with and prefer other fish. One week old zebrafish do not show significant social preference whereas most 3 weeks old zebrafish strongly prefer to remain in a compartment where they can view conspecifics. However, for some individuals, the presence of conspecifics drives avoidance instead of attraction. Social preference is dependent on vision and requires viewing fish of a similar age/size. In addition, over the same 1-3 weeks period larval zebrafish increasingly tend to coordinate their movements, a simple form of social interaction. Finally, social preference and coupled interactions are differentially modified by an NMDAR antagonist and acute exposure to ethanol, both of which are known to alter social behavior in adult zebrafish.

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Structural and functional brain-wide alterations in A350V Iqsec2 mutant mice displaying autistic-like behavior

Translational Psychiatry ◽

10.1038/s41398-021-01289-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Daniela Lichtman ◽

Eyal Bergmann ◽

Alexandra Kavushansky ◽

Nadav Cohen ◽

Nina S. Levy ◽

...

Keyword(s):

Social Behavior ◽

Functional Connectivity ◽

Mouse Model ◽

Ampa Receptor ◽

Social Preference ◽

Autism Spectrum ◽

Receptor Trafficking ◽

Anterior Cingulate ◽

The Impact ◽

Ampa Receptor Trafficking

AbstractIQSEC2 is an X-linked gene that is associated with autism spectrum disorder (ASD), intellectual disability, and epilepsy. IQSEC2 is a postsynaptic density protein, localized on excitatory synapses as part of the NMDA receptor complex and is suggested to play a role in AMPA receptor trafficking and mediation of long-term depression. Here, we present brain-wide structural volumetric and functional connectivity characterization in a novel mouse model with a missense mutation in the IQ domain of IQSEC2 (A350V). Using high-resolution structural and functional MRI, we show that animals with the A350V mutation display increased whole-brain volume which was further found to be specific to the cerebral cortex and hippocampus. Moreover, using a data-driven approach we identify putative alterations in structure–function relations of the frontal, auditory, and visual networks in A350V mice. Examination of these alterations revealed an increase in functional connectivity between the anterior cingulate cortex and the dorsomedial striatum. We also show that corticostriatal functional connectivity is correlated with individual variability in social behavior only in A350V mice, as assessed using the three-chamber social preference test. Our results at the systems-level bridge the impact of previously reported changes in AMPA receptor trafficking to network-level disruption and impaired social behavior. Further, the A350V mouse model recapitulates similarly reported brain-wide changes in other ASD mouse models, with substantially different cellular-level pathologies that nonetheless result in similar brain-wide alterations, suggesting that novel therapeutic approaches in ASD that result in systems-level rescue will be relevant to IQSEC2 mutations.

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