The brain circuits and synaptic processes that underlie alcohol addiction are currently the subject of intensive research. Here we focus on hippocampal circuitry and show that chemogenetic inhibition of dentate gyrus (DG) during presentation of alcohol-associated cues has long-lasting effects on mice behavior. DG inhibition enhances alcohol seeking and drinking, suggesting that DG regulates addiction-related behaviors. To test this hypothesis, we perform whole-cell patch-clamp recordings from the granule cells of DG and look for electrophysiological correlates of alcohol addiction. We observe that presentation of alcohol-associated cue light that induces relapse to alcohol-seeking results in generation of silent synapses, that lack functional AMPA receptors. Furthermore, using human criteria of addiction, we differentiate mice controlling their alcohol consumption from those that undergo transition to addiction to discover that the levels of silent synapses induced by alcohol cues are specifically increased in the addicted mice. As the total level of dendritic spines that harbor synapses is constant at this time point, our data indicate that synapses of perforant path to DG are weakened during cue relapse. Finally we demonstrate that, acamprosate, a drug that limits alcohol drinking and seeking in addicts, prevents generation of silent synapses in DG upon presentation of alcohol-associated cues. Altogether, our data suggest that weakening of DG synapses upon cue relapse contributes to persistent alcohol addiction-related behaviors.

The α-Ca /calmodulin-dependent protein kinase II (αCaMKII), a key regulator of the glutamatergic synapse, has been implicated in many psychiatric disorders characterized by social impairments. Here we tested whether autophosphorylation of αCaMKII at threonine 286, which prolongs the activity of the enzyme, affects social behaviors in mice. We observed that autophosphorylation-deficient (αCaMKII-T286A) mutant female mice showed abnormal social behaviors characterized by decreased social preference and interest in conspecifics of the same sex, as compared to their wild-type littermates. Moreover, we developed a mathematical approach to analyze social interactions in group-housed mice in the automated IntelliCages. Using this approach we observed that αCaMKII-T286A mutants show decreased levels of social interactions in a social group, as compared with WT mice. WT mice increased the frequency of close social interactions when learning about the location of the food reward. This phenomenon was absent in the mutants. Overall, our data indicates that autophosphorylation of αCaMKII affects social interactions.

Social interactions can be and often are rewarding. The effect of social contact strongly depends on circumstances, and the reward may be driven by varied motivational processes, ranging from parental or affiliative behaviors to investigation or aggression. Reward associated with nonreproductive interactions in rodents is measured using the social conditioned place preference (sCPP) paradigm, where a change in preference for an initially neutral context confirms reinforcing effects of social contact. Here, we revised the sCPP method and reexamined social reward in adult female mice. Contrary to earlier studies, we found that robust rewarding effects of social contact could be detected in adult (14-week-old) female C57BL/6 mice when the sCPP task was refined to remove confounding factors. Strikingly, the rewarding effects of social interaction were only observed among female siblings who remained together from birth. Contact with same-age nonsiblings was not rewarding even after 8 weeks of cohousing. Other factors critical for the social reward effect in the sCPP paradigm included the number of conditioning sessions and the inherent preference for contextual cues. Thus, we show that social interaction is rewarding in adult female mice, but this effect strictly depends on the familiarity of the interaction partners. Furthermore, by identifying confounding factors, we provide a behavioral model to study the mechanisms underlying the rewarding effects of nonreproductive social interaction in adult mice.

No abstract

Social interactions can be and often are rewarding. The effect of social contact strongly depends on circumstances, and the reward may be driven by varied motivational processes, ranging from parental or affiliative behaviors to investigation or aggression. Reward associated with nonreproductive interactions in rodents is measured using the social conditioned place preference (sCPP) paradigm, where a change in preference for an initially neutral context confirms reinforcing effects of social contact. Here, we revised the sCPP method and reexamined social reward in adult female mice. Contrary to earlier studies, we found that robust rewarding effects of social contact could be detected in adult (14-week-old) female C57BL/6 mice when the sCPP task was refined to remove confounding factors. Strikingly, the rewarding effects of social interaction were only observed among female siblings who remained together from birth. Contact with same-age nonsiblings was not rewarding even after 8 weeks of cohousing. Other factors critical for the social reward effect in the sCPP paradigm included the number of conditioning sessions and the inherent preference for contextual cues. Thus, we show that social interaction is rewarding in adult female mice, but this effect strictly depends on the familiarity of the interaction partners. Furthermore, by identifying confounding factors, we provide a model to study the mechanisms underlying the rewarding effects of nonreproductive social interaction in adult mice.

Repeated administration of subanesthetic doses of ketamine is a model of psychosis-like state in rodents. In mice, this treatment produces a range of behavioral deficits, including impairment in social interactions and locomotion. To date, these phenotypes were described primarily in the Swiss and C3H/HeHsd mouse strains. A few studies investigated ketamine-induced behaviors in the C57BL/6J strain, but to our knowledge the C57BL/6N strain was not investigated thus far. This is surprising, as both C57BL/6 sub-strains are widely used in behavioral and neuropsychopharmacological research, and are de facto standards for characterization of drug effects. The goal of this study was to determine if C57BL/6N mice are vulnerable to develop social deficits after 5 days withdrawal from sub-chronic ketamine treatment (5 days, 30 mg/kg, i.p.), an experimental schedule shown before to cause deficits in social interactions in C57BL/6J mice. Our results show that sub-chronic administration of ketamine that was reported to cause psychotic-like behavior in C57BL/6J mice does not induce appreciable behavioral alterations in C57BL/6N mice. Thus, we show that the effects of sub-chronic ketamine treatment in mice are sub-strain specific.

Prosocial behavior, defined as voluntary behavior intended to benefit another, has long been regarded as a primarily human characteristic. In recent years, it was reported that laboratory animals also favor prosocial choices in various experimental paradigms, thus demonstrating that prosocial behaviors are evolutionarily conserved. Here, we investigated prosocial choices in adult male and female C57BL/6 laboratory mice in a task where a subject mouse was equally rewarded for entering any of the two compartments of the experimental cage, but only entering of the compartment designated as “prosocial” rewarded an interaction partner. In parallel we have also assessed two traits that are regarded as closely related to prosociality: sensitivity to social reward and the ability to recognize the affective state of another individual. We found that female, but not male, mice increased frequency of prosocial choices from pretest to test. However, both sexes showed similar rewarding effects of social contact in the conditioned place preference test, and similarly, there was no effect of sex on affective state discrimination measured as the preference for interaction with a hungry or relieved mouse over a neutral animal. These observations bring interesting parallels to differences between sexes observed in humans, and are in line with reported higher propensity for prosocial behavior in human females, but differ with regard to sensitivity to social stimuli in males.

Parkinson's disease (PD) is characterized by three main motor symptoms: bradykinesia, rigidity and tremor. PD is also associated with diverse nonmotor symptoms that may develop in parallel or precede motor dysfunctions, ranging from autonomic system dysfunctions and impaired sensory perception to cognitive deficits and depression. Here, we examine the role of the progressive loss of dopaminergic transmission in behaviors related to the nonmotor symptoms of PD in a mouse model of the disease (the TIF IADATCreERT2 strain). We found that in the period from 5 to 12 weeks after the induction of a gradual loss of dopaminergic neurons, mild motor symptoms became detectable, including changes in the distance between paws while standing as well as the step cadence and sequence. Male mutant mice showed no apparent changes in olfactory acuity, no anhedonia-like behaviors, and normal learning in an instrumental task; however, a pronounced increase in the number of operant responses performed was noted. Similarly, female mice with progressive dopaminergic neuron degeneration showed normal learning in the probabilistic reversal learning task and no loss of sweet-taste preference, but again, a robustly higher number of choices were performed in the task. In both males and females, the higher number of instrumental responses did not affect the accuracy or the fraction of rewarded responses. Taken together, these data reveal discrete, dopamine-dependent nonmotor symptoms that emerge in the early stages of dopaminergic neuron degeneration.