Social Behavior Rodents


Modeling Human Sexual Motivation in Rodents: Some Caveats

Frontiers in behavioral neurosciences


Sexual behavior is activated by motivation. An overwhelming majority of experimental studies of the intricacies of sexual motivation has been performed in rodents, most of them in rats. Sometimes it is desirable to generalize results obtained in this species to other species, particularly the human. It is hoped that studies of the neurobiology of rodent sexual behavior may shed light on the central nervous mechanisms operating in the human, and the search for efficient pharmacological treatments of human sexual dysfunctions relies partly on studies performed in rodents. Then the issue of generalizability of the rodent data to the human becomes crucial. We emphasize the importance of distinguishing between copulatory acts, behavior involving the genitals, and the preceding event, the establishment of physical contact with a potential mate. Comparisons between the structure of copulatory behavior in rats and humans show abysmal differences, but there may be some similarity in the underlying mechanisms. The endocrine control of sex behavior is shortly mentioned, and we also compare the effects of the few drugs known to affect both rodent and human copulatory behavior. The stimuli activating sexual motivation, often called desire in the human literature, are examined, and the sexual approach behaviors in rats and humans are compared. There is a striking similarity between these species in how these behaviors respond to drugs. It is then shown that the intensity of sexual approach is unrelated to the intensity of copulatory behavior. Even though the approach is a requisite for copulation, an activity that requires at least two individuals in close physical contact, these two aspects of sexuality do not covary. This is similar to the role of the testosterone in men and male rats: although the hormone is needed for sex behavior, there is no correlation between serum testosterone concentration and the intensity of copulation. It is also pointed out that human sexual behavior is mostly determined by social conventions, whereas this is not the case in rats and other rodents. It is concluded that some observations in rats can be generalized to the human, but extreme caution must be exercised.


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Topographical memory analyzed in mice using the Hamlet Test, a novel complex maze

Neurobiology of Learning and Memory



The Hamlet test is a novel complex environment for testing topographic memory in mice.

Exploration and memory differ in different mouse strains but not gender.

The hippocampus-subiculum-parahippocampal gyrus axis and dopaminergic structures are activated.

Training increased hippocampal neurogenesis (cell proliferation and neuronal maturation).

Topographical disorientation was measured in the Hamlet test using a pharmacological model of Alzheimer's disease.


The Hamlet test is an innovative device providing a complex environment for testing topographic memory in mice. Animals were trained in groups for weeks in a small village with a central agora, streets expanding from it towards five functionalized houses, where they can drink, eat, hide, run, interact with a stranger mouse. Memory was tested by depriving mice from water or food and analyzing their ability to locate the Drink/Eat house. Exploration and memory were analysed in different strains, gender, and after different training periods and delays. After 2 weeks training, differences in exploration patterns were observed between strains, but not gender. Neuroanatomical structures activated by training, identified using FosB/ΔFosB immunolabelling, showed an involvement of the hippocampus-subiculum-parahippocampal gyrus axis and dopaminergic structures. Training increased hippocampal neurogenesis (cell proliferation and neuronal maturation) and modified the amnesic efficacy of muscarinic or nicotinic cholinergic antagonists. Moreover, topographical disorientation in Alzheimer's disease was addressed using intracerebroventricular injection of amyloid β25-35 peptide in trained mice. When retested after 7 days, Aβ25-35-treated mice showed memory impairment. The Hamlet test specifically allows analysis of topographical memory in mice, based on complex environment. It offers an innovative tool for various ethological or pharmacological research needs. For instance, it allows to examine topographical disorientation, a warning sign in Alzheimer's disease.


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Gamma Oscillation Dysfunction in mPFC Leads to Social Deficits in Neuroligin 3 R451C Knockin Mice




Neuroligins (NLs) are critical for synapse formation and function. NL3 R451C is an autism-associated mutation. NL3 R451C knockin (KI) mice exhibit autistic behavioral abnormalities, including social novelty deficits. However, neither the brain regions involved in social novelty nor the underlying mechanisms are clearly understood. Here, we found decreased excitability of fast-spiking interneurons and dysfunction of gamma oscillation in the medial prefrontal cortex (mPFC), which contributed to the social novelty deficit in the KI mice. Neuronal firing rates and phase-coding abnormalities were also detected in the KI mice during social interactions. Interestingly, optogenetic stimulation of parvalbumin interneurons in the mPFC at 40 Hz nested at 8 Hz positively modulated the social behaviors of mice and rescued the social novelty deficit in the KI mice. Our findings suggest that gamma oscillation dysfunction in the mPFC leads to social deficits in autism, and manipulating mPFC PV interneurons may reverse the deficits in adulthood.


Autism ; Neuroligin 3 ; social novelty ; mPFC ; gamma oscillation ; PV interneuron ; excitability ; optogenetic ; stimulation

LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism

Journal of Medicinal Chemistry



Oxytocin (OT) and its receptor (OT-R) are implicated in the etiology of autism spectrum disorders (ASD), and OT-R is a potential target for therapeutic intervention. Very few nonpeptide oxytocin agonists have currently been reported. Their molecular and in vivo pharmacology remain to be clarified, and none of them has been shown to be efficient in improving social interaction in animal models relevant to ASD. In an attempt to rationalize the design of centrally active nonpeptide full agonists, we studied in a systematic way the structural determinants of the affinity and efficacy of representative ligands of the V1a and V2 vasopressin receptor subtypes (V1a-R and V2-R) and of the oxytocin receptor. Our results confirm the subtlety of the structure–affinity and structure–efficacy relationships around vasopressin/oxytocin receptor ligands and lead however to the first nonpeptide OT receptor agonist active in a mouse model of ASD after peripheral ip administration.

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Striatal cholinergic interneurons regulate cognitive and affective dysfunction in partially dopamine‐depleted mice

European Journal of Neuroscience



Early non‐motor symptoms such as mood disorders and cognitive deficits are increasingly recognised in Parkinson's disease (PD). They may precede the characteristic motor symptomatology caused by dopamine (DA) neuronal loss in the substantia nigra pars compacta (SNc). It is well known that striatal cholinergic interneurons (ChIs) are emerging as key regulators of PD motor symptom, however, their involvement in the cognitive and affective alterations occurring in the premotor phase of PD is poorly understood. We used optogenetic photoinhibition of striatal ChIs in mice with mild nigrostriatal 6‐hydroxydopamine (6‐OHDA) lesions and assessed their role in anxiety‐like behaviour in the elevated plus maze, social memory recognition of a congener and visuospatial object recognition. In transgenic mice specifically expressing halorhodopsin (eNpHR) in cholinergic neurons, striatal ChIs photoinhibition reduced the anxiety‐like behaviour and reversed social and spatial short‐term memory impairment induced by moderate DA depletion (e.g., 50% loss of tyrosine hydroxylase TH‐positive neurons in the SNc). Systemic injection of telenzepine (0.3 mg/kg), a preferential M1 muscarinic cholinergic receptors antagonist, improved anxiety‐like behaviour, social memory recognition but not spatial memory deficits. Our results suggest that dysfunction of the striatal cholinergic system may play a role in the short‐term cognitive and emotional deficits of partially DA‐depleted mice. Blocking cholinergic activity with M1 muscarinic receptor antagonists may represent a possible therapeutic target, although not exclusive, to modulate these early non‐motor deficits.

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Altered social behavior in mice carrying a cortical Foxp2 deletion

Human Molecular Genetics



Genetic disruptions of the forkhead box transcription factor FOXP2 in humans cause an autosomal-dominant speech and language disorder. While FOXP2 expression pattern are highly conserved, its role in specific brain areas for mammalian social behaviors remains largely unknown. Here we studied mice carrying a homozygous cortical Foxp2 deletion. The postnatal development and gross morphological architecture of mutant mice was indistinguishable from wildtype (WT) littermates. Unbiased behavioral profiling of adult mice revealed abnormalities in approach behavior towards conspecifics as well as in the reciprocal responses of WT interaction partners. Furthermore mutant mice showed alterations in acoustical parameters of ultrasonic vocalizations (USV), which also differed in function of the social context. Cell type-specific gene expression profiling of cortical pyramidal neurons revealed aberrant regulation of genes involved in social behavior. In particular Foxp2 mutants showed the downregulation of Mint2 (Apba2), a gene involved in approach behavior in mice and autism spectrum disorder in humans. Taken together these data demonstrate that cortical Foxp2 is required for normal social behaviors in mice.


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Transgenerational transmission of enhanced ocular dominance plasticity from enriched mice to their non-enriched offspring



In recent years, evidence has accumulated that non-Mendelian transgenerational inheritance of qualities acquired through experience is possible. In particular, it has been shown that raising rodents in a so-called enriched environment (EE) can not only modify the animals’ behaviour and increase their susceptibility to activity-dependent neuronal network changes, but also influences both behaviour and neuronal plasticity of the non-enriched offspring. Here, we tested whether such a transgenerational transmission can also be observed in the primary visual cortex (V1) using ocular dominance (OD) plasticity after monocular deprivation (MD) as a paradigm. While OD-plasticity after 7 days of MD is absent in standard-cage (SC) raised mice beyond postnatal day (P) 110, it is present lifelong in EE-raised mice. Using intrinsic signal optical imaging to visualize cortical activity, we confirm these previous observations
12 and additionally show that OD-plasticity is not only preserved in adult EE-mice but also in their adult non-enriched offspring: mice born to enriched parents, but raised in SCs at least until P110 displayed similar OD-shifts towards the open eye after 7 days of MD as age matched EE-raised animals. Furthermore, testing the offspring of EE-female versus EE-males with SC-mating partners revealed that only pups of EE-females, but not of EE-males, preserved OD-plasticity into adulthood, suggesting that the life experiences of the mother have a greater impact on the continued V1-plasticity of the offspring. The OD-plasticity of the non-enriched pups of EE-mothers was, however, mechanistically different from that of non enriched pups of EE-parents or EE-mice.

Stress–glucocorticoid–TSC22D3 axis compromises therapy-induced antitumor immunity

Nature Medecine



Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.


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Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression

Molecular Psychiatry



Current antidepressants act principally by blocking monoamine reuptake by high-affinity transporters in the brain. However, these antidepressants show important shortcomings such as slow action onset and limited efficacy in nearly a third of patients with major depression disorder. Here, we report the development of a prodrug targeting organic cation transporters (OCT), atypical monoamine transporters recently implicated in the regulation of mood. Using molecular modeling, we designed a selective OCT2 blocker, which was modified to increase brain penetration. This compound, H2-cyanome, was tested in a rodent model of chronic depression induced by 7-week corticosterone exposure. In male mice, prolonged administration of H2-cyanome induced positive effects on several behaviors mimicking symptoms of depression, including anhedonia, anxiety, social withdrawal, and memory impairment. Importantly, in this validated model, H2-cyanome compared favorably with the classical antidepressant fluoxetine, with a faster action on anhedonia and better anxiolytic effects. Integrated Z-scoring across these depression-like variables revealed a lower depression score for mice treated with H2-cyanome than for mice treated with fluoxetine for 3 weeks. Repeated H2-cyanome administration increased ventral tegmental area dopaminergic neuron firing, which may underlie its rapid action on anhedonia. H2-cyanome, like fluoxetine, also modulated several intracellular signaling pathways previously involved in antidepressant response. Our findings provide proof-of-concept of antidepressant efficacy of an OCT blocker, and a mechanistic framework for the development of new classes of antidepressants and therapeutic alternatives for resistant depression and other psychiatric disturbances such as anxiety.


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