Specific Activation of Estrogen Receptor Alpha and Beta Enhances Male Sexual Behavior and Neuroplasticity in Male Japanese Quail

Two subtypes of estrogen receptors (ER), ERα and ERβ, have been identified in humans and numerous vertebrates, including the Japanese quail. We investigated in this species the specific role(s) of each receptor in the activation of male sexual behavior and the underlying estrogen-dependent neural plasticity. Castrated male Japanese quail received empty (CX) or testosterone-filled (T) implants or were daily injected with the ER general agonist diethylstilbestrol (DES), the ERα-specific agonist PPT, the ERβ-specific agonist DPN or the vehicle, propylene glycol. Three days after receiving the first treatment, subjects were alternatively tested for appetitive (rhythmic cloacal sphincter movements, RCSM) and consummatory aspects (copulatory behavior) of male sexual behavior. 24 hours after the last behavioral testing, brains were collected and analyzed for aromatase expression and vasotocinergic innervation in the medial preoptic nucleus. The expression of RCSM was activated by T and to a lesser extent by DES and PPT but not by the ERβagonist DPN. In parallel, T fully restored the complete sequence of copulation, DES was partially active and the specific activation of ERα or ERβ only resulted in a very low frequency of mount attempts in few subjects. T increased the volume of the medial preoptic nucleus as measured by the dense cluster of aromatase-immunoreactive cells and the density of the vasotocinergic innervation within this nucleus. DES had only a weak action on vasotocinergic fibers and the two specific ER agonists did not affect these neural responses. Simultaneous activation of both receptors or treatments with higher doses may be required to fully activate sexual behavior and the associated neurochemical events

Neural Circuits Underlying Rodent Sociality: A Comparative Approach

All mammals begin life in social groups, but for some species, social relationships persist and develop throughout the course of an individual’s life. Research in multiple rodent species provides evidence of relatively conserved circuitry underlying social behaviors and processes such as social recognition and memory, social reward, and social approach/avoidance. Species exhibiting different complex social behaviors and social systems (such as social monogamy or familiarity preferences) can be characterized in part by when and how they display specific social behaviors. Prairie and meadow voles are closely related species that exhibit similarly selective peer preferences but different mating systems, aiding direct comparison of the mechanisms underlying affiliative behavior. This chapter draws on research in voles as well as other rodents to explore the mechanisms involved in individual social behavior processes, as well as specific complex social patterns. Contrasts between vole species exemplify how the laboratory study of diverse species improves our understanding of the mechanisms underlying social behavior. We identify several additional rodent species whose interesting social structures and available ecological and behavioral field data make them good candidates for study. New techniques and integration across laboratory and field settings will provide exciting opportunities for future mechanistic work in non-model species

Environmental Enrichment Rescues Social Behavioral Deficits and Synaptic Abnormalities in Pten Haploinsufficient Mice

Pten germline haploinsufficient (Pten+/−) mice, which model macrocephaly/autism syndrome, show social and repetitive behavior deficits, early brain overgrowth, and cortical–subcortical hyperconnectivity. Previous work indicated that altered neuronal connectivity may be a substrate for behavioral deficits. We hypothesized that exposing Pten+/− mice to environmental enrichment after brain overgrowth has occurred may facilitate adaptation to abnormal “hard-wired” connectivity through enhancing synaptic plasticity. Thus, we reared Pten+/− mice and their wild-type littermates from weaning under either standard (4–5 mice per standard-sized cage, containing only bedding and nestlet) or enriched (9–10 mice per large-sized cage, containing objects for exploration and a running wheel, plus bedding and nestlet) conditions. Adult mice were tested on social and non-social assays in which Pten+/− mice display deficits. Environmental enrichment rescued sex-specific deficits in social behavior in Pten+/− mice and partially rescued increased repetitive behavior in Pten+/− males. We found that Pten+/− mice show increased excitatory and decreased inhibitory pre-synaptic proteins; this phenotype was also rescued by environmental enrichment. Together, our results indicate that environmental enrichment can rescue social behavioral deficits in Pten+/− mice, possibly through normalizing the excitatory synaptic protein abundance

Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes

BACKGROUND: Germline mutations in the phosphatase PTEN are associated with diverse human pathologies, including tumour susceptibility, developmental abnormalities and autism, but any genotype-phenotype relationships are poorly understood. METHODS: We have studied the functional consequences of seven PTEN mutations identified in patients diagnosed with autism and macrocephaly and five mutations from severe tumour bearing sufferers of PTEN hamartoma tumour syndrome (PHTS). RESULTS: All seven autism-associated PTEN mutants investigated retained the ability to suppress cellular AKT signalling, although five were highly unstable. Observed effects on AKT also correlated with the ability to suppress soma size and the length and density of dendritic spines in primary neurons. Conversely, all five PTEN mutations from severe cases of PHTS appeared to directly and strongly disrupt the ability to inhibit AKT signalling. CONCLUSIONS: Our work implies that alleles causing incomplete loss of PTEN function are more commonly linked to autism than to severe PHTS cases

Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by impaired social interaction, isolated areas of interest, and insistence on sameness. Mutations in Phosphatase and tensin homolog missing on chromosome 10 (PTEN) have been reported in individuals with ASDs. Recent evidence highlights a crucial role of the cerebellum in the etiopathogenesis of ASDs. In the present study we analyzed the specific contribution of cerebellar Purkinje cell (PC) PTEN loss to these disorders. Using the Cre-loxP recombination system, we generated conditional knockout mice in which PTEN inactivation was induced specifically in PCs. We investigated PC morphology and physiology as well as sociability, repetitive behavior, motor learning, and cognitive inflexibility of adult PC PTEN-mutant mice. Loss of PTEN in PCs results in autistic-like traits, including impaired sociability, repetitive behavior and deficits in motor learning. Mutant PCs appear hypertrophic and show structural abnormalities in dendrites and axons, decreased excitability, disrupted parallel fiber and climbing fiber synapses and late-onset cell death. Our results unveil new roles of PTEN in PC function and provide the first evidence of a link between the loss of PTEN in PCs and the genesis of ASD-like traits