Foxp2 mediates sex differences in ultrasonic vocalization by rat pups and directs order of maternal retrieval.

The FOXP2 gene is central to acquisition of speech and language in humans and vocal production in birds and mammals. Rodents communicate via ultrasonic vocalizations (USVs) and newborn pups emit distress USVs when separated from their dam, thereby facilitating their retrieval. We observed that isolated male rat pups emitted substantially more USV calls and these were characterized by a significantly lower frequency and amplitude compared with female rat pups. Moreover, the dam was more likely to first retrieve male pups back to the nest, then females. The amount of Foxp2 protein was significantly higher in multiple regions of the developing male brain compared with females and a reduction of brain Foxp2 by siRNA eliminated the sex differences in USVs and altered the order of pup retrieval. Our results implicate Foxp2 as a component of the neurobiological basis of sex differences in vocal communication in mammals. We extended these observations to humans, a species reported to have gender differences in language acquisition, and found the amount of FOXP2 protein in the left hemisphere cortex of 4-year-old boys was significantly lower than in age-matched girls.

The roles of semantic and phonological information in word production: evidence from Spanish-English bilinguals.

The research investigated the roles of semantic and phonological processing in word production. Spanish-English bilingual individuals produced English target words when cued with definitions that were also written in English. When the correct word was not produced, a secondary task was performed in which participants rated the ease of pronunciation of a Spanish prime word. We varied the relatedness between target and prime words. In related conditions, the target and prime words were cognates (i.e., similar in meaning and sound), false cognates (i.e., similar in sound, but different in meaning), or noncognates (i.e., similar in meaning, but different in sound). In unrelated conditions, target and primes were dissimilar in sound and meaning. The results showed that participants' performance was influenced by semantic as well as phonological information. These results provided evidence that semantic as well as phonological information can influence word production, as is predicted by memory models in which representations for semantic and phonological levels of representation are interconnected.

Dysregulation of neonatal hippocampal cell genesis in the androgen insensitive Tfm rat.

The first two weeks of life are a critical period for hippocampal development. At this time gonadal steroid exposure organizes sex differences in hippocampal sensitivity to activational effects of steroids, hippocampal cell morphology and hippocampus dependent behaviors. Our laboratory has characterized a robust sex difference in neonatal neurogenesis in the hippocampus that is mediated by estradiol. Here, we extend our knowledge of this sex difference by comparing the male and female hippocampus to the androgen insensitive testicular feminized mutant (Tfm) rat. In the neonatal Tfm rat hippocampus, fewer newly generated cells survive compared to males or females. This deficit in cell genesis is partially recovered with the potent androgen DHT, but is more completely recovered following estradiol administration. Tfm rats do not differ from males or females in the level of endogenous estradiol in the neonatal hippocampus, suggesting other mechanisms mediate a differential sensitivity to estradiol in male, female and Tfm hippocampus. We also demonstrate disrupted performance on a hippocampal-dependent contextual fear discrimination task. Tfm rats generalize fear across contexts, and do not exhibit significant loss of fear during extinction exposure. These results extend prior reports of exaggerated response to stress in Tfm rats, and following gonadectomy in normal male rats.

Echolalia from a transdiagnostic perspective.

Background & aims: Echolalia, the repetition of one's or others' utterances, is a behavior present in typical development, autism spectrum disorder, aphasias, Tourette's, and other clinical groups. Despite the broad range of conditions in which echolalia can occur, it is considered primarily through a disorder-specific lens, which limits a full understanding of the behavior. Method: Empirical and review papers on echolalia across disciplines and etiologies were considered for this narrative review. Literatures were condensed into three primary sections, including echolalia presentations, neural mechanisms, and treatment approaches. Main contribution: Echolalia, commonly observed in autism and other developmental conditions, is assessed, observed, and treated in a siloed fashion, which reduces our collective knowledge of this communication difference. Echolalia should be considered as a developmental, transdiagnostic, and communicative phenomenon. Echolalia is commonly considered as a communicative behavior, but little is known about its neural etiologies or efficacious treatments. Conclusions: This review is the first to synthesize echolalia from a transdiagnostic perspective, which allows for the direct comparisons across and within clinical groups to inform assessment, treatment, conceptualization, and research recommendations. Implications: Considering echolalia transdiagnostically highlights the lack of consensus on operationalization and measurement across and within disorders. Clinical and research future directions need to prioritize consistent definitions of echolalia, which can be used to derive accurate prevalence estimates. Echolalia should be considered as a communication strategy, used similarly across developmental and clinical groups, with recommended strategies of shaping to increase its effectiveness.

The role of age of acquisition in bilingual word translation: evidence from Spanish-English bilinguals.

The present research tested the hypothesis that the age at which one's first language (L1) words are learned influences language processing in bilinguals. Prior research on bilingual language processing by Kroll and colleagues has suggested that memory links between L1 words and conceptual representations are stronger than memory links between one's second language (L2) word and conceptual representations. We hypothesized that the strengths of memory links between L1 words and conceptual representations are stronger for words learned early in life than for words learned later in life. Support for the hypothesis was obtained in bilingual translation experiment with 36 Spanish-English bilinguals. Participants translated L1 words into L2 and L2 words into L1. Half of the L1 words were learned early in childhood (early AoA words), and half were learned later in life (late AoA words). The L2 words were translation equivalents of the L1 words tested; the average age at which L2 words were learned was age 7. Target words were presented either in random order or blocked by semantic category. Translation times were longer when trials were blocked by semantic category (i.e., categorical interference) occurred only when early AoA L1 words were translated into L2. Implications for current models of bilingual memory are discussed.

Age, but Not Sex, Modulates Foxp3 Expression in the Rat Brain across Development.

The interconnectivity between brain development and the immune system has become an area of interest for many neuroscientists. However, to date, a limited number of known immune mediators of the peripheral nervous system (PNS) have been found to influence the development of the central nervous system (CNS). FOXP3 is a well-established mediator of regulatory T-cells in the PNS. However, the expression pattern of FOXP3 in the CNS and the PNS throughout development is unknown. To fill this void, we have characterized, in several brain regions, the developmental profile of Foxp3 for both sexes using rats. We found different patterns of Foxp3 in the CNS and PNS. In the CNS, we found Foxp3 was ubiquitously expressed, with the levels of Foxp3 varying by brain region. We also found both Foxp3 mRNA and protein levels peak during embryonic development and then steadily decrease with a peak increase during adulthood. In adulthood, the protein but not mRNA increases to the equivalent levels found at the embryonic stage of life. In the PNS, Foxp3 protein levels were low embryonically and increased steadily over the life of the animal with maximal levels reached in adulthood. Patterns observed for both the PNS and CNS were similar in males and females across all developmental timepoints. Our novel findings have implications for understanding how the neural immune system impacts neurodevelopmental disorders such as autism and schizophrenia.

Androgen modulation of Foxp1 and Foxp2 in the developing rat brain: impact on sex specific vocalization.

Sex differences in vocal communication are prevalent in both the animals and humans. The mechanism(s) mediating gender differences in human language are unknown, although, sex hormones, principally androgens, play a central role in the development of vocalizations in a wide variety of animal species. The discovery of FOXP2 has added an additional avenue for exploring the origins of language and animal communication. The FOXP2 gene is a member of the forkhead box P (FOXP) family of transcription factors. Prior to the prenatal androgen surge in male fetuses, we observed no sex difference for Foxp2 protein levels in cultured cells. In contrast, 24 hours after the onset of the androgen surge, we found a sex difference for Foxp2 protein levels in cultured cortical cells with males having higher levels than females. Furthermore, we observed the potent nonaromatizable androgen dihydrotestosterone altered not only Foxp2 mRNA and protein levels but also Foxp1. Androgen effects on both Foxp2 and Foxp1 were found to occur in the striatum, cerebellar vermis, and cortex. Immunofluorescence microscopy and coimmunoprecipitation demonstrate Foxp2 and the androgen receptor protein interact. Databases for transcription factor binding sites predict a consensus binding motif for androgen receptor on the Foxp2 promoter regions. We also observed a sex difference in rat pup vocalization with males vocalizing more than females and treatment of females with dihydrotestosterone eliminated the sex difference. We propose that androgens might be an upstream regulator of both Foxp2 and Foxp1 expression and signaling. This has important implications for language and communication as well as neuropsychiatric developmental disorders involving impairments in communication.

Hemispheric differences in the processing of words learned early versus later in childhood.

The research investigated whether there are hemispheric differences in processing for words acquired early in childhood (early AoA) and words acquired later in childhood (late AoA). We hypothesized that because of recent evidence suggesting that there is a right hemisphere dominance in early childhood, early AoA words would be represented in the right hemisphere, and late AoA words would be represented in the left hemisphere. This hypothesis differs from an early view that late AoA words would be represented in the left hemisphere, and early AoA words would be represented in both hemispheres (Gazzaniga, 1974). We report two experiments using the divided visual field (DVF) technique. The results showed that there was a right visual field (RVF)/left hemisphere (LH) advantage only for late AoA words. For early AoA words, there was a left visual field (LVF)/right hemisphere advantage (RH). Implications for theories of hemispheric differences in word processing are discussed.

ASD-relevant Animal Models of the Foxp Family of Transcription Factors.

Autism is a neurodevelopmental disorder with a multifaceted association between genes and the environment. Currently, in the majority of patients, the etiology of autism is not known and coupled with increasing prevalence rates, along with the high degree of heritability of autism, the development of animal models is crucial for studying and developing therapies for autism. A key characteristic of autism is marked abnormalities in the acquisition and use of language. Thus, to understand and ultimately treat autism is an especially difficult task because no animal produces language, as it is defined in humans. In this review, we will discuss the FOXP family of genes, which are a group of transcription factors that have been linked to both autism, as well as language in humans. Due to the association of language/communication and the Foxp family of transcription factors, animal models with targeted disruptions of Foxp functioning are powerful tools for understanding the developmental signaling pathways that may be vulnerable in autism.

The role of the FOXP family of transcription factors in ASD.

Autism spectrum disorders (ASD) is a neurodevelopmental disease with complex genetics; however, the genes that are responsible for this disease still remain mostly unknown. Here, we focus on the FOXP family of transcription factors as there is emerging evidence strongly linking these genes to ASD and other genes implicated in ASD. The FOXP family of genes includes three genes expressed in the central nervous system: FOXP1, FOPX2, and FOXP4. This unique group of transcription factors has known functions in brain development as well as the evolution of language. We will also discuss the other genes including transcriptional targets of FOXP genes that have been found to be associated with language and may be important in the pathophysiology of ASD. Finally, we will review the emerging animal models currently being used to study the function of the FOXP genes within the context of ASD symptomology. The combination of gene expression and animal behavior is critical for elucidating how genes such as the FOXP family members are key players within the framework of the developing brain.

A developmental sex difference in hippocampal neurogenesis is mediated by endogenous oestradiol.

BACKGROUND: Oestradiol is a steroid hormone that exerts extensive influence on brain development and is a powerful modulator of hippocampal structure and function. The hippocampus is a critical brain region regulating complex cognitive and emotional responses and is implicated in the aetiology of several mental health disorders, many of which exhibit some degree of sex difference. Many sex differences in the adult rat brain are determined by oestradiol action during a sensitive period of development. We had previously reported a sex difference in rates of cell genesis in the developing hippocampus of the laboratory rat. Males generate more new cells on average than females. The current study explored the effects of both exogenous and endogenous oestradiol on this sex difference. METHODS: New born male and female rat pups were injected with the mitotic marker 5-bromo-2-deoxyuridine (BrdU) and oestradiol or agents that antagonize oestradiol action. The effects on cell number, proliferation, differentiation and survival were assessed at several time points. Significant differences between groups were determined by two- or thee-Way ANOVA. RESULTS: Newborn males had higher rates of cell proliferation than females. Oestradiol treatment increased cell proliferation in neonatal females, but not males, and in the CA1 region many of these cells differentiated into neurons. The increased rate of proliferation induced by neonatal oestradiol persisted until at least 3 weeks of age, suggesting an organizational effect. Administering the aromatase inhibitor, formestane, or the oestrogen receptor antagonist, tamoxifen, significantly decreased the number of new cells in males but not females. CONCLUSION: Endogenous oestradiol increased the rate of cell proliferation observed in newborn males compared to females. This sex difference in neonatal neurogenesis may have implications for adult differences in learning strategy, stress responsivity or vulnerability to damage or disease.