Foxp2 Mediates Sex Differences in Ultrasonic Vocalization by Rat Pups and Directs Order of Maternal Retrieval

Departments of Physiology and Psychiatry, and Department of Pharmacology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201, and Centro de Investigaciones Cerebrales and Doctorado en Neuroetología, Universidad Veracruzana, 91000 Xalapa, México.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2013; 33(8):3276-83. DOI: 10.1523/JNEUROSCI.0425-12.2013
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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.

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    • " the polyclonal rabbit antibody to FoxP1 ( Abcam , Cambridge , MA , #ab16645 ) at 1 : 500 . Primary antibody was omitted for negative controls . Target specificity of the primary antibody for FoxP2 had been previously verified in zebra finches ( Soderstrom and Luo , 2010 ) , while the primary antibody for FoxP1 was pre - viously verified in rats ( Bowers et al . , 2013 ) . We note that the staining pattern for FoxP2 closely matched that for FoxP1 ; overlapping confocal images show coexpression of FoxP2 and FoxP1 ( see Fig . 3 ) . Following overnight incuba - tion at 4 C , sections were washed three times for 5 min each with 1X PBS , then incubated for 2 hours at room tem - perature in PBST / 1% donkey"
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    ABSTRACT: The forkhead domain FOXP2 and FOXP1 transcription factors are implicated in several cognitive disorders with language deficits, notably autism, and thus play a central role in learned vocal motor behavior in humans. Although a similar role for FoxP2 and FoxP1 is proposed for other vertebrate species, including songbirds, the neurodevelopmental expression of these genes are unknown in a species with lifelong vocal learning abilities. Like humans, budgerigars (Melopsittacus undulatus) learn new vocalizations throughout their entire lifetime. Like songbirds, budgerigars have distinct brain nuclei for vocal learning, which include the magnocellular nucleus of the medial striatum (MMSt), a basal ganglia region that is considered developmentally and functionally analogous to Area X in songbirds. Here we used in situ hybridization and immunohistochemistry to investigate FoxP2 and FoxP1 expression in the MMSt of juvenile and adult budgerigars. We found FoxP2 mRNA and protein expression levels in the MMSt that were lower than the surrounding striatum throughout development and adulthood. In contrast, FoxP1 mRNA and protein had an elevated MMSt/striatum expression ratio as birds matured, regardless of their sex. These results show that life-long vocal plasticity in budgerigars is associated with persistent low-level FoxP2 expression in the budgerigar MMSt, and suggests the possibility that FoxP1 plays an organizational role in the neurodevelopment of vocal motor circuitry. Thus, developmental regulation of the FoxP2 and FoxP1 genes in the basal ganglia appears essential for vocal mimicry in a range of species that possess this relatively rare trait. This article is protected by copyright. All rights reserved.
    Developmental Neurobiology 11/2014; 75(7). DOI:10.1002/dneu.22247 · 3.37 Impact Factor
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    • "Our studies are the first to characterize the effect of cerebral ischemia on the USV that ordinarily occurs in a sex-specific and stimulus-specific manner in healthy rats and mice [35, 36]. In the female mouse, baseline vocalization to cage mates is readily measurable, although there is large variance in this behavior among animals. "
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    ABSTRACT: Transmigration of peripheral leukocytes to the brain is a major contributor to cerebral ischemic cell death mechanisms. Humanized partial major histocompatibility complex class II constructs (pMHC), covalently linked to myelin peptides, are effective for treating experimental stroke in males, but new evidence suggests that some inflammatory cell death mechanisms after brain injury are sex-specific. We here demonstrate that treatment with pMHC constructs also improves outcomes in female mice with middle cerebral artery occlusion (MCAO). HLA-DR2 transgenic female mice with MCAO were treated with RTL1000 (HLA-DR2 moiety linked to human MOG-35-55 peptide), HLA-DRa1-MOG-35-55, or vehicle (VEH) at 3, 24, 48, and 72 h after reperfusion and were recovered for 96 h or 2 weeks post-injury for measurement of histology (TTC staining) or behavioral testing. RTL1000- and DRa1-MOG-treated mice had profoundly reduced infarct volumes as compared to the VEH group, although higher doses of DRa1-MOG were needed for females vs. males evaluated previously. RTL1000-treated females also exhibited strongly improved functional recovery in a standard cylinder test. In novel studies of post-ischemic ultrasonic vocalization (USV), as measured by animal calls to their cage mates, we modeled in mice the post-stroke speech deficits common in human stroke survivors. The number of calls was reduced in injured animals relative to pre-MCAO baseline regardless of RTL1000 treatment status. However, call duration was significantly improved by RTL1000 treatment, suggesting benefit to the animal's recovery of vocalization capability. We conclude that both the parent RTL1000 molecule and the novel non-polymorphic DRα1-MOG-35-55 construct were highly effective immunotherapies for treatment of transient cerebral ischemia in females.
    Translational Stroke Research 05/2014; 5(5). DOI:10.1007/s12975-014-0345-y · 2.44 Impact Factor
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    • "These distress vocalizations provide a unique biologically and socially relevant signal essential for early survival and development (Zeskind et al. 2011). Similarly, previous studies in mice and rats have used maternal separation-induced USVs as an early developmental measure of disease (Hodgson et al. 2008; Scattoni et al. 2009; Bowers et al. 2013; Brudzynski 2013). For example , Foxp2 has previously been shown to mediate sex differences in Fibroblast growth factor 17 KO mice, a putative model for schizophrenia has impaired social behavior as well as decreased maternal separation-induced USVs (Scearce-Levie et al. 2008). "
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    ABSTRACT: Reductions in the levels of the neuropeptide vasopressin (VP) and its receptors have been associated with schizophrenia. VP is also critical for appropriate social behaviors in humans as well as rodents. One of the prominent symptoms of schizophrenia is asociality and these symptoms may develop prodromally. A reduction in event-related potential (ERP) peak amplitudes is an endophenotype of schizophrenia. In this study, we use the Brattleboro (BRAT) rat to assess the role of VP deficiency in vocal communication during early development and on auditory ERPs during adulthood. BRAT rats had similar vocal communication to wild-type littermate controls during postnatal days 2 and 5 but the time between vocalizations was increased and the power of the vocalizations was reduced beginning at postnatal day 9. During adulthood, BRAT rats had deficits in auditory ERPs including reduced N40 amplitude and reduced low and high gamma intertrial coherence. These results suggest that the role of VP on vocal communication is an age-dependent process. Additionally, the deficits in ERPs indicate an impairment of auditory information processing related to the reduction in VP. Therefore, manipulation of the VP system could provide a novel mechanism for treatment for negative symptoms of schizophrenia.
    10/2013; 1(5):e00100. DOI:10.1002/phy2.100
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