104 research outputs found
Protein-Protein Interaction Among the FoxP Family Members and their Regulation of Two Target Genes, VLDLR and CNTNAP2 in the Zebra Finch Song System
The Forkhead transcription factor FOXP2 is implicated in speech perception and
production. The avian homolog, FoxP21 contributes to song learning and
production in birds. In human cell lines, transcriptional activity of FOXP2
requires homo-dimerization or dimerization with paralogs FOXP1 or FOXP4.
Whether FoxP dimerization occurs in the brain is unknown. We recently showed
that FoxP1, FoxP2 and FoxP4 (FoxP1/2/4) proteins are co-expressed in neurons
of Area X, a song control region in zebra finches. We now report on dimer- and
oligomerization of zebra finch FoxPs and how this affects transcription. In
cell lines and in the brain we identify homo- and hetero-dimers, and an
oligomer composed of FoxP1/2/4. We further show that FoxP1/2 but not FoxP4
bind to the regulatory region of the target gene Contactin-associated protein-
like 2 (CNTNAP2). In addition, we demonstrate that FoxP1/4 bind to the
regulatory region of very low density lipoprotein receptor (VLDLR), as has
been shown for FoxP2 previously. Interestingly, FoxP1/2/4 individually or in
combinations regulate the promoters for SV40, zebra finch VLDLR and CNTNAP2
differentially. These data exemplify the potential for complex transcriptional
regulation of FoxP1/2/4, highlighting the need for future functional studies
dissecting their differential regulation in the brain
“Bird Song Metronomics”: Isochronous Organization of Zebra Finch Song Rhythm
The human capacity for speech and vocal music depends on vocal imitation.
Songbirds, in contrast to non-human primates, share this vocal production
learning with humans. The process through which birds and humans learn many of
their vocalizations as well as the underlying neural system exhibit a number
of striking parallels and have been widely researched. In contrast, rhythm, a
key feature of language, and music, has received surprisingly little attention
in songbirds. Investigating temporal periodicity in bird song has the
potential to inform the relationship between neural mechanisms and behavioral
output and can also provide insight into the biology and evolution of
musicality. Here we present a method to analyze birdsong for an underlying
rhythmic regularity. Using the intervals from one note onset to the next as
input, we found for each bird an isochronous sequence of time stamps, a
“signal-derived pulse,” or pulseS, of which a subset aligned with all note
onsets of the bird's song. Fourier analysis corroborated these results. To
determine whether this finding was just a byproduct of the duration of notes
and intervals typical for zebra finches but not dependent on the individual
duration of elements and the sequence in which they are sung, we compared
natural songs to models of artificial songs. Note onsets of natural song
deviated from the pulseS significantly less than those of artificial songs
with randomized note and gap durations. Thus, male zebra finch song has the
regularity required for a listener to extract a perceived pulse (pulseP), as
yet untested. Strikingly, in our study, pulsesS that best fit note onsets
often also coincided with the transitions between sub-note elements within
complex notes, corresponding to neuromuscular gestures. Gesture durations
often equaled one or more pulseS periods. This suggests that gesture duration
constitutes the basic element of the temporal hierarchy of zebra finch song
rhythm, an interesting parallel to the hierarchically structured components of
regular rhythms in human music
the ‘FOXP2’ gene's journey through time
How did humans evolve language? The fossil record does not yield enough
evidence to reconstruct its evolution and animals do not talk. But as the
neural and molecular substrates of language are uncovered, their genesis and
function can be addressed comparatively in other species. FOXP2 is such a case
– a gene with a strong link to language that is also essential for learning in
mice, birds and even flies. Comparing the role FOXP2 plays in humans and other
animals is starting to reveal common principles that may have provided
building blocks for language evolution
Next stop: Language : the ?FOXP2? gene?s journey through time
How did humans evolve language? The fossil record does not yield enough evidence to reconstruct its evolution and animals do not talk. But as the neural and molecular substrates of language are uncovered, their genesis and function can be addressed comparatively in other species. FOXP2 is such a case ? a gene with a strong link to language that is also essential for learning in mice, birds and even flies. Comparing the role FOXP2 plays in humans and other animals is starting to reveal common principles that may have provided building blocks for language evolution
Dynamic FoxP2 levels in male zebra finches are linked to morphology of adult-born Area X medium spiny neurons
The transcription factor FOXP2 is crucial for the formation and function of cortico-striatal circuits. FOXP2 mutations are associated with specific speech and language impairments. In songbirds, experimentally altered FoxP2 expression levels in the striatal song nucleus Area X impair vocal learning and song production. Overall FoxP2 protein levels in Area X are low in adult zebra finches and decrease further with singing. However, some Area X medium spiny neurons (MSNs) express FoxP2 at high levels (FoxP2(high) MSNs) and singing does not change this. Because Area X receives many new neurons throughout adulthood, we hypothesized that the FoxP2(high) MSNs are newly recruited neurons, not yet integrated into the local Area X circuitry and thus not active during singing. Contrary to our expectation, FoxP2 protein levels did not predict whether new MSNs were active during singing, assayed via immediate early gene expression. However, new FoxP2(high) MSNs had more complex dendrites, higher spine density and more mushroom spines than new FoxP2(low) MSNs. In addition, FoxP2 expression levels correlated positively with nucleus size of new MSNs. Together, our data suggest that dynamic FoxP2 levels in new MSNs shape their morphology during maturation and their incorporation into a neural circuit that enables the maintenance and social modulation of adult birdsong
Food for Song: Expression of C-Fos and ZENK in the Zebra Finch Song Nuclei during Food Aversion Learning
BACKGROUND: Specialized neural pathways, the song system, are required for acquiring, producing, and perceiving learned avian vocalizations. Birds that do not learn to produce their vocalizations lack telencephalic song system components. It is not known whether the song system forebrain regions are exclusively evolved for song or whether they also process information not related to song that might reflect their 'evolutionary history'. METHODOLOGY/PRINCIPAL FINDINGS: To address this question we monitored the induction of two immediate-early genes (IEGs) c-Fos and ZENK in various regions of the song system in zebra finches (Taeniopygia guttata) in response to an aversive food learning paradigm; this involves the association of a food item with a noxious stimulus that affects the oropharyngeal-esophageal cavity and tongue, causing subsequent avoidance of that food item. The motor response results in beak and head movements but not vocalizations. IEGs have been extensively used to map neuro-molecular correlates of song motor production and auditory processing. As previously reported, neurons in two pallial vocal motor regions, HVC and RA, expressed IEGs after singing. Surprisingly, c-Fos was induced equivalently also after food aversion learning in the absence of singing. The density of c-Fos positive neurons was significantly higher than that of birds in control conditions. This was not the case in two other pallial song nuclei important for vocal plasticity, LMAN and Area X, although singing did induce IEGs in these structures, as reported previously. CONCLUSIONS/SIGNIFICANCE: Our results are consistent with the possibility that some of the song nuclei may participate in non-vocal learning and the populations of neurons involved in the two tasks show partial overlap. These findings underscore the previously advanced notion that the specialized forebrain pre-motor nuclei controlling song evolved from circuits involved in behaviors related to feeding
Diminished FoxP2 Levels Affect Dopaminergic Modulation of Corticostriatal Signaling Important to Song Variability
SummaryMutations of the FOXP2 gene impair speech and language development in humans and shRNA-mediated suppression of the avian ortholog FoxP2 disrupts song learning in juvenile zebra finches. How diminished FoxP2 levels affect vocal control and alter the function of neural circuits important to learned vocalizations remains unclear. Here we show that FoxP2 knockdown in the songbird striatum disrupts developmental and social modulation of song variability. Recordings in anesthetized birds show that FoxP2 knockdown interferes with D1R-dependent modulation of activity propagation in a corticostriatal pathway important to song variability, an effect that may be partly attributable to reduced D1R and DARPP-32 protein levels. Furthermore, recordings in singing birds reveal that FoxP2 knockdown prevents social modulation of singing-related activity in this pathway. These findings show that reduced FoxP2 levels interfere with the dopaminergic modulation of vocal variability, which may impede song and speech development by disrupting reinforcement learning mechanisms
CNTNAP2 is a direct FoxP2 target in vitro and in vivo in zebra finches: complex regulation by age and activity
Mutations of FOXP2 are associated with altered brain structure, including the
striatal part of the basal ganglia, and cause a severe speech and language
disorder. Songbirds serve as a tractable neurobiological model for speech and
language research. Experimental downregulation of FoxP2 in zebra finch Area X,
a nucleus of the striatal song control circuitry, affects synaptic
transmission and spine densities. It also renders song learning and production
inaccurate and imprecise, similar to the speech impairment of patients
carrying FOXP2 mutations. Here we show that experimental downregulation of
FoxP2 in Area X using lentiviral vectors leads to reduced expression of
CNTNAP2, a FOXP2 target gene in humans. In addition, natural downregulation of
FoxP2 by age or by singing also downregulated CNTNAP2 expression. Furthermore,
we report that FoxP2 binds to and activates the avian CNTNAP2 promoter in
vitro. Taken together these data establish CNTNAP2 as a direct FoxP2 target
gene in songbirds, likely affecting synaptic function relevant for song
learning and song maintenance
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