Investigating Vocal Deficits in Songbirds with Neurotoxin Induced Dopamine Depletion in the Basal Ganglia

Dopamine (DA) input from the midbrain modulates the activity of basal ganglia circuitry important for motor learning and control in a variety of taxa. DA loss is associated with movement disorders in humans. In songbirds, DA is important for motivational behavior underlying reproductive drive. Within the zebra finch species, DA modulates social-context dependent behavior when the bird is vocally practicing alone versus performing to a potential female mate. During these singing behaviors, there are differences in DA levels within Area X, the specialized sub-region of the zebra finch basal ganglia dedicated to song learning and ongoing adult song maintenance. These natural differences in DA levels are associated with quantifiable changes in features of song, suggesting that the songbird may be a suitable model for investigating DA-driven changes in voice associated with early stages of Parkinson's Disease. In the present study, I used Western blotting to characterize natural changes in protein biomarkers of DA, such as tyrosine hydroxylase, across non-singing and singing behaviors. In a separate group of birds, I injected the neurotoxin 6-hydroxydopamine (6-OHDA) into Area X and assessed the effects of DA depletion on these biomarkers and on features of song in different behavioral contexts. With 6-OHDA administration, measurable decreases in DA biomarkers were detected, and select acoustic features of song became more stereotyped. Ongoing investigations will determine how this DA loss impacts receptor-mediated changes in the underlying neural circuitry

Reduced vocal variability in a zebra finch model of dopamine depletion: implications for Parkinson disease.

Midbrain dopamine (DA) modulates the activity of basal ganglia circuitry important for motor control in a variety of species. In songbirds, DA underlies motivational behavior including reproductive drive and is implicated as a gatekeeper for neural activity governing vocal variability. In the zebra finch, Taeniopygia guttata, DA levels increase in Area X, a song-dedicated subregion of the basal ganglia, when a male bird sings his courtship song to a female (female-directed; FD). Levels remain stable when he sings a less stereotyped version that is not directed toward a conspecific (undirected; UD). Here, we used a mild dose of the neurotoxin 6-hydroxydopamine (6-OHDA) to reduce presynaptic DA input to Area X and characterized the effects on FD and UD behaviors. Immunoblots were used to quantify levels of tyrosine hydroxylase (TH) as a biomarker for DA afferent loss in vehicle- and 6-OHDA-injected birds. Following 6-OHDA administration, TH signals were lower in Area X but not in an adjacent subregion, ventral striatal-pallidum (VSP). A postsynaptic marker of DA signaling was unchanged in both regions. These observations suggest that effects were specific to presynaptic afferents of vocal basal ganglia. Concurrently, vocal variability was reduced during UD but not FD song. Similar decreases in vocal variability are observed in patients with Parkinson disease (PD), but the link to DA loss is not well-understood. The 6-OHDA songbird model offers a unique opportunity to further examine how DA loss in cortico-basal ganglia pathways affects vocal control

Relationship of a common OXTR gene variant to brain structure and default mode network function in healthy humans

Highlights - A sex-dependent impact of OXTR variants on the structure and function in DMN. - A neural mechanism for genetically increased risk for social impairments in males. Abstract A large body of research suggests that oxytocin receptor (OXTR) gene polymorphisms may influence both social behaviors and psychiatric conditions related to social deficits, such as autism spectrum disorders (ASDs), schizophrenia, and mood and anxiety disorders. However, the neural mechanism underlying these associations is still unclear. Relative to controls, patients with these psychiatric conditions show differences in brain structure, and in resting state fMRI (rs-fMRI) signal synchronicity among default mode network (DMN) regions (also known as functional connectivity). We used a stepwise imaging genetics approach in 328 healthy young adults to test the hypothesis that 10 SNPs in OXTR are associated with differences in DMN synchronicity and structure of some of the associated brain regions. As OXTR effects may be sex-dependent, we also tested whether our findings were modulated by sex. OXTR rs2254298 A allele carriers had significantly lower rsFC with PCC in a cluster extending from the right fronto-insular cortex to the putamen and globus pallidus, and in bilateral dorsal anterior cingulate cortex (dACC) compared to individuals with the GG genotype; all observed effects were found only in males. Moreover, compared to the male individuals with GG genotype ofrs2254298, the male A allele carriers demonstrated significantly thinner cortical gray matter in the bilateral dACC. Our findings suggest that there may be sexually dimorphic mechanisms by which a naturally occurring variation of the OXTR gene may influence brain structure and function in DMN-related regions implicated in neuropsychiatric disorders

Thicker temporal cortex associates with a developmental trajectory for psychopathic traits in adolescents.

Psychopathy is a clinical condition characterized by a failure in normal social interaction and morality. Recent studies have begun to reveal brain structural abnormalities associated with psychopathic tendencies in children. However, little is known about whether variations in brain morphology are linked to the developmental trajectory of psychopathic traits over time. In this study, structural magnetic resonance imaging (sMRI) data from 108 14-year-old adolescents with no history of substance abuse (54 males and 54 females) were examined to detect cortical thickness variations associated with psychopathic traits and individual rates of change in psychopathic traits from ages 9 to 18. We found cortical thickness abnormalities to correlate with psychopathic traits both cross-sectionally and longitudinally. Specifically, at age 14, higher psychopathic scores were correlated with thinner cortex in the middle frontal gyrus, particularly in females, and thicker cortex in the superior temporal gyrus, middle temporal gyrus, and parahippocampal gyrus, particularly in males. Longitudinally, individual rates of change in psychopathic tendency over time were correlated with thicker cortex in the superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, parahippocampal gyrus, and posterior cingulate gyrus, particularly in males. Findings suggest that abnormal cortical thickness may reflect a delay in brain maturation, resulting in disturbances in frontal and temporal functioning such as impulsivity, sensation-seeking, and emotional dysregulation in adolescents. Thus, findings provide initial evidence supporting that abnormal cortical thickness may serve as a biomarker for the development of psychopathic propensity in adolescents

A comparison of network definitions for detecting sex differences in brain connectivity using support vector machines

Human brain connectomics is a rapidly evolving area of research, using various methods to define connections or interactions between pairs of regions. Here we evaluate how the choice of (1) regions of interest, (2) definitions of a connection, and (3) normalization of connection weights to total brain connectivity and region size, affect our calculation of the structural connectome. Sex differences in the structural connectome have been established previously. We study how choices in reconstruction of the connectome affect our ability to classify subjects by sex using a support vector machine (SVM) classifier. The use of cluster-based regions led to higher accuracy in sex classification, compared to atlas-based regions. Sex classification was more accurate when based on finer cortical partitions and when using dilations of regions of interest prior to computing brain networks

The heritability of the functional connectome is robust to common nonlinear registration methods

Nonlinear registration algorithms are routinely used in brain imaging, to align data for inter-subject and group comparisons, and for voxelwise statistical analyses. To understand how the choice of registration method affects maps of functional brain connectivity in a sample of 611 twins, we evaluated three popular nonlinear registration methods: Advanced Normalization Tools (ANTs), Automatic Registration Toolbox (ART), and FMRIB's Nonlinear Image Registration Tool (FNIRT). Using both structural and functional MRI, we used each of the three methods to align the MNI152 brain template, and 80 regions of interest (ROIs), to each subject's T1-weighted (T1w) anatomical image. We then transformed each subject's ROIs onto the associated resting state functional MRI (rs-fMRI) scans and computed a connectivity network or functional connectome for each subject. Given the different degrees of genetic similarity between pairs of monozygotic (MZ) and same-sex dizygotic (DZ) twins, we used structural equation modeling to estimate the additive genetic influences on the elements of the function networks, or their heritability. The functional connectome and derived statistics were relatively robust to nonlinear registration effects

Concurrent Correlations between Cortical Thickness and Psychopathy Scores in Males and Females.

<p>FDR-corrected P value maps show significant correlations between cortical thickness and psychopathic traits at 14 years old in males and females with the corresponding uncorrected beta maps show the direction of the correlation.</p

Mean CPS Score and the Slope Score (Rate of Change) for Total Sample, Males, and Females across Four Waves.

<p>^a. CPS total score was obtained from 88 subjects (44 males and 44 females) at wave 1, 66 subjects (34 males and 32 females) at wave 2, 108 subjects (54 males and 54 females) at wave 3, and 46 subjects (23 males and 23 females) at wave 4.</p><p>Mean CPS Score and the Slope Score (Rate of Change) for Total Sample, Males, and Females across Four Waves.</p

Mean CPS Scores for Total Sample, Males, and Females across Four Waves.

<p>Mean CPS Scores for Total Sample, Males, and Females across Four Waves.</p