Julie Elizabeth Miller

Julie Elizabeth Miller

Associate Professor, Neuroscience
Associate Professor, Speech, Language, and Hearing Sciences
Primary Department

Work Summary

I am a neuroscientist who studies the impact of aging and neurodegenerative disease on voice and speech. My laboratory seeks a better understanding of the molecules, cells and circuits in the brain that support vocal production.

Research Interest

My laboratory studies neurogenetic mechanisms which underlie normal and abnormal motor speech using the zebra finch songbird. My particular focus is to investigate molecular and cellular pathways altered by speech disorders associated with natural aging and neurological diseases such as Parkinson’s Disease. To carry out these investigations, we use a combination of behavioral, genetic, biochemical and electrophysiological approaches that enable us to link changes at the molecular/cellular levels to alterations in neural circuits for birdsong/human speech. We also have collaborations with researchers working in mouse models to understand shared molecular pathway for vocal function. The end goal is to leverage the advantages offered by each species and an array of biological tools to further advance our understanding of how the brain controls vocalizations. Our laboratory website, including an updated publication list, can be found at: https://julieemiller.lab.arizona.edu/content/publications-abstracts


Medina, C.A., Vargas, E., Munger, S.J., and Miller, J.E. (2022). Vocal Changes in a Zebra Finch Model of Parkinson’s Disease Characterized by Alpha-synuclein Overexpression in the Song-Dedicated Anterior Forebrain Pathway. PLoS ONE, 17 (5), e0265604. PMID: 35507553

Deterioration in the quality of a person’s voice and speech is an early marker of Parkinson’s disease (PD). In humans, the neural circuit that supports vocal motor control consists of a cortico-basal ganglia-thalamo-cortico loop. The basal ganglia regions, striatum and globus pallidus, in this loop play a role in modulating the acoustic features of vocal behavior such as loudness, pitch, and articulatory rate. In PD, this area is implicated in pathogenesis. In animal models of PD, the accumulation of toxic aggregates containing the neuronal protein alpha-synuclein (αsyn) in the midbrain and striatum result in limb and vocal motor impairments. It has been challenging to study vocal impairments given the lack of well-defined cortico-basal ganglia circuitry for vocalization in rodent models. Furthermore, whether deterioration of voice quality early in PD is a direct result of αsyn-induced neuropathology is not yet known. Here, we take advantage of the well-characterized vocal circuits of the adult male zebra finch songbird to experimentally target a song-dedicated pathway, the anterior forebrain pathway, using an adeno-associated virus expressing the human wild-type αsyn gene, SNCA. We found that overexpression of αsyn in this pathway coincides with higher levels of insoluble, monomeric αsyn compared to control finches. Impairments in song production were also detected along with shorter and poorer quality syllables, which are the most basic unit of song. These vocal changes are similar to the vocal abnormalities observed in individuals with PD.

Ausra, J., Munger, S.J., Azami, A., Burton, A., Peralta, R., Miller, J.E., and Gutruf, P. (2021) Wireless Battery Free Fully Implantable Multimodal Recording and Neuromodulation Tools for Songbirds. Nature Communications 12: 1968. doi: 10.1038/s41467-021-22138-8 Epub Mar 30. PMID: 33785751

BIO5 Collaborators
Julie Elizabeth Miller, Philipp Gutruf

Wireless battery free and fully implantable tools for the interrogation of the central and peripheral nervous system have quantitatively expanded the capabilities to study mechanistic and circuit level behavior in freely moving rodents. The light weight and small footprint of such devices enables full subdermal implantation that results in the capability to perform studies with minimal impact on subject behavior and yields broad application in a range of experimental paradigms. While these advantages have been successfully proven in rodents that move predominantly in 2D, the full potential of a wireless and battery free device can be harnessed with flying species, where interrogation with tethered devices is very difficult or impossible. Here we report on a wireless, battery free and multimodal platform that enables optogenetic stimulation and physiological temperature recording in a highly miniaturized form factor for use in songbirds. The systems are enabled by behavior guided primary antenna design and advanced energy management to ensure stable optogenetic stimulation and thermography throughout 3D experimental arenas. Collectively, these design approaches quantitatively expand the use of wireless subdermally implantable neuromodulation and sensing tools to species previously excluded from in vivo real time experiments.

So, L.Y. and Miller, J.E. (2021) Social Context-Dependent Singing Alters Molecular Markers of Synaptic Plasticity Signaling in Finch Basal Ganglia Area X. Behav Brain Res. 398:112955. doi: 10.1016/j.bbr.2020.112955. Epub 2020 Oct 6. PMID: 33031871 

Vocal communication is a crucial skill required throughout life. However, there is a critical gap in our understanding of the underlying molecular brain mechanisms, thereby motivating our use of the zebra finch songbird model. Adult male zebra finches show differences in neural activity patterns in song-dedicated brain nuclei when they sing in two distinct social contexts: a male singing by himself (undirected, UD) and a male singing to a female (female-directed, FD). In our prior work, we showed that in song-dedicated basal ganglia Area X, protein levels of a N-methyl-D-aspartate receptor subtype 2B (NMDAR2B) increased with more UD song and decreased with more FD song. We hypothesized that molecules downstream of this receptor would show differential protein expression levels in Area X between UD and FD song. Specifically, we investigated calcium/calmodulin dependent protein kinase II beta (CaMKIIB), homer scaffold protein 1 (HOMER1), serine/threonine protein kinase (Akt), and mechanistic target of rapamycin kinase (mTOR) following singing and non-singing states in Area X. We show relationships between social context and protein levels. HOMER1 protein levels decreased with time spent singing FD song, and mTOR protein levels decreased with the amount of and time spent singing FD song. For both HOMER1 and mTOR, there were no differences with the amount of UD song. With time spent singing UD, CaMKIIB protein levels trended in a U-shaped curve whereas Akt protein levels trended down. Both molecules showed no change with FD song. Our results support differential involvement of molecules in synaptic plasticity pathways between UD and FD song behaviors.

Badwal, A., Borgstrom, M., Samlan, R.A., and Miller, J.E. (2020). Middle Age: a Key Timepoint for Changes in Birdsong and Human Voice. Behav Neurosci 134(3):208-221. doi: 10.1037/bne0000363 Epub Mar 12. PMID: 32162938.  

Voice changes caused by natural aging and neurodegenerative diseases are prevalent in the aging population and diminish quality of life. Most treatments involve behavioral interventions that target the larynx because of a limited understanding of central brain mechanisms. The songbird offers a unique entry point into studying age-related changes in vocalizations because of a well-characterized neural circuitry for song that shares homology to human vocal control areas. Previously we established a translational dictionary for evaluating acoustic features of birdsong in the context of human voice measurements. In the present study, we conduct extensive analyses of birdsongs from young, middle-aged, and old male zebra finches. Our findings show that birdsongs become louder with age, and changes in periodic energy occur at middle age but are transient; songs appear to stabilize in old birds. Furthermore, faster songs are detected in finches at middle age compared with young and old finches. Vocal disorders in humans emerge at middle age, but the underlying brain pathologies are not well identified. The current findings will motivate future investigations using the songbird model to identify possible brain mechanisms involved in human vocal disorders of aging.

Badwal, A., Poertner, J., Samlan, R.A., and Miller, J. E. (2019). Common Terminology and Acoustic Measures for Human Voice and Birdsong. J Speech Lang Hear Res 30; 62(1):60-69. doi: 10.1044/2018_JSLHR-S-18-0218. PMID: 30540871

Purpose The zebra finch is used as a model to study the neural circuitry of auditory-guided human vocal production. The terminology of birdsong production and acoustic analysis, however, differs from human voice production, making it difficult for voice researchers of either species to navigate the literature from the other. The purpose of this research note is to identify common terminology and measures to better compare information across species. Method Terminology used in the birdsong literature will be mapped onto terminology used in the human voice production literature. Measures typically used to quantify the percepts of pitch, loudness, and quality will be described. Measures common to the literature in both species will be made from the songs of 3 middle-age birds using Praat and Song Analysis Pro. Two measures, cepstral peak prominence (CPP) and Wiener entropy (WE), will be compared to determine if they provide similar information. Results Similarities and differences in terminology and acoustic analyses are presented. A core set of measures including frequency, frequency variability within a syllable, intensity, CPP, and WE are proposed for future studies. CPP and WE are related yet provide unique information about the syllable structure. Conclusions Using a core set of measures familiar to both human voice and birdsong researchers, along with both CPP and WE, will allow characterization of similarities and differences among birds. Standard terminology and measures will improve accessibility of the birdsong literature to human voice researchers and vice versa.