The basal ganglia (BG) circuit is a clinically relevant group of deep brain structures that appear to play similar functions in humans and birds-motor sequence learning. Even though current therapies in humans involve the stimulation of electrodes chronically implanted into BG structures, we still do not understand how electrical signals propagate through the circuit to influence behavior. Songbirds have specialized BG pathway devoted entirely to single task-song learning. Having performed the first recordings from distinct cell classes in the songbird BG (Goldberg and Fee, 2010;Goldberg et al., 2010), I am now poised to ask basic questions of BG function: How are BG outputs processed in the thalamus? How do distinct BG cell classes implement motor learning? What are the neural interactions within the BG circuit? In this proposal, I outline the path to my long term goal: to build a laboratory that harnesses the advantages of the songbird model system to study how basal ganglia microcircuits contribute to normal and abnormal motor function. For my PhD thesis, I used cellular physiology and two-photon imaging to study distinct cell classes in the cortical microcircuit. In medical school, I was trained in the care of patients with basal ganglia-related neurological disease, and in the first phase of my post-doctoral training, I have learned to record from connected neurons in the basal ganglia of freely moving animals. The training plan formulated in this proposal is specifically designed to bring me new techniques that will enable me to execute novel experiments and to transition to an independent position. For example, my immediate goals are to learn the computational, digital signal processing skills required to implement a novel song-conditioning paradigm, to develop a new method for extracellular recording from multiple neurons simultaneously during behavior, and to learn to use a recently developed intracellular microdrive for recording intracellularly from freely moving animals. These goals are to be completed in the mentored phase, before I apply for positions in the fall of 2011. As I acquire these techniques, I will be able to address basic questions of basal ganglia and thalamic function. First, I will examine how the motor thalamus integrates its two major inputs, from the BG and the cortex, by recording from connected pallidal and thalamic neurons, and by recording from antidromically identified corticothalamic projection neurons during singing. Next, I will examine BG output signals during experimentally controlled motor learning by combining neural recordings with a novel conditional auditory feedback paradigm that induces rapid trial and error song learning. Finally, I will embark on a long-term project of studying how each of the six major BG cell classes changes its activity during this learning, and how small groups of these neurons interact during behavior.
This final aim i ncludes the development of a technique to record intracellularly from BG neurons in singing birds, and constitutes the research program that I will continue, with Michale Fee's support, in the R00 phase of this grant. This training and research will take place in Michale Fee's laboratory at the McGovern Institute for Brain and Cognitive Sciences at MIT, where I am surrounded by talented graduate students, post-docs and faculty. The department is very stimulating with two weekly seminar series, world-renowned speakers and first rate facilities. Finally, even though Michale is well funded (two R01s), I am one of only two post-docs in the lab. This means Michale and I are very invested in one another and we frequently spend hours per day together, discussing experiments, writing papers and building new devices. As part of this grant resubmission Michale and I carefully formulated the experiments, the training plan, and the path to independence, and he has agreed to personally train and support me as I transition to the R00 phase, when I will begin to pursue the role that specific striatal and pallidal cell classes play in BG function. The timeline for these endeavors, which will constitute my benchmarks for progress, is presented in the Career Goals section of this proposal.
The basal ganglia are a set of brain nuclei highly conserved among vertebrates, including humans, critical for motor control and learning. Songbirds have a specialized basal ganglia circuit required for singing behavior that is extremely accessible to study. This proposal will use the songbird as a model system to understand basic mechanisms of basal ganglia function, with the aim of translating insights to mammalian biology and human disease.
|Pidoux, Morgane; Bollu, Tejapratap; Riccelli, Tori et al. (2015) Origins of basal ganglia output signals in singing juvenile birds. J Neurophysiol 113:843-55|
|Goldberg, Jesse H; Farries, Michael A; Fee, Michale S (2013) Basal ganglia output to the thalamus: still a paradox. Trends Neurosci 36:695-705|
|Gadagkar, Vikram; Goldberg, Jesse H (2013) A variability-generating circuit goes awry in a songbird model of the FOXP2 speech disorder. Neuron 80:1341-4|
|Goldberg, Jesse H; Farries, Michael A; Fee, Michale S (2012) Integration of cortical and pallidal inputs in the basal ganglia-recipient thalamus of singing birds. J Neurophysiol 108:1403-29|