The ability to select proper actions is critical for flexible adaptive behavior. In vertebrates, multiple neural systems have evolved to coordinate different aspects of motor selection, execution, and learning. Key among these systems is the basal ganglia, a set of subcortical nuclei that are critical for motor planning and habit learning, and which are also implicated in Parkinson disease (PD), among the most commonly-diagnosed movement disorders. The anatomical connectivity of the basal ganglia is well characterized, and general hypotheses about basal ganglia function and the role of dopamine have been proposed. However, the mechanisms underlying dysfunction of basal ganglia circuits in PD is not well understood. In order to gain new insight into the dysfunction of the basal ganglia, we will target two new understudied aspects of basal ganglia circuitry: (1) the inputs from the thalamus to the striatum, and (2) the outputs from the substantia nigra reticulata/entopeduncular nucleus to the pedunculopontine tegmentum (PPTg). We have obtained compelling preliminary evidence that these regions are involved in motor dysfunction in animal models of PD, and we propose to thoroughly investigate the cellular, synaptic, and circuit mechanisms that underlie this dysfunction. The goal is to identify new therapeutic targets and strategies for treating PD, without the debilitating side effects associated with long-term use of dopamine replacement therapy.
The ability to select appropriate actions is critical for survival. Movement disorders such as Parkinson's disease (PD) are characterized by difficulties selecting or changing actions. This results from dysfunction of neural circuits in the striatum, a core regio of the brain involved in motor planning. Here, we will investigate two new therapeutic targets for treating PD: the thalamostriatal synapse and the pedunculopontine nucleus. Each of these areas is relatively understudied, yet has great potential to lead to new therapeutic strategies for the treatment of PD.
| Owen, Scott F; Berke, Joshua D; Kreitzer, Anatol C (2018) Fast-Spiking Interneurons Supply Feedforward Control of Bursting, Calcium, and Plasticity for Efficient Learning. Cell 172:683-695.e15 |
| Sun, Fangmiao; Zeng, Jianzhi; Jing, Miao et al. (2018) A Genetically Encoded Fluorescent Sensor Enables Rapid and Specific Detection of Dopamine in Flies, Fish, and Mice. Cell 174:481-496.e19 |
| Lee, Jin Hyung; Kreitzer, Anatol C; Singer, Annabelle C et al. (2017) Illuminating Neural Circuits: From Molecules to MRI. J Neurosci 37:10817-10825 |
| Roseberry, Thomas K; Lee, A Moses; Lalive, Arnaud L et al. (2016) Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia. Cell 164:526-37 |
| Kharkwal, Geetika; Brami-Cherrier, Karen; Lizardi-Ortiz, José E et al. (2016) Parkinsonism Driven by Antipsychotics Originates from Dopaminergic Control of Striatal Cholinergic Interneurons. Neuron 91:67-78 |
| Parker, Philip R L; Lalive, Arnaud L; Kreitzer, Anatol C (2016) Pathway-Specific Remodeling of Thalamostriatal Synapses in Parkinsonian Mice. Neuron 89:734-40 |
| Lee, Hyun Joo; Weitz, Andrew J; Bernal-Casas, David et al. (2016) Activation of Direct and Indirect Pathway Medium Spiny Neurons Drives Distinct Brain-wide Responses. Neuron 91:412-24 |
| Nelson, Alexandra B; Kreitzer, Anatol C (2014) Reassessing models of basal ganglia function and dysfunction. Annu Rev Neurosci 37:117-35 |
| Nelson, Alexandra B; Bussert, Timothy G; Kreitzer, Anatol C et al. (2014) Striatal cholinergic neurotransmission requires VGLUT3. J Neurosci 34:8772-7 |
| Nelson, Alexandra B; Hammack, Nora; Yang, Cindy F et al. (2014) Striatal cholinergic interneurons Drive GABA release from dopamine terminals. Neuron 82:63-70 |
Showing the most recent 10 out of 26 publications
