Function and Regulation of ALDH1A1-positive Nigrostriatal Dopaminergic Neurons in Motor Performance and Parkinson's disease

National Institute On Aging

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Abstract

To investigate the activity and regulation of ALDH1A1-positive nigrostriatal dopaminergic neurons (DANs) during motor control and motor skill learning, we will use fiber photometry to record dopamine release and presynaptic calcium transients from Aldh1a1+ DAN axon terminals in the dorsal striatum during open-field, treadmill, and rotarod tasks. This will allow us to determine how ALDH1A1+ DAN activity is modulated across distinct epochs and stages of locomotion and learning. To establish causal relationships between ALDH1A1+ DAN activity and motor performance, we will manipulate both somatic spiking and axonal dopamine release using optogenetic and chemogenetic approaches. Light-gated chloride channels (e.g., JAWS) will be expressed via Cre-dependent viral vectors to enable transient inhibition of somatic firing through optic fibers implanted in the SNc. These manipulations, particularly of burst firing, will be precisely time-locked to specific behavioral epochs to assess their impact on learning. In parallel, we will express excitatory or inhibitory DREADDs to bidirectionally modulate neuronal excitability during task performance. Because axonal dopamine release can be regulated independently of somatic firing, we will also suppress dopamine release from ALDH1A1+ DAN axons in defined projection targets using light-activated Gi/o-coupled receptors. Behavioral effects from these manipulations will be compared to sham controls to define the contributions of distinct activity components. For example, reduced excitability may delay motor learning, whereas increased excitability could accelerate it; inhibition at movement initiation may increase motor errors, while inhibition during sensory cue presentation could impair reward association. Suppression of striatal dopamine release is also expected to produce learning-stage-specific effects. To dissect upstream regulation, we will selectively eliminate excitatory or inhibitory inputs to ALDH1A1+ DANs by crossbreeding Aldh1a1-CreERT2 mice with Grin1-flox or Gabbr1-flox mice. Preliminary results from Grin1 cKO mice indicate that glutamatergic input is dispensable for both locomotion and motor skill learning, whereas GABAergic input is critical for locomotion control but not learning. Notably, ALDH1A1+ SNc DANs exhibit prominent rebound firing in response to GABA-B receptor (Gabbr1)-mediated inhibition from dSPNs. We are therefore generating Gabbr1 cKO mice to selectively disrupt GABA-B signaling in ALDH1A1+ DANs, enabling us to directly assess the contribution of Gabbr1-mediated rebound and burst firing to motor control and skill learning. Finally, we have established whole-cell recordings from DANs in brain slices, positioning us to investigate the selective vulnerability of ALDH1A1+ nigrostriatal DANs to mitochondrial dysfunction. These studies will provide critical mechanistic insights into PD-related neurodegeneration and may inform targeted neuroprotective strategies.