Synaptic integration and intrinsic firing properties of basal ganglia neurons

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

The Cellular Neurophysiology Section examines the cellular, synaptic and circuit function of midbrain dopamine-releasing neurons and their contribution to behavior. Dopamine neuron activity is tied historically to motor and reward learning. However, as subset of dopamine neurons located in the substantia nigra pars lateralis (SNL) has more recently been shown to participate in salience and aversive learning. These neurons are also relatively spared in Parkinson’s patients. Our recent work (Sansalone et al. bioRxiv 2024 – accepted at Nat Communications) has shown that these neurons differ substantially in from canonical midbrain dopamine neurons in their intrinsic and circuit properties. We also functionally mapped inputs to these neurons and found that they receive strong innervation from auditory and temporal association cortexes. This is the first direct significant corticonigral projection identified to any substantia nigra (SN) dopamine neuron population. In behavioral experiments, we found that auditory cortex projections to SNL contribute to auditory threat conditioning. Thus, our study showed that auditory cortex directly projects to SNL DANs and that this corticonigral projection is critical for learning during threat behaviors. These findings may enhance our understanding of the altered sensory processing associated with post-traumatic stress disorder (PTSD) and phobias. We have also been examining the control of dopaminergic axons and by local striatal circuits. In a recent study (Brill-Weil et al., biorXiv; in revisions Cell Reports), we investigated how GABAA and nicotinic receptors interact to influence dopaminergic axon excitability. Direct axonal recordings on dopaminergic axons and showed that diazepam (‘Valium”), a positive allosteric modulator of GABA-A receptors, suppresses subthreshold axonal input from cholinergic interneurons (CINs). In imaging experiments, we found that GABAAR antagonism with gabazine selectively enhanced nAChR-evoked axonal signals. Thus, we showed that GABAARs on dopaminergic axons regulate integration of nicotinic input to shape presynaptic excitability. We also continue to examine dopaminergic neurons in the context of Parkinson’s Disease mouse models. Anthony Yanez tested the excitability of dopaminergic neurons in a PD mouse model of viral alpha-synuclein over expression. This work was released a preprint at bioRxiv (Barcomb et al. 2025). Lastly, axons tend to show the earliest degeneration in Parkinson’s patients and this axonal ‘die back’ is not well understood. Dr. Anna Lipkin has been examining axonal propagation in the dopaminergic neurons in a PD mouse model called MitoPark which is a undergo slow degeneration of dopaminergic neurons. Dr. Lipkin presented this work at our ASAP Team Edwards Group Meeting at UCSF in May.