Chen, R. Y.-T. | bioRxiv Science

bioRxiv2026

Chronic nicotine reduces nigral dopaminergic activity and remodels pedunculopontine cholinergic subpopulations

Chronic nicotine is linked to neuroprotective effects and reduced Parkinsons disease (PD) risk, yet its physiological effects on vulnerable substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons are not fully understood. These populations exhibit specialized properties such as spontaneous pacemaking and elevated dendritic calcium influx that contribute to their selective neurodegeneration in PD. Here, we used whole-cell patch-clamp, two-photon calcium imaging, and morphological reconstruction in acute brain slices from adult mice of both sexes following 8-10 weeks of oral nicotine. Chronic nicotine reduced spontaneous pacemaking, burst propensity, and rebound firing in SNc dopaminergic neurons, while decoupling tonic firing rate from proximal dendritic calcium levels. The changes in the SNc occurred without altering L-type channel contributions, dendritic arborization, or excitatory synaptic drive. In PPN cholinergic neurons, chronic nicotine induced subregion-specific plasticity. Rostral PPN neurons showed depolarized membrane potentials, broadened action potentials, and dendritic pruning, whereas caudal PPN neurons showed reduced spike frequency adaptation and accelerated excitatory postsynaptic current kinetics. These findings reveal potential cellular and circuit mechanisms by which nicotine may contribute to resilience against PD. Significant StatementEpidemiological studies have revealed nicotines surprising protective effect in Parkinsons disease (PD). Interestingly, this protection appears only preventative, as nicotine shows no therapeutic benefits after PD diagnosis. Here, we evaluated the effects of chronic nicotine on two brainstem populations known to selectively degenerate in PD: substantia nigra pars compacta (SNc) dopaminergic neurons and pedunculopontine (PPN) cholinergic neurons. Chronic nicotine decreases activity levels of SNc neurons, depolarizes rostral PPN neurons, and enhances sustained firing capability in caudal PPN neurons. Notably, this is the first study to assess whether chronic nicotine alters the physiology and dendritic morphology of these vulnerable subpopulations. These cellular insights uncover potential mechanisms for promoting neuronal resilience in neurodegenerative diseases.

neuroscience↗

bioRxiv2023

Comparing tonic and phasic calcium in the dendrites of vulnerable midbrain neurons

Several midbrain nuclei degenerate in Parkinsons Disease (PD). Many of these nuclei share the common characteristics that are thought to contribute to their selective vulnerability, including pacemaking activity and high levels of calcium influx. In addition to the well-characterized dopaminergic neurons of the substantia nigra pars compacta (SNc), the cholinergic neurons of the pedunculopontine nucleus (PPN) also degenerate in PD. It is well established that the low-threshold L-type calcium current is a main contributor to tonic calcium in SNc dopaminergic neurons and is hypothesized to contribute to their selective vulnerability. However, it is not yet clear whether the vulnerable PPN cholinergic neurons share this property. Therefore, we used two-photon dendritic calcium imaging and whole-cell electrophysiology to evaluate the role of L-type calcium channels in the tonic and phasic activity of PPN neurons and the corresponding dendritic calcium signal and directly compare these characteristics to SNc neurons. We found that blocking L-type channels reduces tonic firing rate and dendritic calcium levels in SNc neurons. By contrast, the calcium load in PPN neurons during pacemaking did not depend on L-type channels. However, we find that blocking L-type channels reduces phasic calcium influx in PPN dendrites. Together, these findings show that L-type calcium channels play different roles in the activity of SNc and PPN neurons, and suggest that low-threshold L-type channels are not responsible for tonic calcium levels in PPN cholinergic neurons and are therefore not likely to be a source of selective vulnerability in these cells.

neuroscience↗