Biology subjects

Evans, R. C.

Publications and source records attributed to Evans, R. C..

10 recordsLinked to original sources

bioRxiv2026

Brainstem cholinergic cell loss causes slowly-developing motor impairments

Pedunculopontine nucleus (PPN) cholinergic degeneration is a feature of Parkinson's disease (PD), but it is difficult to isolate the symptoms and circuit alterations caused by cholinergic cell loss in PD, where multiple nuclei are simultaneously degenerating. Here we develop a novel mouse model of brainstem cholinergic cell loss to define the timeline of symptom development and map physiological adaptations within the brainstem. Mild motor symptoms, including balance and motor learning deficits reminiscent of early-stage PD, developed after cholinergic lesion with an unexpected long delay. Ex vivo whole-cell recordings showed that cholinergic cell loss increased excitatory synaptic drive onto glutamatergic PPN neurons and increased their intrinsic ability to generate sustained action potential output. In parallel, fiber photometry experiments revealed a slight increase in glutamatergic sensory responsiveness that closely tracked the delayed onset of behavioral symptoms. Together, these results reveal that brainstem cholinergic cell loss triggers the reorganization of motor-related brainstem circuits, providing critical insight into the consequences of non-dopaminergic degeneration in PD.

neuroscience↗

bioRxiv2026

Dendrite-specific synaptic inputs onto dopaminergic SNc neurons

Substantia nigra pars compacta (SNc) dopaminergic neurons integrate synaptic inputs through dendrites that project laterally within the SNc and ventrally into the substantia nigra pars reticulata (SNr), which then determines dopaminergic output. We use spatially-specific optogenetics to map excitatory subthalamic nucleus (STN) and pedunculopontine nucleus (PPN) as well as inhibitory SNr inputs that provide feedforward inhibition onto SNc neurons. Using multiple GABAergic mouse lines, we find that SNr inputs selectively inhibit SNc somas and proximal dendrites without preference for SNr versus SNc dendrites. Using glutamatergic mouse lines, we find that PPN inputs selectively excite somas and proximal dendrites, while STN inputs selectively excite SNr dendrites, mirroring dendrite-selective inhibition from striosomes. These findings reveal a high level of spatial organization in SNc synaptic inputs and point to separate functional roles for STN versus PPN control of dopaminergic activity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/742307v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@ac8c5borg.highwire.dtl.DTLVardef@32cb89org.highwire.dtl.DTLVardef@d08f79org.highwire.dtl.DTLVardef@7b546d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

α-Synuclein pathology differentially alters T-type calcium currents in vulnerable and resilient substantia nigra dopaminergic subpopulations.

Aggregation of -synuclein protein is a characteristic of Parkinsons disease pathology that relates to the degeneration of vulnerable dopaminergic neurons and motor symptoms of the disease. However, -synuclein pathology can contribute to neuronal dysfunction by disrupting several processes within the cell, including intracellular calcium balance, mitochondrial function, and synaptic function. Here, we use a preformed fibril (PFF) model of synucleinopathy to examine effects of striatal -synuclein seeding on dopamine neurons of the substantia nigra pars compacta (SNc). The SNc is heterogeneous and contains dopaminergic neurons with differential vulnerability to Parkinsons disease pathology. We found that intrastriatal injections of PFFs differentially affect these SNc neuron subtypes by increasing the excitability of resilient SNc neurons, while altering tonic firing patterns and T-type calcium currents in vulnerable SNc neurons. In addition, we performed comprehensive electrophysiological analyses and neural morphology reconstructions on SNc neurons from PFF and monomer injected mice. These findings provide insights to the selective vulnerability of SNc neuron subtypes and further our understanding of the role of -synuclein in Parkinsons disease progression and circuit dysfunction.

neuroscience↗

bioRxiv2026

Sex-specific effects of exercise on motor coordination and extended basal ganglia physiology.

Exercise broadly affects the basal ganglia, brain structures involved in motor coordination. Exercise-induced changes in these regions can improve pathological conditions such as Parkinsons disease and substance use disorders. Importantly, biological sex is a significant factor in the effects of exercise and in the presentation of these basal ganglia-related conditions. Here, we find surprising sex differences in exercises influence over motor coordination and neural activity across three extended basal ganglia structures: dorsomedial striatum cholinergic interneurons (CINs), substantia nigra pars compacta (SNc) dopaminergic neurons, and caudal pedunculopontine nucleus (PPN) cholinergic neurons. Using voluntary wheel running, accelerating rotarod, ex vivo electrophysiology, and morphological reconstructions, we found that exercise enhances motor coordination, increases SNc excitability, and strengthens excitatory input onto the PPN selectively in female mice. By contrast, exercise increases spontaneous firing rate and reduces dendritic complexity selectively in male CINs. These data reveal sex-specific exercise effects correlated across behavioral and cellular levels. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/720719v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@d0f755org.highwire.dtl.DTLVardef@11e2335org.highwire.dtl.DTLVardef@199a591org.highwire.dtl.DTLVardef@44e4d9_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIOne week of exercise enhances motor coordination in females but not males C_LIO_LIExercise increases SNc excitability and excitatory input onto the PPN in females C_LIO_LIExercise increases dorsomedial striatal cholinergic neurons activity in males C_LIO_LIBaseline sex differences in morphology of striatal cholinergic and SNc neurons C_LI

neuroscience↗

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↗

bioRxiv2024

Corticonigral projections recruit substantia nigra pars lateralis dopaminergic neurons for auditory threat memories

Dopaminergic neurons (DANs) in the lateral substantia nigra project to the tail of striatum (TS), which is involved in threat conditioning. Auditory cortex also contributes to threatening behaviors, but whether it directly interacts with midbrain DANs and how these interactions might influence threat conditioning remain unclear. Here, functional mapping revealed robust excitatory input from auditory and temporal association cortexes to substantia nigra pars lateralis (SNL) DANs, but not to pars compacta (SNc) DANs. SNL DANs exhibited unique firing patterns, with irregular pacemaking and higher maximal firing, reflecting different channel complements than SNc DANs. Behaviorally, inhibiting cortex to SNL projections impaired memory retrieval during auditory threat conditioning. Thus, we demonstrate robust corticonigral projections to SNL DANs, contrasting with previous observations of sparse cortical input to substantia nigra DANs. These findings distinguish SNL DANs from other nigral populations, highlighting their role in threatening behaviors and expanding knowledge of cortex to midbrain interactions.

neuroscience↗

bioRxiv2024

Inhibitory basal ganglia nuclei differentially innervate pedunculopontine nucleus subpopulations and evoke opposite motor and valence behaviors.

The canonical basal ganglia model predicts that the substantia nigra pars reticulata (SNr) and the globus pallidus externa (GPe) will have specific effects on locomotion: the SNr inhibiting locomotion and the GPe enhancing it. In this study, we use in vivo optogenetics to show that the GPe exerts non-canonical effects on locomotion while the SNr has no gross motor impact through inhibition of the PPN. We also show that these structures mediate opposing effects on reward. To understand how these structures differentially modulate the PPN, we use ex vivo whole-cell recording with optogenetics to comprehensively dissect the SNr and GPe synaptic connections to regionally- and molecularly-defined populations of PPN neurons. The SNr inhibits all PPN subtypes, but most strongly inhibits caudal glutamatergic neurons. The GPe selectively inhibits caudal glutamatergic and GABAergic neurons, avoiding both cholinergic and rostral cells. This circuit characterization reveals non-canonical basal ganglia pathways for locomotion and valence. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/606694v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@11e6a13org.highwire.dtl.DTLVardef@1c63735org.highwire.dtl.DTLVardef@5282b7org.highwire.dtl.DTLVardef@103da4a_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2024

Muscarinic receptor activation preferentially inhibits rebound in vulnerable dopaminergic neurons

Dopaminergic subpopulations of the substantia nigra pars compacta (SNc) differentially degenerate in Parkinsons disease and are characterized by unique electrophysiological properties. The vulnerable population expresses a T-type calcium channel-mediated afterdepolarization (ADP) and shows rebound activity upon release from inhibition, whereas the resilient population does not have an ADP and is slower to fire after hyperpolarization. This rebound activity can trigger dopamine release in the striatum, an important component of basal ganglia function. Using whole-cell patch clamp electrophysiology on ex vivo slices from adult mice of both sexes, we find that muscarinic activation with the non-selective muscarinic agonist Oxotremorine inhibits rebound activity more strongly in vulnerable vs resilient SNc neurons. Here, we show that this effect depends on the direct activation of muscarinic receptors on the SNc dopaminergic neurons. Through a series of pharmacological and transgenic knock-out experiments, we tested whether the muscarinic inhibition of rebound was mediated through the canonical rebound-related ion channels: T-type calcium channels, hyperpolarization-activated cation channels (HCN), and A-type potassium channels. We find that muscarinic receptor activation inhibits HCN-mediated current (Ih) in vulnerable SNc neurons, but that Ih activity is not necessary for the muscarinic inhibition of rebound activity. Similarly, we find that Oxotremorine inhibits rebound activity independently of T-type calcium channels and A-type potassium channels. Together these findings reveal new principles governing acetylcholine and dopamine interactions, showing that muscarinic receptors directly affect SNc rebound activity in the midbrain at the somatodendritic level and differentially modify information processing in distinct SNc subpopulations. Significance StatementDopaminergic neurons in the substantia nigra pars compacta (SNc) can be divided into functional subpopulations with distinct basal ganglia connectivity and different degeneration patterns in Parkinsons disease. We show that the vulnerable and resilient subpopulations of SNc dopaminergic neurons are differentially modulated by muscarinic receptor activation. Specifically, muscarinic receptor activation inhibits rebound activity more strongly in the vulnerable SNc neurons than in the resilient. We find that this inhibition occurs through a non-canonical rebound-related pathway and is not mediated through the channels best known for modulating rebound in midbrain dopaminergic neurons. These findings are important because they reveal novel acetylcholine-dopamine interactions that occur in the midbrain and affect information processing in distinct basal ganglia circuits.

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↗

bioRxiv2019

Functional dissection of basal ganglia inhibitory input onto SNc dopaminergic neurons

Substania nigra (SNc) dopaminergic neurons show a pause-rebound firing pattern in response to aversive events. Because these neurons integrate information from predominately inhibitory brain areas, it is important to determine which inputs functionally inhibit the dopamine neurons and whether this pause-rebound firing pattern can be produced by a solely inhibitory input. Here, we functionally map genetically-defined inhibitory projections from the dorsal striatum (striosome and matrix) and globus pallidus (GPe; parvalbumin and Lhx6) onto SNc neurons. We find that GPe and striosomal inputs both pause firing in SNc neurons, but rebound firing only occurs after inhibition from striosomes. Indeed, we find that striosomes are synaptically optimized to produce rebound and preferentially inhibit a subpopulation of ventral, intrinsically rebound-ready SNc dopaminergic neurons on their reticulata dendrites. Therefore, we describe a self-contained dendrite-specific striatonigral circuit that can produce pause-rebound firing in the absence of excitatory input.

neuroscience↗