Biology subjects

Cannon, J.

Publications and source records attributed to Cannon, J..

6 recordsLinked to original sources

bioRxiv2025

A model of rhythm production and rhythmic auditory stimulation in healthy and Parkinsonian basal ganglia

In fMRI experiments, the basal ganglia is consistently activated by rhythmic action and sensorimotor synchronization to a metronome, and conditions like Parkinsons Disease that affect basal ganglia and its dopaminergic modulation are experimentally seen to affect performance on both types of task. However, it is not clear what role this circuit or dopaminergic modulation play during rhythm production and synchronization tasks. Here, we propose that the basal ganglia may specify, maintain, and adapt the tempo with which rhythmic action (e.g. finger tapping or walking) is performed. We build a model based on previous "action selection" models of the cortico-basal-ganglia loop, altered such that cortico-basal-ganglia loops correspond not to distinct actions but to a continuum of possible action tempi. During rhythm production, an initial tempo is selected by cortical input, and rhythmic action can be automatized to continue in the absence of cortical input if tonic dopamine levels in striatum are sufficiently high. When striatal dopamine is reduced, our model reproduces two key features of dopamine deprivation in Parkinsons disease: freezing of gait, and increased variation in produced intertap intervals during rhythmic tapping. By reanalyzing data from a recent experiment with Parkinsonian patients, we confirm the models prediction that increased interval variability should be largely attributable to increased tempo drift (rather than, e.g., increased timekeeper noise). This model of rhythm production is the first to invoke specific features of basal ganglia circuitry. It augments existing models of action selection in basal ganglia with the addition of continuous action parameters, and in doing so provides a starting point for further modeling of action timing and rhythm in the motor system. It offers a new model of the mechanism by which rhythmic auditory stimulation supports gait in Parkinsons patients, and makes a new, testable prediction about sensorimotor synchronization under conditions of low tonic dopamine.

neuroscience↗

bioRxiv2022

A morphological basis for path dependent evolution of visual systems

Path dependence influences macroevolutionary predictability by constraining potential outcomes after stochastic evolutionary events. Although demonstrated in laboratory experiments, the basis of path dependence is difficult to demonstrate in natural systems because of a lack of independent replicates. Here we show two types of complex distributed visual systems each recently evolved twice within chiton mollusks, demonstrating rapid and path dependent evolution. The type of visual system a chiton lineage evolves is constrained by the number of openings for optic nerves in its shell plates: lineages with more openings evolve visual systems with thousands of eyespots, whereas those with fewer evolve visual systems with hundreds of shell eyes. These macroevolutionary outcomes shaped by path dependence are both deterministic and stochastic because possibilities are restricted yet not entirely predictable. One-Sentence SummaryMultiple convergent origins of visual systems show macroevolution of complex traits can be rapid and contingent upon pre-existing structures

evolutionary biology↗

bioRxiv2022

Complementary biological and computational approaches identify distinct mechanisms of chlorpyrifos versus chlorpyrifos oxon induced dopaminergic neurotoxicity

Organophosphate (OP) pesticides are widely used in agriculture. While acute cholinergic toxicity has been extensively studied, chronic effects on other neurons are less understood. Here, we demonstrated that the OP pesticide chlorpyrifos (CPF) and its oxon metabolite are dopaminergic neurotoxicants in Caenorhabditis elegans. CPF treatment led to inhibition of mitochondrial complex II, II + III, and V in rat liver mitochondria, while CPF oxon did not (complex II + III, and IV inhibition observed only at high doses). While the effect on C. elegans cholinergic behavior was mostly reversible with toxicant washout, dopamine-associated deficits persisted, suggesting dopaminergic neurotoxicity was irreversible. CPF reduced the mitochondrial content in a dose-dependent manner and the fat modulatory genes cyp-35A2 and cyp-35A3 were found to have a key role in CPF neurotoxicity. These findings were consistent with in vitro effects of CPF and CPF oxon on nuclear receptor signaling and fatty acid/steroid metabolism observed in ToxCast assays. Two-way hierarchical analysis revealed in vitro effects on estrogen receptor (ER,) pregnane X receptor (PXR), and peroxisome proliferator-activated receptor gamma (PPAR gamma) pathways as well as neurotoxicity of chlorpyrifos, malathion, and diazinon, while these effects were not detected in malaoxon and diazoxon. Taken together, our study suggests that mitochondrial toxicity and metabolic effects of CPF, but not CPF-oxon, have a key role of CPF neurotoxicity in the low-dose, chronic exposure. Further mechanistic studies are needed to examine mitochondria as a common target for all OP pesticide parent compounds, since this has important implications on cumulative pesticide risk assessment.

pharmacology and toxicology↗

bioRxiv2022

Heterocyclic aromatic amines (HAAs) target mitochondrial physiology

Heterocyclic aromatic amines (HAA) may be found naturally in plants or are formed through the Maillard reaction when meat is cooked at high temperatures. Previous studies have indicated HAAs are especially toxic to dopaminergic neurons, whereas specific exposures may also affect other neuronal populations such as cholinergic neurons. Biochemical mechanisms of neurotoxic action implicate elevated oxidative stress and afflicted mitochondria. Notably, these mechanisms are of importance in Alzheimers disease (AD) and Parkinsons disease (PD). Most neurodegenerative disease cases are sporadic, where environmental and dietary factors may modulate risk. To further investigate HAA neurotoxicity, we tested the effect of common HAA (harmane, harmine, norharmane, PhIP, and HONH-PhIP) exposure on mitochondrial physiology, a key pathogenic target in AD and PD. Upon assessing mitochondrial bioenergetics, we observed a significant reduction in basal respiration, ATP production, maximal respiratory capacity, and non-mitochondrial respiration, indicating that HAA negatively impacts mitochondrial respiration. Followed by more specific studies on individual mitochondrial complexes, it was found that harmane, harmine, norharmane specifically inhibit complex I enzyme activity, whereas HONH-PhiP, a reactive metabolite of PhIP, inhibits Complex III enzyme activity. Our findings provide significant advancement with respect to underlying mechanisms of toxicity, though also validating HAA exposure as a potential risk factor for AD and PD.

neuroscience↗

bioRxiv2019

Developmental exposure to perfluorooctane sulfononate (PFOS) and perfluorooctanoic acid (PFOA) selectively decreases brain dopamine levels in northern leopard frogs

Per- and polyfluoroalkyl substances (PFAS) are synthetic compounds that are a major public health concern due to widespread use, long environmental and biological half-lives, detection in most human plasma samples, and links to multiple adverse health outcomes. The literature suggests that some PFAS may be neurotoxic. However, there are major gaps in the literature with respect to how environmentally-relevant doses during development may influence the nervous system. To address this gap, we utilized a sentinel species, Northern leopard frogs (Lithobates pipiens) to determine the effects of developmental exposure to environmentally relevant perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) on major neurotransmitter systems. Frog larvae at Gosner stage 25 were exposed to 10, 100, or 1000 ppb PFOS or PFOA for 30 days before neurochemical analysis. High performance liquid chromatography (HPLC) with electrochemical detection or fluorescent detection assays was used to measure neurotransmitter levels, which were normalized to protein levels in each sample. Dopamine (DA) decreased significantly in the brains of frogs treated with PFOA (1000 ppb) and PFOS (100 and 1000 ppb). Significant increases in DA turnover also resulted from PFOA and PFOS treatment. Neither PFOS, nor PFOA produced detectable alterations in serotonin (nor its metabolite), norepinephrine, gamma-amino butyric acid (GABA), glutamate, or acetylcholine. PFAS body burdens showed that PFOS accumulated relative to dose, while PFOA did not. These data suggest that DArgic neurotransmission is selectively affected in developmentally exposed amphibians and that PFAS should be evaluated for a potential role in diseases that target the DA system.

pharmacology and toxicology↗

bioRxiv2018

The single mitochondrion of the kinetoplastid parasite Crithidia fasciculata is a dynamic network

Mitochondria are central organelles in cellular metabolism. Their structure is highly dynamic, allowing them to adapt to different energy requirements, to be partitioned during cell division, and to maintain functionality. Mitochondrial dynamics, including membrane fusion and fission reactions, are well studied in yeast and mammals but it is not known if these processes are conserved throughout eukaryotic evolution. Kinetoplastid parasites are some of the earliest-diverging eukaryotes to retain a mitochondrion. Each cell has only a single mitochondrial organelle, making them an interesting model for the role of dynamics in controlling mitochondrial architecture. We have investigated the mitochondrial division cycle in the kinetoplastid Crithidia fasciculata. The majority of mitochondrial biogenesis occurs during the G1 phase of the cell cycle, and the mitochondrion is divided symmetrically in a process coincident with cytokinesis. Mitochondrial division was not inhibited by the putative dynamin inhibitor mdivi-1, although mitochondrial membrane potential and cell size were affected. Live cell imaging revealed that the mitochondrion is highly dynamic, with frequent changes in the topology of the branched network. These remodeling reactions include tubule fission, fusion, and sliding, as well as new tubule formation. We hypothesize that the function of this dynamic remodeling is to homogenize mitochondrial contents and to facilitate rapid transport of mitochondria-encoded gene products from the area containing the mitochondrial nucleoid to other parts of the organelle.

cell biology↗