Opposing patterns of abnormal D1 and D2 receptor dependent cortico-striatal plasticity explain increased risk taking in patients with DYT1 dystonia

Patients with DYT1 dystonia caused by the mutated TOR1A gene exhibit risk neutral behaviour compared to controls who are risk averse in the same reinforcement learning task. It is unclear whether this behaviour can be linked to changes in cortico-striatal plasticity demonstrated in animal models which share the same TOR1A mutation. We hypothesised that we could reproduce the experimental risk taking behaviour using a model of the basal ganglia under conditions where cortico-striatal plasticity was abnormal. As dopamine exerts opposing effects on cortico-striatal plasticity via different receptors expressed on medium spiny neurons (MSN) of the direct (D1R dominant, dMSNs) and indirect (D2R dominant, iMSNs) pathways, we tested whether abnormalities in cortico-striatal plasticity in one or both of these pathways could explain the patient's behaviour. Our model could generate simulated behaviour indistinguishable from patients when cortico-striatal plasticity was abnormal in both dMSNs and iMSNs in opposite directions. The risk neutral behaviour of the patients was replicated when increased cortico-striatal long term potentiation in dMSN's was in combination with increased long term depression in iMSN's. This result is consistent with previous observations in rodent models of increased cortico-striatal plasticity at in dMSNs, but contrasts with the pattern reported in vitro of dopamine D2 receptor dependant increases in cortico-striatal LTP and loss of LTD at iMSNs. These results suggest that additional factors in patients who manifest motor symptoms may lead to divergent effects on D2 receptor dependant cortico-striatal plasticity that are not apparent in rodent models of this disease

Impaired value-based decision-making in Parkinson’s Disease Apathy

Apathy is a common and disabling complication of Parkinson’s disease characterized by reduced goal-directed behaviour. Several studies have reported dysfunction within prefrontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision-making. Specifically, these neuromodulators have overlapping contributions to encoding the value of decisions, and influence whether to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesized that apathy in Parkinson’s disease should be associated with an impairment in value-based learning. Using a four-armed restless bandit reinforcement learning task, we studied decision-making in 75 volunteers; 53 patients with Parkinson’s disease, with and without clinical apathy, and 22 age-matched healthy control subjects. Patients with apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patient’s apathy severity measured using the Lille Apathy Rating Scale (R = −0.46, P &lt; 0.001). Computational modelling of the patient’s choices confirmed the apathy group made decisions that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration, which also correlated with apathy scores (R = −0.5, P &lt; 0.001). We went on to acquire functional MRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age-matched controls performing the Restless Bandit Task. Analysis of the functional MRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinson’s disease, which was more marked in apathy, but not predictive of their individual apathy severity. Using a model-based categorization of choice type, decisions to explore lower value bandits in the apathy group activated prefrontal cortex to a similar degree to the age-matched controls. In contrast, Parkinson’s patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched control subjects, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinson’s disease.</p

Impaired value-based decision-making in Parkinson’s Disease Apathy

Apathy is a common and disabling complication of Parkinson’s disease characterized by reduced goal-directed behaviour. Several studies have reported dysfunction within prefrontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision-making. Specifically, these neuromodulators have overlapping contributions to encoding the value of decisions, and influence whether to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesized that apathy in Parkinson’s disease should be associated with an impairment in value-based learning. Using a four-armed restless bandit reinforcement learning task, we studied decision-making in 75 volunteers; 53 patients with Parkinson’s disease, with and without clinical apathy, and 22 age-matched healthy control subjects. Patients with apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patient’s apathy severity measured using the Lille Apathy Rating Scale (R = −0.46, P &lt; 0.001). Computational modelling of the patient’s choices confirmed the apathy group made decisions that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration, which also correlated with apathy scores (R = −0.5, P &lt; 0.001). We went on to acquire functional MRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age-matched controls performing the Restless Bandit Task. Analysis of the functional MRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinson’s disease, which was more marked in apathy, but not predictive of their individual apathy severity. Using a model-based categorization of choice type, decisions to explore lower value bandits in the apathy group activated prefrontal cortex to a similar degree to the age-matched controls. In contrast, Parkinson’s patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched control subjects, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinson’s disease.</p

Organism-sediment interactions govern post-hypoxia recovery of ecosystem functioning

Hypoxia represents one of the major causes of biodiversity and ecosystem functioning loss for coastal waters. Since eutrophication-induced hypoxic events are becoming increasingly frequent and intense, understanding the response of ecosystems to hypoxia is of primary importance to understand and predict the stability of ecosystem functioning. Such ecological stability may greatly depend on the recovery patterns of communities and the return time of the system properties associated to these patterns. Here, we have examined how the reassembly of a benthic community contributed to the recovery of ecosystem functioning following experimentally-induced hypoxia in a tidal flat. We demonstrate that organism-sediment interactions that depend on organism size and relate to mobility traits and sediment reworking capacities are generally more important than recovering species richness to set the return time of the measured sediment processes and properties. Specifically, increasing macrofauna bioturbation potential during community reassembly significantly contributed to the recovery of sediment processes and properties such as denitrification, bedload sediment transport, primary production and deep pore water ammonium concentration. Such bioturbation potential was due to the replacement of the small-sized organisms that recolonised at early stages by large-sized bioturbating organisms, which had a disproportionately stronger influence on sediment. This study suggests that the complete recovery of organism-sediment interactions is a necessary condition for ecosystem functioning recovery, and that such process requires long periods after disturbance due to the slow growth of juveniles into adult stages involved in these interactions. Consequently, repeated episodes of disturbance at intervals smaller than the time needed for the system to fully recover organism-sediment interactions may greatly impair the resilience of ecosystem functioning.

The importance of livestock demography and infrastructure in driving Foot and Mouth disease dynamics

Transboundary animal diseases, such as foot and mouth disease (FMD) pose a significant and ongoing threat to global food security. Such diseases can produce large, spatially complex outbreaks. Mathematical models are often used to understand the spatio-temporal dynamics and create response plans for possible disease introductions. Model assumptions regarding transmission behavior of premises and movement patterns of livestock directly impact our understanding of the ecological drivers of outbreaks and how to best control them. Here, we investigate the impact that these assumptions have on model predictions of FMD outbreaks in the U.S. using models of livestock shipment networks and disease spread. We explore the impact of changing assumptions about premises transmission behavior, both by including within-herd dynamics, and by accounting for premises type and increasing the accuracy of shipment predictions. We find that the impact these assumptions have on outbreak predictions is less than the impact of the underlying livestock demography, but that they are important for investigating some response objectives, such as the impact on trade. These results suggest that demography is a key ecological driver of outbreaks and is critical for making robust predictions but that understanding management objectives is also important when making choices about model assumptions

The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma

Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G-protein Gsα, as a potent tumor suppressor gene that defines a subset of aggressive Sonic Hedgehog (Shh)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically-distinct progenitors is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gsα is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh-signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation of a Gsα effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas mutants. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gsα that acts as a molecular link across Shh-group medulloblastomas of disparate cellular and anatomical origins, illuminating G-protein modulation as a potential therapeutic avenue

explore-exploitDBS

Behavioural data, RLDDM model fitting outputs and Rmaps for Marcelino et. al. 2022 Pallidal neuromodulation of the explore/exploit trade-off in decision-making https://www.biorxiv.org/content/10.1101/2022.04.21.489010v1.article-metric