Reconstructing the three-dimensional GABAergic microcircuit of the striatum

A system's wiring constrains its dynamics, yet modelling of neural structures often overlooks the specific networks formed by their neurons. We developed an approach for constructing anatomically realistic networks and reconstructed the GABAergic microcircuit formed by the medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) of the adult rat striatum. We grew dendrite and axon models for these neurons and extracted probabilities for the presence of these neurites as a function of distance from the soma. From these, we found the probabilities of intersection between the neurites of two neurons given their inter-somatic distance, and used these to construct three-dimensional striatal networks. The MSN dendrite models predicted that half of all dendritic spines are within 100 mu m of the soma. The constructed networks predict distributions of gap junctions between FSI dendrites, synaptic contacts between MSNs, and synaptic inputs from FSIs to MSNs that are consistent with current estimates. The models predict that to achieve this, FSIs should be at most 1% of the striatal population. They also show that the striatum is sparsely connected: FSI-MSN and MSN-MSN contacts respectively form 7% and 1.7% of all possible connections. The models predict two striking network properties: the dominant GABAergic input to a MSN arises from neurons with somas at the edge of its dendritic field; and FSIs are interconnected on two different spatial scales: locally by gap junctions and distally by synapses. We show that both properties influence striatal dynamics: the most potent inhibition of a MSN arises from a region of striatum at the edge of its dendritic field; and the combination of local gap junction and distal synaptic networks between FSIs sets a robust input-output regime for the MSN population. Our models thus intimately link striatal micro-anatomy to its dynamics, providing a biologically grounded platform for further study

Differential Extinction and the Contrasting Structure of Polar Marine Faunas

Background: The low taxonomic diversity of polar marine faunas today reflects both the failure of clades to colonize or diversify in high latitudes and regional extinctions of once-present clades. However, simple models of polar evolution are made difficult by the strikingly different faunal compositions and community structures of the two poles. Methodology/Principal Findings: A comparison of early Cenozoic Arctic and Antarctic bivalve faunas with modern ones, within the framework of a molecular phylogeny, shows that while Arctic losses were randomly distributed across the tree, Antarctic losses were significantly concentrated in more derived families, resulting in communities dominated by basal lineages. Potential mechanisms for the phylogenetic structure to Antarctic extinctions include continental isolation, changes in primary productivity leading to turnover of both predators and prey, and the effect of glaciation on shelf habitats. Conclusions/Significance: These results show that phylogenetic consequences of past extinctions can vary substantially among regions and thus shape regional faunal structures, even when due to similar drivers, here global cooling, and provide the first phylogenetic support for the ‘‘retrograde’ ’ hypothesis of Antarctic faunal evolution

Increases in physical activity may affect quality of life differently in men and women: the PACE project

PURPOSE: Obesity is associated with impaired quality of life (QoL), but less is known about physical activity. We investigated how decreases in body mass index (BMI) and increases in activity affect obesity-specific QoL and potential gender differences in associations. METHODS: In a large worksite-randomized trial of a multilevel intervention on diet and physical activity behaviors, we conducted a cohort analysis at two years of follow-up. Self-reported activity and Obesity and Weight-Loss Quality Of Life (OWLQOL) were analyzed for individual-level associations using linear mixed models accounting for random worksite effects. RESULTS: Gender modified the BMI-OWLQOL relationship, so analyses were conducted for males and females separately. Adjusting for demographic confounders, baseline OWLQOL, and several worksite-level variables including intervention arm, a 1.9 unit decrease in BMI (the interquartile range) was associated with an OWLQOL increase of 1.7 (95% CI: 1.2, 2.2) in males and 3.6 (95% CI: 3.2, 4.0) in females. Similarly, a 23 unit increase in physical activity score was associated with an OWLQOL increase of 0.9 (95% CI: 0.5, 1.4) in males and 1.6 (95% CI: 1.0, 2.3) in females. Physical activity associations were attenuated when adjusting for change in BMI, but remained significant for women (mean BMI 27.8 kg/m(2)). CONCLUSIONS: This is the first study to demonstrate that increasing physical activity may improve obesity-specific QoL to a greater extent in women, particularly among overweight women, independent of BMI. Results may inform the design of interventions tailored to women targeting well-being through messages of increasing physical activity

Opposite Effects of Stimulant and Antipsychotic Drugs on Striatal Fast-Spiking Interneurons

Psychomotor stimulants and typical antipsychotic drugs have powerful but opposite effects on mood and behavior, largely through alterations in striatal dopamine signaling. Exactly how these drug actions lead to behavioral change is not well understood, as previous electrophysiological studies have found highly heterogeneous changes in striatal neuron firing. In this study, we examined whether part of this heterogeneity reflects the mixture of distinct cell types present in the striatum, by distinguishing between medium spiny projection neurons (MSNs) and presumed fast-spiking interneurons (FSIs), in freely moving rats. The response of MSNs to both the stimulant amphetamine (0.5 or 2.5 mg/kg) and the antipsychotic eticlopride (0.2 or 1.0 mg/kg) remained highly heterogeneous, with each drug causing both increases and decreases in the firing rate of many MSNs. By contrast, FSIs showed a far more uniform, dose-dependent response to both drugs. All FSIs had decreased firing rate after high eticlopride. After high amphetamine most FSIs increased firing rate, and none decreased. In addition, the activity of the FSI population was positively correlated with locomotor activity, whereas the MSN population showed no consistent response. Our results show a direct relationship between the psychomotor effects of dopaminergic drugs and the firing rate of a specific striatal cell population. Striatal FSIs may have an important role in the behavioral effects of these drugs, and thus may be a valuable target in the development of novel therapies