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Kevin Gurney

Publications and source records attributed to Kevin Gurney.

5 recordsLinked to original sources

The basal ganglia and cortex implement optimal decision making between alternative actions.

Neurophysiological studies have identified a number of brain regions critically involved in solving the problem of action selection or decision making. In the case of highly practiced tasks, these regions include cortical areas hypothesized to integrate evidence supporting alternative actions and the basal ganglia, hypothesized to act as a central switch in gating behavioral requests. However, despite our relatively detailed knowledge of basal ganglia biology and its connectivity with the cortex and numerical simulation studies demonstrating selective function, no formal theoretical framework exists that supplies an algorithmic description of these circuits. This article shows how many aspects of the anatomy and physiology of the circuit involving the cortex and basal ganglia are exactly those required to implement the computation defined by an asymptotically optimal statistical test for decision making: the multihypothesis sequential probability ratio test (MSPRT). The resulting model of basal ganglia provides a new framework for understanding the computation in the basal ganglia during decision making in highly practiced tasks. The predictions of the theory concerning the properties of particular neuronal populations are validated in existing experimental data. Further, we show that this neurobiologically grounded implementation of MSPRT outperforms other candidates for neural decision making, that it is structurally and parametrically robust, and that it can accommodate cortical mechanisms for decision making in a way that complements those in basal ganglia.

Algorithms↗

The short-latency dopamine signal: a role in discovering novel actions?

An influential concept in contemporary computational neuroscience is the reward prediction error hypothesis of phasic dopaminergic function. It maintains that midbrain dopaminergic neurons signal the occurrence of unpredicted reward, which is used in appetitive learning to reinforce existing actions that most often lead to reward. However, the availability of limited afferent sensory processing and the precise timing of dopaminergic signals suggest that they might instead have a central role in identifying which aspects of context and behavioural output are crucial in causing unpredicted events.

Animals↗

A robot model of the basal ganglia: behavior and intrinsic processing.

The existence of multiple parallel loops connecting sensorimotor systems to the basal ganglia has given rise to proposals that these nuclei serve as a selection mechanism resolving competitions between the alternative actions available in a given context. A strong test of this hypothesis is to require a computational model of the basal ganglia to generate integrated selection sequences in an autonomous agent, we therefore describe a robot architecture into which such a model is embedded, and require it to control action selection in a robotic task inspired by animal observations. Our results demonstrate effective action selection by the embedded model under a wide range of sensory and motivational conditions. When confronted with multiple, high salience alternatives, the robot also exhibits forms of behavioral disintegration that show similarities to animal behavior in conflict situations. The model is shown to cast light on recent neurobiological findings concerning behavioral switching and sequencing.

Basal Ganglia↗

Computational models of the basal ganglia: from robots to membranes.

With the rapid accumulation of neuroscientific data comes a pressing need to develop models that can explain the computational processes performed by the basal ganglia. Relevant biological information spans a range of structural levels, from the activity of neuronal membranes to the role of the basal ganglia in overt behavioural control. This viewpoint presents a framework for understanding the aims, limitations and methods for testing of computational models across all structural levels. We identify distinct modelling strategies that can deliver important and complementary insights into the nature of problems the basal ganglia have evolved to solve, and describe methods that are used to solve them.

Animals↗

Human immunodeficiency virus envelope (gp120) binding to DC-SIGN and primary dendritic cells is carbohydrate dependent but does not involve 2G12 or cyanovirin binding sites: implications for structural analyses of gp120-DC-SIGN binding.

The calcium-dependent lectin, DC-SIGN, binds to human immunodeficiency virus (HIV) (and simian immunodeficiency virus) gp120 and mediates the binding and transfer of HIV from monocyte-derived dendritic cells (MDDCs) to permissive T cells. However, it has been recently reported that DC-SIGN binding to HIV gp120 may be carbohydrate independent. Here, we formally demonstrate that gp120 binding to DC-SIGN and MDDCs is largely if not wholly carbohydrate dependent. Endo-beta-N-glucosaminidase H (EndoH) treatment of gp120-Fc under conditions that maintained wild-type CD4 binding-and the full complement of complex glycans-significantly decreased (>90%) binding to DC-SIGN expressing cell lines, as well as to MDDCs. Any residual binding of EndoH-treated gp120-Fc to DC-SIGN was completely competed off with mannan. Mutational analysis indicated that no single glycosylation site affected the ability of gp120-Fc to bind DC-SIGN. To further guide our efforts in mapping the DC-SIGN binding sites on gp120, we used two well-characterized HIV inhibitory agents (2G12 monoclonal antibody and cyanovirin) that bind to high-mannose sugars on gp120. We showed that 2G12 and DC-SIGN bound to nonoverlapping sites in gp120 because (i) 2G12 did not block soluble gp120 or virion binding to DC-SIGN, (ii) 2G12 bound to gp120-Fc that was prebound to cell surface DC-SIGN, and (iii) gp120-Fc mutants that lack glycosylation sites involved in 2G12's epitope were also fully capable of binding DC-SIGN. These data were substantiated by the inability of cyanovirin to block gp120-Fc binding to DC-SIGN. Cyanovirin has been shown to effectively compete for 2G12 binding to gp120. Indeed, high concentrations of cyanovirin dramatically enhanced gp120-Fc binding to cell surfaces in the presence or absence of DC-SIGN. We provide evidence that this enhancement may be due to cyanovirin's ability to bridge gp120 to mannosylated cell surface proteins. These results have implications for antiviral therapeutics and for ongoing efforts to finely map the glycan structures on gp120 responsible for DC-SIGN binding.

Antibodies, Monoclonal↗