Transient and steady-state selection in the striatal microcircuit

Although the basal ganglia have been widely studied and implicated in signal processing and action selection, little information is known about the active role the striatal microcircuit plays in action selection in the basal ganglia-thalamo-cortical loops. To address this knowledge gap we use a large scale three dimensional spiking model of the striatum, combined with a rate coded model of the basal ganglia-thalamo-cortical loop, to asses the computational role the striatum plays in action selection. We identify a robust transient phenomena generated by the striatal microcircuit, which temporarily enhances the difference between two competing cortical inputs. We show that this transient is sufficient to modulate decision making in the basal ganglia-thalamo-cortical circuit. We also find that the transient selection originates from a novel adaptation effect in single striatal projection neurons, which is amenable to experimental testing. Finally, we compared transient selection with models implementing classical steady-state selection. We challenged both forms of model to account for recent reports of paradoxically enhanced response selection in Huntington's disease patients. We found that steady-state selection was uniformly impaired under all simulated Huntington's conditions, but transient selection was enhanced given a sufficient Huntington's-like increase in NMDA receptor sensitivity. Thus our models provide an intriguing hypothesis for the mechanisms underlying the paradoxical cognitive improvements in manifest Huntington's patients

Action selection in the striatum: Implications for Huntington's disease

Although the basal ganglia have been widely studied and implicated in signal processing and action selection, little information is known about the active role that the striatal microcircuit plays in action selection in the basal ganglia-cortical-thalamic loops. To address this knowledge gap we use a large scale three dimensional spiking model of the striatum, combined with a rate coded model of the basal ganglia-cortical-thalamic loop, to asses the computational role the striatum plays in action selection. We identify robust transient phenomena generated by the striatal microcircuit, which temporarily enhances the difference between two competing cortical inputs. We show that this transient is sufficient to modulate decision making in the basal ganglia-thalamo-cortical circuit. We also find that the transient selection originates from a novel adaptation effect in single striatal projection neurons, which is amenable to experimental testing. Finally, we compared transient selection with models implementing classical steady-state selection. We challenged both forms of model to account for recent reports of paradoxically enhanced response selection in Huntington's disease patients. We found that steady-state selection was uniformly impaired under all simulated Huntington's conditions, but transient selection was enhanced given a sufficient Huntington's-like increase in NMDA receptor sensitivity. I propose a mechanistic underpinning to a novel neural compensatory mechanism, responsible for improved cognition in severe neuro-degeneration. Thus, our models provide an intriguing hypothesis for the mechanisms underlying the paradoxical cognitive improvements in manifest Huntington's patients, which is consistent with recent behavioural data

Striatal neuropeptides enhance selection and rejection of sequential actions

The striatum is the primary input nucleus for the basal ganglia, and receives glutamatergic afferents from the cortex. Under the hypothesis that basal ganglia perform action selection, these cortical afferents encode potential “action requests.” Previous studies have suggested the striatum may utilize a mutually inhibitory network of medium spiny neurons (MSNs) to filter these requests so that only those of high salience are selected. However, the mechanisms enabling the striatum to perform clean, rapid switching between distinct actions that form part of a learned action sequence are still poorly understood. Substance P (SP) and enkephalin are neuropeptides co-released with GABA in MSNs preferentially expressing D1 or D2 dopamine receptors respectively. SP has a facilitatory effect on subsequent glutamatergic inputs to target MSNs, while enkephalin has an inhibitory effect. Blocking the action of SP in the striatum is also known to affect behavioral transitions. We constructed phenomenological models of the effects of SP and enkephalin, and integrated these into a hybrid model of basal ganglia comprising a spiking striatal microcircuit and rate–coded populations representing other major structures. We demonstrated that diffuse neuropeptide connectivity enhanced the selection of unordered action requests, and that for true action sequences, where action semantics define a fixed structure, a patterning of the SP connectivity reflecting this ordering enhanced selection of actions presented in the correct sequential order and suppressed incorrect ordering. We also showed that selective pruning of SP connections allowed context–sensitive inhibition of specific undesirable requests that otherwise interfered with selection of an action group. Our model suggests that the interaction of SP and enkephalin enhances the contrast between selection and rejection of action requests, and that patterned SP connectivity in the striatum allows the “chunking” of actions and improves selection of sequences. Efficient execution of action sequences may therefore result from a combination of ordered cortical inputs and patterned neuropeptide connectivity within striatum

Cell assembly dynamics of sparsely-connected inhibitory networks: a simple model for the collective activity of striatal projection neurons

Striatal projection neurons form a sparsely-connected inhibitory network, and this arrangement may be essential for the appropriate temporal organization of behavior. Here we show that a simplified, sparse inhibitory network of Leaky-Integrate-and-Fire neurons can reproduce some key features of striatal population activity, as observed in brain slices [Carrillo-Reid et al., J. Neurophysiology 99 (2008) 1435{1450]. In particular we develop a new metric to determine the conditions under which sparse inhibitory networks form anti-correlated cell assemblies with time-varying activity of individual cells. We found that under these conditions the network displays an input-specific sequence of cell assembly switching, that effectively discriminates similar inputs. Our results support the proposal [Ponzi and Wickens, PLoS Comp Biol 9 (2013) e1002954] that GABAergic connections between striatal projection neurons allow stimulus-selective, temporally-extended sequential activation of cell assemblies. Furthermore, we help to show how altered intrastriatal GABAergic signaling may produce aberrant network-level information processing in disorders such as Parkinson's and Huntington's diseases.Comment: 22 pages, 9 figure

The role of cortical oscillations in a spiking neural network model of the basal ganglia.

Although brain oscillations involving the basal ganglia (BG) have been the target of extensive research, the main focus lies disproportionally on oscillations generated within the BG circuit rather than other sources, such as cortical areas. We remedy this here by investigating the influence of various cortical frequency bands on the intrinsic effective connectivity of the BG, as well as the role of the latter in regulating cortical behaviour. To do this, we construct a detailed neural model of the complete BG circuit based on fine-tuned spiking neurons, with both electrical and chemical synapses as well as short-term plasticity between structures. As a measure of effective connectivity, we estimate information transfer between nuclei by means of transfer entropy. Our model successfully reproduces firing and oscillatory behaviour found in both the healthy and Parkinsonian BG. We found that, indeed, effective connectivity changes dramatically for different cortical frequency bands and phase offsets, which are able to modulate (or even block) information flow in the three major BG pathways. In particular, alpha (8-12Hz) and beta (13-30Hz) oscillations activate the direct BG pathway, and favour the modulation of the indirect and hyper-direct pathways via the subthalamic nucleus-globus pallidus loop. In contrast, gamma (30-90Hz) frequencies block the information flow from the cortex completely through activation of the indirect pathway. Finally, below alpha, all pathways decay gradually and the system gives rise to spontaneous activity generated in the globus pallidus. Our results indicate the existence of a multimodal gating mechanism at the level of the BG that can be entirely controlled by cortical oscillations, and provide evidence for the hypothesis of cortically-entrained but locally-generated subthalamic beta activity. These two findings suggest new insights into the pathophysiology of specific BG disorders

Action selection in the rhythmic brain: The role of the basal ganglia and tremor.

Low-frequency oscillatory activity has been the target of extensive research both in cortical structures and in the basal ganglia (BG), due to numerous reports of associations with brain disorders and the normal functioning of the brain. Additionally, a plethora of evidence and theoretical work indicates that the BG might be the locus where conflicts between prospective actions are being resolved. Whereas a number of computational models of the BG investigate these phenomena, these models tend to focus on intrinsic oscillatory mechanisms, neglecting evidence that points to the cortex as the origin of this oscillatory behaviour. In this thesis, we construct a detailed neural model of the complete BG circuit based on fine-tuned spiking neurons, with both electrical and chemical synapses as well as short-term plasticity between structures. To do so, we build a complete suite of computational tools for the design, optimization and simulation of spiking neural networks. Our model successfully reproduces firing and oscillatory behaviour found in both the healthy and Parkinsonian BG, and it was used to make a number of biologically-plausible predictions. First, we investigate the influence of various cortical frequency bands on the intrinsic effective connectivity of the BG, as well as the role of the latter in regulating cortical behaviour. We found that, indeed, effective connectivity changes dramatically for different cortical frequency bands and phase offsets, which are able to modulate (or even block) information flow in the three major BG pathways. Our results indicate the existence of a multimodal gating mechanism at the level of the BG that can be entirely controlled by cortical oscillations, and provide evidence for the hypothesis of cortically-entrained but locally-generated subthalamic beta activity. Next, we explore the relationship of wave properties of entrained cortical inputs, dopamine and the transient effectiveness of the BG, when viewed as an action selection device. We found that cortical frequency, phase, dopamine and the examined time scale, all have a very important impact on the ability of our model to select. Our simulations resulted in a canonical profile of selectivity, which we termed selectivity portraits. Taking together, our results suggest that the cortex is the structure that determines whether action selection will be performed and what strategy will be utilized while the role of the BG is to perform this selection. Some frequency ranges promote the exploitation of actions of whom the outcome is known, others promote the exploration of new actions with high uncertainty while the remaining frequencies simply deactivate selection. Based on this behaviour, we propose a metaphor according to which, the basal ganglia can be viewed as the ''gearbox" of the cortex. Coalitions of rhythmic cortical areas are able to switch between a repertoire of available BG modes which, in turn, change the course of information flow back to and within the cortex. In the same context, dopamine can be likened to the ''control pedals" of action selection that either stop or initiate a decision. Finally, the frequency of active cortical areas that project to the BG acts as a gear lever, that instead of controlling the type and direction of thrust that the throttle provides to an automobile, it dictates the extent to which dopamine can trigger a decision, as well as what type of decision this will be. Finally, we identify a selection cycle with a period of around 200 ms, which was used to assess the biological plausibility of the most popular architectures in cognitive science. Using extensions of the BG model, we further propose novel mechanisms that provide explanations for (1) the two distinctive dynamical behaviours of neurons in globus pallidus external, and (2) the generation of resting tremor in Parkinson's disease. Our findings agree well with experimental observations, suggest new insights into the pathophysiology of specific BG disorders, provide new justifications for oscillatory phenomena related to decision making and reaffirm the role of the BG as the selection centre of the brain.Open Acces

Functional Properties of Striatal Fast-Spiking Interneurons

Striatal fast-spiking interneurons (FSIs) have a major influence over behavioral output, and a deficit in these cells has been observed in dystonia and Tourette syndrome. FSIs receive cortical input, are coupled together by gap junctions, and make perisomatic GABAergic synapses onto many nearby projection neurons. Despite being critical components of striatal microcircuits, until recently little was known about FSI activity in behaving animals. Striatal FSIs are near-continuously active in awake rodents, but even neighboring FSIs show uncorrelated activity most of the time. A coordinated “pulse” of increased FSI firing occurs throughout striatum when rats initiate one chosen action while suppressing a highly trained alternative. This pulse coincides with a drop in globus pallidus population activity, suggesting that pallidostriatal disinhibition may have a important role in timing or coordinating action execution. In addition to changes in firing rate, FSIs show behavior-linked modulation of spike timing. The variability of inter-spike intervals decreases markedly following instruction cues, and FSIs also participate in fast striatal oscillations that are linked to rewarding events and dopaminergic drugs. These studies have revealed novel and unexpected properties of FSIs, that should help inform new models of striatal information processing in both normal and aberrant conditions

A biophysical model of striatal microcircuits suggests delta/theta - rhythmically interleaved gamma and beta oscillations mediate periodicity in motor control

First author draf