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

A Kinetic Model of Dopamine- and Calcium-Dependent Striatal Synaptic Plasticity

Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD), the combination with dopamine switches LTD to long-term potentiation (LTP), which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32), as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA), protein phosphatase 2A (PP2A), and the phosphorylation site at threonine 75 of DARPP-32 (Thr75) served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B)-CK1 (casein kinase 1)-Cdk5 (cyclin-dependent kinase 5)-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP). The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The present model elucidated the mechanisms involved in bidirectional regulation of corticostriatal synapses and will allow for further exploration into causes and therapies for dysfunctions such as drug addiction

Role of FoxP2 during functional recruitment of post-hatch-generated medium spiny neurons in a brain region relevant for vocal learning in male zebra finches

Adult neurogenesis is a process in which new neurons are generated in neurogenic niches and become recruited into distinct regions of the mature brain. In the adult songbird brain, new neurons are incorporated into areas that facilitate learning, production and maintenance of song. The striatal song nucleus Area X constantly receives new medium spiny neurons (MSNs) throughout adulthood, but it was not known if they are functionally integrated into the preexisting circuitry. To address this question, I applied Bromodeoxyuridine (BrdU) and lentiviral vector-mediated labelling of progenitor cells and examined the maturation, connectivity and singing elicited activation and of their progeny in Area X after different survival periods. Six weeks after their birth, the majority of new neurons expressed a marker for mature MSNs, show pre- and postsynaptic connections and expressed dopamine receptors, indicative of dopaminergic innervation. The expression of the immediate early gene EGR-1 (early growth response protein 1) was used to assess if and at what age new neurons were activated by singing. Already three weeks after their labelling, a small fraction of new MSNs expressed EGR-1 after singing and this fraction increased with progressing maturation. Measuring MSN densities in zebra finches up to seven years of age provided insights into the dynamics of striatal adult neurogenesis and revealed that it is a process of constant new neuron addition. New MSNs that are recruited into Area X express the forkhead box protein P2 (FoxP2). This transcription factor has important functions in mammalian brain development and mutations in FOXP2 cause speech and language impairments in humans. In zebra finches, correct FoxP2 expression levels in Area X are crucial for successful song learning and for song modulation between different social contexts. FoxP2 levels in Area X are high during the phase of song learning but generally low in adults and are downregulated by singing. MSNs in Area X exhibit different FoxP2 expression levels. Since FoxP2 downregulation after singing only occurs in MSNs with low FoxP2 levels (FoxP2low) and not in MSNs with high FoxP2 levels (FoxP2high), I postulated that the latter were recently recruited and need to become FoxP2low MSNs before they would be activated by singing. This hypothesis was tested by measuring FoxP2 protein levels and EGR-1 expression in individual new MSNs of singing and non-singing birds at different time points after BrdU birth dating. Interestingly, FoxP2high and FoxP2low MSNs were equally activated during singing, indicating that this is a process independent of FoxP2 levels. Further, I identified that one third of new MSNs expressed FoxP2 at high levels during early stages of their maturation. However, the majority of matured MSNs expressed FoxP2 at low levels, indicating an age-related decrease of FoxP2 levels in a subset of newly recruited MSNs. Because Foxp2 was shown to enhance neuronal outgrowth and differentiation, I analyzed the dendrite morphology and the density of dendritic spines of FoxP2high and FoxP2low new MSNs that were virally labelled and expressed the green fluorescent protein. FoxP2high new MSNs had more complex dendrites and a higher density of the mature mushroom spines than FoxP2low new MSNs and thus probably received more pallial inputs during a narrow timeframe of their maturation. Comparing my results to what is known about MSNs of the direct and indirect pathway of the basal ganglia of rodents, I hypothesize that early differences in FoxP2 levels and concomitant diverging new MSNs morphology might indicate the existence of distinct MSN subtypes in Area X of zebra finches. Altogether, the presented data illustrate that new MSNs recruited into Area X of adult zebra finches are functional and might play a role for the maintenance of song. Within the first six weeks after their birth new MSNs exhibited dynamic FoxP2 expression levels which are liked to their dendritic arborization and spine density, thus broadening FoxP2 function by an implication in striatal adult neurogenesis

Basal ganglia role in learning rewarded actions and executing previously learned choices: Healthy and diseased states

The basal ganglia (BG) is a collection of nuclei located deep beneath the cerebral cortex that is involved in learning and selection of rewarded actions. Here, we analyzed BG mechanisms that enable these functions. We implemented a rate model of a BG-thalamo-cortical loop and simulated its performance in a standard action selection task. We have shown that potentiation of corticostriatal synapses enables learning of a rewarded option. However, these synapses became redundant later as direct connections between prefrontal and premotor cortices (PFC-PMC) were potentiated by Hebbian learning. After we switched the reward to the previously unrewarded option (reversal), the BG was again responsible for switching to the new option. Due to the potentiated direct cortical connections, the system was biased to the previously rewarded choice, and establishing the new choice required a greater number of trials. Guided by physiological research, we then modified our model to reproduce pathological states of mild Parkinson's and Huntington's diseases. We found that in the Parkinsonian state PMC activity levels become extremely variable, which is caused by oscillations arising in the BG-thalamo-cortical loop. The model reproduced severe impairment of learning and predicted that this is caused by these oscillations as well as a reduced reward prediction signal. In the Huntington state, the potentiation of the PFC-PMC connections produced better learning, but altered BG output disrupted expression of the rewarded choices. This resulted in random switching between rewarded and unrewarded choices resembling an exploratory phase that never ended. Along with other computational studies, our results further reconcile the apparent contradiction between the critical involvement of the BG in execution of previously learned actions and yet no impairment of these actions after BG output is ablated by lesions or deep brain stimulation. We predict that the cortico-BG-thalamo-cortical loop conforms to previously learned choice in healthy conditions, but impedes those choices in disease states

Value encoding in the globus pallidus: fMRI reveals an interaction effect between reward and dopamine drive

The external part of the globus pallidus (GPe) is a core nucleus of the basal ganglia (BG) whose activity is disrupted under conditions of low dopamine release, as in Parkinson's disease. Current models assume decreased dopamine release in the dorsal striatum results in deactivation of dorsal GPe, which in turn affects motor expression via a regulatory effect on other nuclei of the BG. However, recent studies in healthy and pathological animal models have reported neural dynamics that do not match with this view of the GPe as a relay in the BG circuit. Thus, the computational role of the GPe in the BG is still to be determined. We previously proposed a neural model that revisits the functions of the nuclei of the BG, and this model predicts that GPe encodes values which are amplified under a condition of low striatal dopaminergic drive. To test this prediction, we used an fMRI paradigm involving a within-subject placebo-controlled design, using the dopamine antagonist risperidone, wherein healthy volunteers performed a motor selection and maintenance task under low and high reward conditions. ROI-based fMRI analysis revealed an interaction between reward and dopamine drive manipulations, with increased BOLD activity in GPe in a high compared to low reward condition, and under risperidone compared to placebo. These results confirm the core prediction of our computational model, and provide a new perspective on neural dynamics in the BG and their effects on motor selection and cognitive disorders

Insights into Parkinson’s disease from computational models of the basal ganglia

Movement disorders arise from the complex interplay of multiple changes to neural circuits. Successful treatments for these disorders could interact with these complex changes in myriad ways, and as a consequence their mechanisms of action and their amelioration of symptoms are incompletely understood. Using Parkinson's disease as a case study, we review here how computational models are a crucial tool for taming this complexity, across causative mechanisms, consequent neural dynamics and treatments. For mechanisms, we review models that capture the effects of losing dopamine on basal ganglia function; for dynamics, we discuss models that have transformed our understanding of how beta-band (15-30?Hz) oscillations arise in the parkinsonian basal ganglia. For treatments, we touch on the breadth of computational modelling work trying to understand the therapeutic actions of deep brain stimulation. Collectively, models from across all levels of description are providing a compelling account of the causes, symptoms and treatments for Parkinson's disease

Mutant huntingtin enhances activation of dendritic Kv4 K+ channels in striatal spiny projection neurons

Huntington\u27s disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued by knocking-down expression of Kv4 channels, by disrupting KChIP binding, by restoring TrkB receptor signaling or by lowering mutant-Htt (mHtt) levels with a zinc finger protein. Collectively, these studies demonstrate that mHtt induces reversible alterations in the dendritic excitability of iSPNs that could contribute to the motor symptoms of HD

Electrical Advantages of Dendritic Spines

Many neurons receive excitatory glutamatergic input almost exclusively onto dendritic spines. In the absence of spines, the amplitudes and kinetics of excitatory postsynaptic potentials (EPSPs) at the site of synaptic input are highly variable and depend on dendritic location. We hypothesized that dendritic spines standardize the local geometry at the site of synaptic input, thereby reducing location-dependent variability of local EPSP properties. We tested this hypothesis using computational models of simplified and morphologically realistic spiny neurons that allow direct comparison of EPSPs generated on spine heads with EPSPs generated on dendritic shafts at the same dendritic locations. In all morphologies tested, spines greatly reduced location-dependent variability of local EPSP amplitude and kinetics, while having minimal impact on EPSPs measured at the soma. Spine-dependent standardization of local EPSP properties persisted across a range of physiologically relevant spine neck resistances, and in models with variable neck resistances. By reducing the variability of local EPSPs, spines standardized synaptic activation of NMDA receptors and voltage-gated calcium channels. Furthermore, spines enhanced activation of NMDA receptors and facilitated the generation of NMDA spikes and axonal action potentials in response to synaptic input. Finally, we show that dynamic regulation of spine neck geometry can preserve local EPSP properties following plasticity-driven changes in synaptic strength, but is inefficient in modifying the amplitude of EPSPs in other cellular compartments. These observations suggest that one function of dendritic spines is to standardize local EPSP properties throughout the dendritic tree, thereby allowing neurons to use similar voltage-sensitive postsynaptic mechanisms at all dendritic locations.This work was supported by National Institutes of Health grant R01 MH83806 (ATG), the National Health and Medical Research Council of Australia (GJS), and NIH grants NS11613 and DC00086 (NTC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript