Striatal Fast-Spiking Interneurons: From Firing Patterns to Postsynaptic Impact

In the striatal microcircuit, fast-spiking (FS) interneurons have an important role in mediating inhibition onto neighboring medium spiny (MS) projection neurons. In this study, we combined computational modeling with in vitro and in vivo electrophysiological measurements to investigate FS cells in terms of their discharge properties and their synaptic efficacies onto MS neurons. In vivo firing of striatal FS interneurons is characterized by a high firing variability. It is not known, however, if this variability results from the input that FS cells receive, or if it is promoted by the stuttering spike behavior of these neurons. Both our model and measurements in vitro show that FS neurons that exhibit random stuttering discharge in response to steady depolarization do not show the typical stuttering behavior when they receive fluctuating input. Importantly, our model predicts that electrically coupled FS cells show substantial spike synchronization only when they are in the stuttering regime. Therefore, together with the lack of synchronized firing of striatal FS interneurons that has been reported in vivo, these results suggest that neighboring FS neurons are not in the stuttering regime simultaneously and that in vivo FS firing variability is more likely determined by the input fluctuations. Furthermore, the variability in FS firing is translated to variability in the postsynaptic amplitudes in MS neurons due to the strong synaptic depression of the FS-to-MS synapse. Our results support the idea that these synapses operate over a wide range from strongly depressed to almost fully recovered. The strong inhibitory effects that FS cells can impose on their postsynaptic targets, and the fact that the FS-to-MS synapse model showed substantial depression over extended periods of time might indicate the importance of cooperative effects of multiple presynaptic FS interneurons and the precise orchestration of their activity

Local dynamics of gap-junction-coupled interneuron networks

Interneurons coupled by both electrical gap-junctions (GJs) and chemical GABAergic synapses are major components of forebrain networks. However, their contributions to the generation of specific activity patterns, and their overall contributions to network function, remain poorly understood. Here we demonstrate, using computational methods, that the topological properties of interneuron networks can elicit a wide range of activity dynamics, and either prevent or permit local pattern formation. We systematically varied the topology of GJ and inhibitory chemical synapses within simulated networks, by changing connection types from local to random, and changing the total number of connections. As previously observed we found that randomly coupled GJs lead to globally synchronous activity. In contrast, we found that local GJ connectivity may govern the formation of highly spatially heterogeneous activity states. These states are inherently temporally unstable when the input is uniformly random, but can rapidly stabilize when the network detects correlations or asymmetries in the inputs. We show a correspondence between this feature of network activity and experimental observations of transient stabilization of striatal fast-spiking interneurons (FSIs), in electrophysiological recordings from rats performing a simple decision-making task. We suggest that local GJ coupling enables an active search-and-select function of striatal FSIs, which contributes to the overall role of cortical-basal ganglia circuits in decision-making.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/85426/1/ph10_1_016015.pd

Fast oscillations in cortical-striatal networks switch frequency following rewarding events and stimulant drugs

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72155/1/j.1460-9568.2009.06843.x.pd

Delta/theta-rhythmically interleaved gamma and beta oscillations in striatum: modeling and data analysis

Striatal oscillatory activity associated with movement, reward, and decision-making is observed in several interacting frequency bands. Rodent striatal local field potential recordings show dopamine- and reward-dependent transitions between a 'spontaneous' state involving beta (15-30 Hz) and low gamma (40-60 Hz) and a 'dopaminergic' state involving theta (4-8 Hz) and high gamma (60-100 Hz) activity. The mechanisms underlying these rhythmic dynamics and their functional consequences are not well understood. In this thesis, I construct a biophysical model of striatal microcircuits that comprehensively describes the generation and interaction of these rhythms as well as their modulation by dopamine and rhythmic inputs, and test its predictions using human electroencephalography (EEG) data. Chapter 1 describes the striatal model and its dopaminergic modulation. Building on previous work suggesting striatal projection neuron (SPN) networks can generate beta oscillations, I construct a model network of striatal fast-spiking interneurons (FSIs) capable of generating delta/theta (2-6 Hz) and gamma rhythms. This FSI network produces low gamma oscillations under low (simulated) dopaminergic tone, and high gamma activity nested within a delta/theta oscillation under high dopaminergic tone. In a combined model under high dopaminergic tone SPN network beta oscillations are interrupted by delta/theta-periodic bursts of gamma-frequency FSI inhibition. This high dopamine-induced periodic inhibition may enable switching between beta-rhythmic SPN cell assemblies representing motor programs, suggesting that dopamine facilitates movement in part by allowing for rapid, periodic changes in motor program execution. Chapter 2 describes the model's response to square-wave periodic cortical inputs. Comparing models with and without FSIs reveals that the FSI network: (i) prevents the SPN network's generation of phase-locked beta oscillations in response to beta's harmonic frequencies, ensuring fidelity of transmission of cortical beta rhythms; and (ii) limits or entrains SPN activity in response to certain gamma frequency inputs. Chapter 3 describes an analysis of phase-amplitude coupling at cortical electrodes in human EEG data during a reward task. The alternating rhythms predicted by the model appear in response to positive feedback. While the origins of these rhythms remain unclear, if they represent striatal signals, they provide a direct link between human behavior and striatal cellular function

Integrating Early Results on Ventral Striatal Gamma Oscillations in the Rat

A vast literature implicates the ventral striatum in the processing of reward-related information and in mediating the impact of such information on behavior. It is characterized by heterogeneity at the local circuit, connectivity, and functional levels. A tool for dissecting this complex structure that has received relatively little attention until recently is the analysis of ventral striatal local field potential oscillations, which are more prominent in the gamma band compared to the dorsal striatum. Here we review recent results on gamma oscillations recorded from freely moving rats. Ventral striatal gamma separates into distinct frequency bands (gamma-50 and gamma-80) with distinct behavioral correlates, relationships to different inputs, and separate populations of phase-locked putative fast-spiking interneurons. Fast switching between gamma-50 and gamma-80 occurs spontaneously but is influenced by reward delivery as well as the application of dopaminergic drugs. These results provide novel insights into ventral striatal processing and highlight the importance of considering fast-timescale dynamics of ventral striatal activity

On striatum in silico

The basal ganglia are a collection of subcortical nuclei involved in movement and action selection. The striatum is the main input nucleus with extensive projections from the cortex and thalamus, and dopaminergic projections from SNc and VTA. The two main cell types are the striatal projection neurons (SPNs), which are divided into the direct (dSPN) and indirect (iSPN) pathways, based on the downstream projections and the expression of dopamine D1 and D2 receptors, respectively. The remaining 5% consists mainly of GABAergic interneurons, such as parvalbumin-expressing fastspiking interneurons (FS) and low threshold spiking interneurons (LTS). The cholinergic interneuron (ChIN) is spontaneously active and unlike the other interneurons releases acetylcholine. This thesis is focused on investigating the function of the striatum and the role of SPNs and the striatal interneurons. This is achieved by building a platform, tools, and a database of multi-compartmental models of SPN, FS, ChIN, and LTS; and through simulations systematically uncovering the roles of these striatal neuron types and external input and, more specifically, the role of neuromodulation and intrastriatal inhibition. In Paper I, Snudda, a platform for simulating large-scale networks, is developed and includes multicompartmental models of dSPN, iSPN, FS, LTS, and ChIN. The tools include methods to generate external input from the cortex and thalamus; and dopaminergic modulation from SNc. Paper II investigates the relationship between ChIN and LTS. The ChIN releases ACh, which activates both nicotinic and muscarinic receptors within the striatum. The dominating effect on LTS is inhibition caused by muscarinic M4 receptors. LTS, on the other hand, releases NO which excites ChINs. Paper II showed that the interaction between these neuromodulators could control the activity of ChIN and LTS, which are generally spontaneously active. In the subsequent Paper III, Snudda was complemented with the neuromodulation package called Neuromodcell, a Python Package, for creating models of neuromodulation, which can be included in large-scale network simulations in Snudda. The method of simulating neuromodulators in Snudda was expanded to include multiple simultaneously active modulators. This resulted in several simulations with simultaneous ACh pause with DA burst as well as an ACh burst with a DA burst. In Paper IV, the effect of intrastriatal surround inhibition on striatal activity was investigated by utilizing ablations, clustered input, dopaminergic modulation, and other features in Snudda. These simulations demonstrated that shunting inhibition could reduce the amplitude of corticostriatal input onto SPNs. The surround inhibition can further modulate the plateau potentials in SPNs, which is dependent on the GABA reversal. Lastly, the competition between populations of SPNs can be modified by varying the strength, size, and positions of populations. Furthermore, dopaminergic modulation can enhance the effect of dSPNs, while increasing the inhibition onto iSPNs. Overall, this thesis provides an analysis of the striatal microcircuit and a tool for further investigations of the striatum in silico; and demonstrates the importance to consider the different components of the striatal microcircuit and how neuromodulators can reshape microcircuits on both single neuron and network levels

Heterogeneity and Diversity of Striatal GABAergic Interneurons

The canonical view of striatal GABAergic interneurons has evolved over several decades of neuroanatomical/neurochemical and electrophysiological studies. From the anatomical studies, three distinct GABAergic interneuronal subtypes are generally recognized. The best-studied subtype expresses the calcium-binding protein, parvalbumin. The second best known interneuron type expresses a number of neuropeptides and enzymes, including neuropeptide Y, somatostatin, and nitric oxide synthase. The last GABAergic interneuron subtype expresses the calcium binding protein, calretinin. There is no overlap or co-localization of these three different sets of markers. The parvalbumin-immunoreactive GABAergic interneurons have been recorded in vitro and shown to exhibit a fast-spiking phenotype characterized by short duration action potentials with large and rapid spike AHPs. They often fire in a stuttering pattern of high frequency firing interrupted by periods of silence. They are capable of sustained firing rates of over 200 Hz. The NPY/SOM/NOS interneurons have been identified as PLTS cells, exhibiting very high input resistances, low threshold spike and prolonged plateau potentials in response to intracellular depolarization or excitatory synaptic stimulation. Thus far, no recordings from identified CR interneurons have been obtained. Recent advances in technological approaches, most notably the generation of several BAC transgenic mouse strains which express a fluorescent marker, enhanced green fluorescent protein, specifically and selectively only in neurons of a certain genetic makeup (e.g., parvalbumin-, neuropeptide Y-, or tyrosine hydroxylase-expressing neurons etc.) have led to the ability of electrophysiologists to visualize and patch specific neuron types in brain slices with epifluorescence illumination. This has led to a rapid expansion of the number of neurochemically and/or electrophysiologically identified interneuronal cell types in the striatum and elsewhere. This article will review the anatomy, neurochemistry, electrophysiology, synaptic connections, and function of the three “classic” striatal GABAergic interneurons as well as more recent data derived from in vitro recordings from BAC transgenic mice as well as recent in vivo data

Recurrent inhibitory network among cholinergic inerneurons of the striatum

textThe striatum is the initial input nuclei of the basal ganglia, and it serves as an integral processing center for action selection and sensorimotor learning. Glutamatergic projections from the cortex and thalamus converge with dense dopaminergic axons from the midbrain to provide the primary inputs to the striatum. Striatal output is then relayed to downstream basal ganglia nuclei by GABAergic medium – sized spiny neurons, which comprise at least 95% of the population of neurons in the striatum. The remaining population of local circuit neurons is dedicated to regulating the activity of spiny projection neurons, and although spiny neurons form a weak lateral inhibitory network among themselves via local axon collaterals, feedforward modulation exerts more powerful control over spiny neuron excitability. Of the striatal interneurons, only one class is not GABAergic. These neurons are cholinergic and correspond to the tonically active neurons (TANs) recorded in vivo, which respond to specific environmental stimuli with a transient depression, or pause, of tonic firing. Striatal cholinergic interneurons account for less than 2 % of the striatal neuronal population, yet their axons form an extensive and complex network that permeates the entire striatum and significantly shapes striatal output by acting at numerous targets via varied receptor types. Indeed, the persistent level of ambient striatal acetylcholine as well as changes to that basal acetylcholine level underlie the major mechanisms of cholinergic signaling in the striatum, however regulation of this system by the local striatal microcircuitry is not well understood. This dissertation finds that activation of intrastriatal cholinergic fibers elicits polysynaptic GABAA inhibitory postsynaptic currents (IPSCs) in cholinergic interneurons recorded in brain slices. Excitation of striatal GABAergic neurons via nicotinic acetylcholine receptors (nAChRs) mediates this polysynaptic inhibition in a manner independent of dopamine. Moreover, activation of a single cholinergic interneuron is capable of eliciting polysynaptic GABAA IPSCs onto itself and nearby cholinergic interneurons. These findings provide an important insight into the striatal microcircuitry controlling cholinergic neuron excitability.Cellular and Molecular Biolog