Tiroshi, L. | bioRxiv Science

bioRxiv2018

Wave-like activity patterns in the neuropil of striatal cholinergic interneurons in freely moving mice represent their collective spiking dynamics

Cholinergic interneurons (CINs) are believed to form synchronous cell assemblies that modulate the striatal microcircuitry and possibly orchestrate local dopamine release. We expressed GCaMP6s, a genetically encoded calcium indicator (GECIs), selectively in CINs, and used microendoscopes to visualize the putative CIN assemblies in the dorsal striatum of freely moving mice. The GECI fluorescence signal from the dorsal striatum was composed of signals from individual CIN somata that were engulfed by a widespread fluorescent neuropil. Bouts of synchronous activation of the cholinergic neuropil revealed traveling-wave-like patterns of activity that preceded the signal from individual somata. To investigate the nature of the neuropil signal and why it precedes the somatic signal, we target-patched GECI-expressing CINs in acute striatal slices in conjunction with multiphoton imaging or wide-field imaging that emulates the microendoscopes specifications. The ability to detect fluorescent transients associated with individual action potential was constrained by the long decay constant of GECIs (relative to common inorganic dyes) to slowly firing (< 2 spikes/s) CINs. The microendoscopes resolving power and sampling rate further diminished this ability. Additionally, we found that only back-propagating action potentials but not synchronous optogenetic activation of thalamic inputs elicited observable calcium transients in CIN dendrites. Our data suggest that only bursts of CIN activity (but not their tonic firing) are visible using endoscopic imaging, and that the spatiotemporal neuropil patterns are a physiological measure of the collective recurrent CIN network spiking activity.\n\nSignificance StatementCholinergic interneurons (CINs) are key modulators of the striatal microcircuitry that are necessary for assigning action value and behavioral flexibility. We present a first endoscopic imaging study of multiple molecularly identified CINs in freely moving mice. We reveal the presence of traveling-wave-like activity in the CIN neuropil. We then use ex vivo electrophysiological and imaging techniques to show that the neuropil signal is the integrated fluorescence arising from the axo-dendritic arbors of CINs dispersed throughout the striatum. We conclude that the neuropil signal acts as a mean-field readout of the striatal CIN network activity.

neuroscience↗

bioRxiv2018

Population dynamics and entrainment of basal ganglia pacemakers are shaped by their dendritic arbors

The theory of phase oscillators is an essential tool for understanding population dynamics of pacemaking neurons. GABAergic pacemakers in the substantia nigra pars reticulata (SNr), a main basal ganglia (BG) output nucleus, receive inputs from the direct and indirect pathways at distal and proximal regions of their dendritic arbors, respectively. We combine theory, optogenetic stimulation and electrophysiological experiments in acute brain slices to ask how dendritic properties impact the propensity of the various inputs, arriving at different locations along the dendrite, to recruit or entrain SNr pacemakers.\n\nBy combining cable theory with sinusoidally-modulated optogenetic activation of either proximal somatodendritic regions or the entire dendritic arbor of SNr neurons, we construct an analytical model that accurately fits the empirically measured somatic current response to inputs arising from illuminating various portions of the dendritic field. We show that the extent of the dendritic tree that is illuminated generates measurable and systematic differences in the pacemakers phase response curve (PRC), causing a shift in its peak. Finally we show that the divergent PRCs correctly predict differences in two major features of the collective dynamics of SNr neurons: the fidelity of population responses to sudden step-like changes in inputs; and the phase latency at which SNr neurons are entrained by rhythmic stimulation, which can occur in the BG under both physiological and pathophysiological conditions.\n\nOur novel method generates measurable and physiologically meaningful spatial effects, and provides the first empirical demonstration of how the collective responses of SNr pacemakers are determined by the transmission properties of their dendrites. SNr dendrites may serve to delay distal striatal inputs so that they impinge on the spike initiation zone simultaneously with pallidal and subthalamic inputs in order to guarantee a fair competition between the influence of the monosynaptic direct- and polysynaptic indirect pathways.\n\nAuthor SummaryThe substantia nigra pars reticulata (SNr) is a main output nucleus of the basal ganglia (BG), where inputs from the competing direct and indirect pathways converge onto the same neurons. Interestingly, these inputs are differentially distributed with direct and indirect pathway projections arriving at distal and proximal regions of the dendritic arbor, respectively. We employ a novel method combining theory with electrophysiological experiments and optogenetics to study the distinct effects of inputs arriving at different locations along the dendrite.\n\nOur approach represents a useful compromise between complexity and reduction in modelling. Our work addresses the question of high fidelity encoding of inputs by networks of neurons in the new context of pacemaking neurons, which are driven to fire by their intrinsic dynamics rather than by a network state. We provide the first empirical demonstration that dendritic delays can introduce latencies in the responses of a population of neurons that are commensurate with synaptic delays, suggesting a new role for SNr dendrites with implications for BG function.

neuroscience↗